CA2873075A1 - Nampt inhibitors - Google Patents

Abstract

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

Description

NAMPT INHIBITORS
This application claims priority to United States Provisional Application Serial No.
61/645685, filed May 11, 2012, United States Provisional Application Serial No. 61/719008, filed October 26, 2012, and United States Provisional Application Serial No.
61/779702, filed March 13, 2013, which are incorporated by reference in their entirety.
FIELD OF THE INVENTION
This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.
BACKGROUND OF THE INVENTION
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem.
267,1550-1564, 2000). NAD is necessary for several signaling pathways including among others poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G-protein-coupled signaling, and NAD is also required by sirtuins for their deacetylase activity (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
NAMPT (also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin) is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in one of two pathways that salvage NAD.
nicotinamide NAMPT ,,OP03- mononucleotide H2N Ir N _,... H2N1N+õ, 0 adenylyltranferase ________________________________________________________ .-- NAD
0 0 (NMNAT) HO OH
Nicotinamide Nicotinamide mononucleotide (NMN) NAD
synthetase HON _õ.. HO y +N, ,, ss,s NAMNAT
________________________________________________________ 7..- NAAD

HO OH
Nicotinic acid mononucleotide Nicotinic acid (NAMN) Increasing evidence suggests that NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT
expression has been reported in colorectal cancer (Van Beijnum, J.R. et al Int. J. Cancer 101, 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, CM 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) ii %
Xi X2 H
1(11R1 N

Ri 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 \
1 ____________ / \
I......D \
N
< N N
or \
N
=
, flzr N
....
wherein L%11-,- 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, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), 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, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of Rs, 0R5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHRs, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5 , NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHRs, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), 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, ORs, 5R8, S(0)R8, 502R8, NHR8, N(R8)2, C(0)R8 , C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHSO2R8, NHC(0)0R8, 502NH2, SO2NHR8, 502N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (0), C(0)0H, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, 5R9, S(0)R9, 502R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, 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 R19, 0R19, 5R19, S(0)R19, C(0)C(0)R19, 502R19, C(0)R19, CO(0)R19, OC(0)R19, OC(0)0R19, NH2, NHR19, N(R19)2, NHC(0)R19, NR19C(0)R19, NHS(0)2R19, NR195(0)2R19, NHC(0)0R19, NR19C(0)0R19, NHC(0)NH2, NHC(0)NHR19, NHC(0)N(R19)2, NR19C(0)NHR19, NR19C(0)N(R19)2, C(0)NH2, C(0)NHR19, C(0)N(R10)2, C(0)NHOH, C(0)NHOR19, C(0)NH502R19, C(0)NR19502R19, 502NH2, 502NHR19, 502N(R19)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R19, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R19 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R19 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), R1, at each occurrence, is hydrogen. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen. In another ________________________________________ j\

=
(N.<N ________________________________________ , embodiment of Formula (IA), y1 is wherein 'Ill,' 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 ..
______________ j\

=
(N.<N ______________ , wherein 'Ill,' indicates the point of attachment to the carbonyl ....
1 5 and \
indicates the point of attachment to the nitrogen containing heteroaryl; and R2 is phenyl; wherein each R2 phenyl is substituted with one 0R4. In another embodiment of ..
z ...

N _______________________________ =
(11{. , Formula (IA), y1 is wherein 1,- 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 ..

N _________________________________________________ =
(1.1{. , 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 0R4, and, R4, at each occurrence, is heterocyclyl. In another embodiment of Formula , ______________________ /%%%%%

N _________________________ =
< , (IA), Y1 is.
wherein 1-1-11-,- 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-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(5-fluoropyridin-3-y1)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- {[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(6-methylpyridin-3-y1)-N-(4-{[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;

N-(4- { 1 -[(2S)-2-methylbutanoy1]- 1 ,2,3 ,6-tetrahydropyridin-4-y1} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 - [(2R)-tetrahydro furan-2-ylcarb onyl] - 1 ,2,3 ,6-tetrahydropyridin-4-y1} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbony1]- 1 ,2,3 ,6-1 0 tetrahydropyridin-4-y1} phenyl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-hydroxy-2-methylpropanoy1)- 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-cyanopheny1)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
tert-butyl 4- [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yl]carbonyl}
amino)butyl]piperidine- 1 -carb oxylate ;
N- {4- [1 -(2,2-dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(3,3 -dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(3,3,3 -trifluoropropanoy1)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl } azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(4,4,4-trifluorobutanoy1)- 1,2,3 ,6-tetrahydropyridin-4-yl]phenyl } azetidine- 1 -carboxamide;
N- {4- [1 -(methoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(methylsulfanyl)acety1]- 1,2,3 ,6-tetrahydropyridin-4-y1} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 - (ethoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acety1]- 1 ,2,3 ,6-tetrahydropyridin-4-y1}
phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1- [3 -(methylsulfanyl)prop anoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-y1}
phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(cyclopropylcarbony1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 -(cyclopropylacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-methylpropanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

3 -(pyridin-3 -y1)-N- [4-( { 1 - [(2R)-tetrahydro furan-2-ylcarb onyl]
azetidin-3 -y1} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { 1- [(2 S)-tetrahydro furan-2-ylcarb onyl]
azetidin-3 -y1} oxy)phenyl]azetidine- 1 -carboxamide;
N-(4- { [1 -(2-hydroxy-2-methylpropanoyl)azetidin-3 -yl]oxy} phenyl)-3 -(pyridin-3 -1 0 yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { 1- [(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-y1} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(thiophen-3 -ylcarbonyl)piperidin-4-yl]oxy} phenyl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [( 1 -acetylpiperidin-4-yOcarbonyl]piperidin-4-y1} oxy)phenyl] -3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-y1} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(1 -methyl- 1 H-pyrrol-2-yl)c arb onyl]pip eridin-4-y1}
oxy)pheny1]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [3 -(morpholin-4-yl)propanoyl]piperidin-4-y1} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [3 -(4-methylpiperazin- 1 -yl)propanoyl]piperidin-4-y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { 1- [3 -(pyrrolidin- 1 -yl)propanoyl]piperidin-4-y1} 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-carboxamide;
N-(4- { [1 -(2,2- dimethylpropanoyl)piperidin-4-yl] oxy} phenyl)-3 - (pyridin-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(methoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-carboxamide;
3-(pyridin-3-y1)-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]pheny1}-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
N- {4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1 -benzoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -y1) azetidine- 1 -carb oxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(3,3,3 -trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine- 1 -carb oxamide ;
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-l-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-y1)-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-y1)-N-(4- {1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-yl} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-3-ylcarb onyl)pyrro lidin-3-yl]phenyl } azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carb oxamide ;
N- {4- [1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-b enzoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]phenyl } azetidine-1-c arb oxamide ;
N- {4- [1- (cyclopropylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4- (1-butanoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 -yl} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-benzoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;

3-(pyridin-3-y1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(2S)-2-methylbutanoyl]pyrro lidin-3-yl}oxy)phenyl]-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-butanoylpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2S)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-yl}oxy)phenyl] azetidine-l-carb oxamide ;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2R)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-yl}oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-benzoylpyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]oxy}phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3S)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-yl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-butanoylpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl}azetidine-l-carboxamide;
N- {4- [1- (2-methylprop anoyl)azetidin-3-yl]pheny11-3-(pyridin-3-yl)azetidine-carboxamide;

3-(pyridin-3-y1)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]azetidin-3-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4-[1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]phenyl}azetidine-l-carboxamide;
N- {4-[1-(cyclopropylacetyl)azetidin-3-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylazetidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4-[1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]phenyl}azetidine-1-carboxamide;
N- {4-[1-(cyclopropylcarbonyl)azetidin-3-yl]pheny1}-3-(pyridin-3-yl)azetidine-carboxamide;
N-(4- {1-[(2S)-2-methylbutanoyl]azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-[4-(1-butanoylazetidin-3-yl)pheny1]-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(furan-2-ylcarbonyl)azetidin-3-yl]oxy}pheny1)-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]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-({1-[(2-methoxyethoxy)acetyl]azetidin-3-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {[1-(ethoxyacetyl)azetidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(methoxyacetyl)azetidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-(4- { [1-(3-methylpentanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4-( {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl] azetidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [142,3- 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-carb oxamide ;
N- [4-( {1- [(2-methylcyclopropyl)carbonyl]azetidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1- (4,4,4-trifluorobutanoyl)azetidin-3-yl] oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [1-(2-methylpropanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [142,2- dimethylpropanoyl)azetidin-3-yl] oxy} phenyl)-3-(pyridin-3 -yl)azetidine-l-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- { [142,2- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- { [1-(3-methylbutanoyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [143,3- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(2-methylpentanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N- {4- [(1-acetylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(cyclohexylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [1-(cyclohexylcarbonyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;

N-(4- { [1-(cyclopropylcarbonyl)azetidin-3-yl]oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-c arb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
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} pheny1)-3-(pyridin-3-yl)azetidine-1-c arb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N- [4-( {1- [(3,5-dimethy1-1,2-oxazol-4-y1)carbonyl]azetidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-4-ylcarbonyl)azetidin-3 -yl] oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [1-(1,2-oxazo 1-5-ylcarb onyl) azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {1- [(4-methylpiperazin-1-yl)acetyl]azetidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4-( {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} oxy)pheny1]-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N-(4- { [1-(cyclopentylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1- (pyrro lidin-l-ylacetyl)azetidin-3-yl] oxy}
phenyl)azetidine-1-c arb oxamide ;
3-(2-fluoropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl } azetidine-l-carboxamide;
N- {4- [1- (2-methylpropy1)-1H-pyrazol-4-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N- [4- (1-propy1-1H-pyrazol-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide ;

3-(pyridin-3-y1)-N-(4- {1- [(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-y1} phenyl)azetidine-l-carboxamide;
3-(4-chloropyridin-3-y1)-N-(4- {1- [(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-y1} phenyl)azetidine-l-carboxamide;
3-(2-chloropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl} azetidine-l-carboxamide;
4-(pyridin-3-y1)-N-(4- { [1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl)piperazine-l-carboxamide;
N- [4- (1-p entanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyc lopropyl)c arb onyl]pip eridin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(3-ethoxypropanoyl)piperidin-4-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N- {4- [142,2- 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-dimethylprop anoyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-y1) azetidine-1-carboxamide;
N- [4- (1-butanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1-(3-methylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-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-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylc arb onyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;

N- {4- [1- (cyclohexylacetyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pip eridin-4-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyclop entylc arb onyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]piperidin-4-y1} pheny1)-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-ac etylpip eridin-4-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylc arb onyl)pip eridin-4-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- {4- [1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylc arb onyl)pip eridin-4-yl]phenyl }
azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-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-methy1-1H-pyrrol-2-y1)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)piperidin-4-yl]phenyl}
azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1-(cyclopentylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;

N- {4- [142,3- dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-p entanoylazetidin-3-yOphenyl] -3- (pyridin-3-y1) azetidine-l-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carb onyl] azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
1 0 N-(4- {1- [(1S,4R)-bicyclo [2.2.1]hept-2-ylacetyl]azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-ethoxyprop anoyl)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-dimethylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)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-y1} pheny1)-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- (cyc lohexylacetyl)azetidin-3-yl] phenyl } -3-(pyridin-3-yl)azetidine-1 -carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyc lop entylcarb onyl) azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;

N- {4- [1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-ac etylazetidin-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-y1)-N- {4- [1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylazetidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)azetidin-3-yl]phenyl }
azetidine-l-carboxamide;
N- {4- [1- (cyclop entylacetyl)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-carboxamide;
N- {4- [1-(cyclohexylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [143,3- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylp entyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;

N- {4- [1- (2-methylpropyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-ethylbutyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-y1) azetidine-carboxamide;
N- {4- [1- (2,2- dimethylpropyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylbutyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-butylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-propylpip eridin-4-yl)pheny1]-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(2-cyclopropylethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl} azetidine-l-carboxamide;
N- {4- [142,2- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclop entylmethyl)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- [143,3- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclopropylmethyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1 -carboxamide;
N- {4- [1- (2-methylp entyl) azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-2-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [1- (2-methylpropyl) azetidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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-y1)-N- {4- [1- (tetrahydro furan-3-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [142,2- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-p entanoylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (3-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]pyrro lidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclop entylacetyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)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-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)pyrrolidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (N,N-dimethyl-beta- alanyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)pyrro lidin-3-yl]phenyl } azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} phenyl)-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-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-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-ac etylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylacetyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpyrro lidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [142,2- dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1} 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-y1} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (3,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-oxoprop anoyl)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 - (cyclohexylcarb onyl)pyrro lidin-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 - (cyclop entylcarb onyl)pyrro lidin-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)pyrro lidin-3 -yl]oxy} phenyl)-3 -(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopentylacetyl)pyrrolidin-3 -yl]oxy} phenyl)-3 -(pyridin-yl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(2-methylcyclopropyl)carbonyl]pyrrolidin-3 -y1}
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 -y1)-N-(4- { [(3R)- 1 - (pyrro lidin- 1 -ylacetyl)pyrro lidin-3-yl]oxy} phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(5- oxo-D-pro lyl)pyrro lidin-3 -yl]oxy} phenyl)-3 -(pyridin-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 -y1)-N-(4- { [(3R)- 1 -(1,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [(3R)- 1 -(thiophen-3 -ylcarbonyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(1 -methylcyclopropyl)carbonyl]pyrrolidin-3 -y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

N- [4-( {(3R)-1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} oxy)phenyl] -1 0 (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- {[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-propanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4-( {(3R)-1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-l-carb oxamide;
N- [4-( {(3R)-1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy} phenyl)-3-(pyridin-yl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [3- (pip eridin-l-yl)prop anoyl]pyrro lidin-3-y1} oxy)phenyl]
-3-(pyridin-4 0 3-yl)azetidine-1-carboxamide;

N-(4- { [(3R)-1-(ethoxyacetyl)pyrrolidin-3-y1] oxy } pheny1)-3-(pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- { [(3R)-1-(3,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(2,2-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-1 0 yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl]oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(2,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4- (1-b enzoylpip eridin-4-yl)phenyl] -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylb enzoyl)pip eridin-4-yl]phenyl } -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylprop anoyl)pip eridin-4-yl]phenyl } -3-(pyridazin-3-yl)azetidine-1-c arb oxamide ;
N- {4- [1-(cyclopropylcarbonyl)piperidin-4-yl]phenyl} -3- (pyridazin-3-yl)azetidine-1-carb oxamide ;
N- [4- (1-ac etylpip eridin-4-yl)phenyl] -3- (pyridazin-3-yl)azetidine-1-carb oxamide;
N- {4- [143,3- dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lobutylcarb onyl)pip eridin-4-yl]phenyl } -3-(pyridazin-3-yl)azetidine-1-carboxamide;
3-(pyridazin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyl}
azetidine-1-c arb oxamide ;
3-(pyridazin-3-y1)-N- {4- [1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl} azetidine-l-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridazin-4 0 yl)azetidine-l-carboxamide;

N- {4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridazin-3-yl)azetidine-carboxamide;
N- {4-[(1-benzoylpiperidin-4-yl)methyl]pheny1}-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(2-fluorobenzoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N-(4- {[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(2-ethylbutanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
3-(pyridazin-3-y1)-N-(4- {[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-l-carboxamide;
N-(4- {[1-(2-methylpropanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4- [( 1 -acetylpiperidin-4-yl)methyl]phenyl} -3 -(pyridazin-3 -yl)azetidine- 1 -carb oxamide ;
N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)pheny1]-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)pheny1]-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, "Ci-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(0)-0H.
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 -C1), 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(0)-.
The term "aminocarbonyl" (alone or in combination with another term(s)) means -C(0)-NH2.
The term "oxo" (alone or in combination with another term(s)) means (=0).
The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -0-.
The term "alkylhydroxy" (alone or in combination with another term(s)) means ¨

alkyl-OH.
The term "alkylamino" (alone or in combination with another term(s)) means ¨alkyl-NH2.
The term "alkyloxy" (alone or in combination with another term(s)) means an alkylether substituent, i.e., -0-alkyl. Examples of such a substituent include methoxy (-0-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term "alkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl.
The term "aminoalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-NH2.
The term "alkyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-alkyl.

The term "carbocyclylcarbonyl" (alone or in combination with another term(s)) means -C(0)-carbocyclyl.
Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term(s)) means -C(0)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-carbocyclyl.
Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another term(s)) means -C(0)-alkyl-heterocyclyl.
The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-carbocyclyl.
The term "carbocyclylalkyloxycarbonyl" (alone or in combination with another term(s)) means -C(0)-0-alkyl-carbocyclyl.
The term "thio" or "thia" (alone or in combination with another term(s)) means a thiaether substituent, i.e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl" means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).
The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means a sulfhydryl substituent, and may be depicted as -SH.
The term "(thiocarbonyl)" (alone or in combination with another term(s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
The term "sulfonyl" (alone or in combination with another term(s)) means -S(0)2-.
The term "aminosulfonyl" (alone or in combination with another term(s)) means -S(0)2-NH2.
The term "sulfinyl" or "sulfoxido" (alone or in combination with another term(s)) means -S(0)-.
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-oxadiazoly1 (furazanyl), or 1,3,4-oxadiazoly1), oxatriazolyl (including 1,2,3,4-oxatriazoly1 or 1,2,3,5-oxatriazoly1), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazoly1), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), or pyrazinyl (1,4-diaziny1)), piperazinyl, pyrrolidin-2-only, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triaziny1)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxaziny1)), oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiaziny1)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiaziny1)), 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-benzaziny1)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiaziny1)), 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-benzisoxaziny1). 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-oxadiazoly1 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 Ci-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Ci-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix "halo" on haloalkyloxyalkyl indicates that only the alkyloxy component of the alkyloxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkyloxyalkyl" rather than "haloalkyloxyalkyl." And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as "alkyloxyhaloalkyl."
The terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

The terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of a kinase. "Modulation", as used herein in its various forms, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with kinase. Kinase inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction. Kinase activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
Isotope Enriched or Labeled Compounds Compounds of the invention can exist in isotope-labeled or iostope-enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 180, 32p, 35s, 18F, 36C1, and 1251. 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/D20. 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 W01997010223, W02005099353, W01995007271, W02006008754; US Patent Nos.
7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; 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 0 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, yl, 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 Xi, x2, yl, R1, and R2 can be combined with embodiments defined for any other of Xi, )(2, y 1 , 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) ii H

N

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 .. .
.
.. .
%.
I j%

, or N µµµ
, N =
....
wherein 1-1-1-1,- 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, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), 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, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;

R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of Rs, 0R5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHRs, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5 , NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHRs, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), 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, ORs, 5R8, S(0)R8, 502R8, NHR8, N(R8)2, C(0)R8 , C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHSO2R8, NHC(0)0R8, 502NH2, SO2NHR8, 502N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (0), C(0)0H, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, 5R9, S(0)R9, 502R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, 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 R19, 0R19, 5R19, S(0)R19, C(0)C(0)R19, 502R19, C(0)R19, CO(0)R19, OC(0)R19, OC(0)0R19, NH2, NHR19, N(R19)2, NHC(0)R19, NR19C(0)R19, NHS(0)2R19, NR195(0)2R19, NHC(0)0R19, NR19C(0)0R19, NHC(0)NH2, NHC(0)NHR19, NHC(0)N(R19)2, NR19C(0)NHR19, NR19C(0)N(R19)2, C(0)NH2, C(0)NHR19, C(0)N(R10)2, C(0)NHOH, C(0)NHOR19, C(0)NH502R19, C(0)NR19502R19, 502NH2, 502NHR19, 502N(R19)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R19, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R19 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R19 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (I), X1 is N and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is N. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (I), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (I), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, 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 ... .
.
/ .. \
1 N ____________________________ . . .1\I - D
. .1.. , N , or ..
N
=
czzr N , ..
wherein 11-11, i ..
indicates the point of attachment to the carbonyl and µ= indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (I), Y1 is .. %
%
%
/ .. 7N7\
I
I ____________ N N
'111/. , or , wherein ..
11-11, i ..
ndicates the point of attachment to the carbonyl and µ= indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula (I), Y1 is ..
..
I
N _________________ =
"7/
wherein (-I'LL- indicates the point of attachment to the carbonyl ..., and µ= 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 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, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R2 aryl, 3-membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl;
wherein each R2 C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (I), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (I), R2 is C4-C6-alkyl;
wherein each R2 C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (I), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (I), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (I), R2 is phenyl;
wherein each R2 phenyl is substituted with one 0R4. 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, 0R5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHRs, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S (0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR
6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, 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(0)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(0)R6.

In one embodiment of Formula (I), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (I), R6, at each occurrence, is alkyl.
In one embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, 0R10, 5R10, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (I), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, 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(0)C(0)R10, C(0)R10, CO(0)R10 , F, CI, Br and I.

In one embodiment of Formula (I), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (I), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (I), R10, at each occurrence, is independently selected 1 0 from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, s(0)R11, s02R11, c(0)R11, c0(0)R11, oc(p )1( OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, mis(0)2R11, NR11so)2- 11, NHC(0)OR11, NR11C(0)0R11, 1 5 NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, -'1-1NR11C(0)NHR11, NR11C(0)N(R11)2/
C(0)NH2, C(0)NHR11, C(0)N(R11)2 , C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR1 s02 K 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or 20 more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, c(o)R12, co(o)R12, oc(0)-K 12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12c(o)R12, NHS(0)2R12, NR125(0)2-K 12, NHC(0)0R12, -- 12 NK C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12c (0)NHR12, N-K12-L(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, 25 C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, c(N)Nii -K 12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, 30 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 R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 2 5R11, N(-11.), NHC(0)R11, 35 OH, F, CI, Br and I; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)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 40 substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (I), R1 , at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, sR11, 2 N(R11s), NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected 1 0 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 1 5 Formula (I) ii %
Xi X2 H
Yi1R1 N

Ri Formula (I);
wherein X1 is CR1 and X2 is CR1;
...%
7 %
.. %
%
%.

N _______________________ `111.<. , orY i N
(72.6, =
, 20 1 s wherein ..
.
\
i .
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;
25R2 is =
independently selected from the group consisting of C4-C6-a1kyl, and aryl;
wherein each R2 C4-C6-a1kyl 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, 0R4, CO(0)R4, C(0)NHR4, and CN;

R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 areindependently optionally substituted with one or more substituents independently selected from the group consisting of R10 , C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (I), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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) N
%
Xi X2 Ri H

Ri (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 CRi; or X1 is CR1 and X2 is N; or X1 is CR1 and X2 is CRi;
R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I;
R2 is independently selected from the group consisting of 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, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), 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, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4S02R4, SO2NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of Rs, 0R5, 5R5, S(0)R5, 502R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHRs, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5 , NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHRs, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, ORs, 5R8, S(0)R8, 502R8, NHR8, N(R8)2, C(0)R8 , C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHSO2R8, NHC(0)0R8, 502NH2, SO2NHR8, 502N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (0), C(0)0H, N3, CN, NH2, F, CI, Br and I;

R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, 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 R1 , 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NEIS02R12, C(0)NR12S02R12, SO2NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, 1 0 alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy;
wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (II), X1 is N and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is N. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (II), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (II), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, 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-a1kynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-a1kenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, 0R3, 5R3, S(0)R3, 502R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R2 aryl, 3-membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NE12, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4S02R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl;
wherein each R2 C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (II), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (II), R2 is C4-C6-alkyl;
wherein each R2 C4-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, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (II), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (II), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (II), R2 is phenyl;
wherein each R2 phenyl is substituted with one 0R4. 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, 0R5, 5R5, S(0)R5, 502R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6S02R6, SO2NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, 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(0)R6, F, CI, Br and I. In another embodiment of Formula (II), R3, at each occurrence, is independently heterocyclyl;
wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6.
In one embodiment of Formula (II), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, 5R9, S(0)R9, 502R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (II), R6, at each occurrence, is alkyl.
In one embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R1 , 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (II), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)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(0)C(0)R10, C(0)R10 , CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (II), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (II), R7, at each occurrence, is independently heterocyclyl.
In one embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, S(0)R11, S02R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2/
C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11502R11, 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, N(R11)2, NHC(0)R11, OH, F, CI, Br and I; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)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 1 0 embodiment of Formula (II), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, sRii, 2 N(Rii,), NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (II) N
%
Xi X2 Ri H
N N
Ri 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-a1kyl, and aryl;
wherein each R2 C4-C6-a1kyl 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, 0R4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;

R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 areindependently optionally substituted with one or more substituents independently selected from the group consisting of R10 , C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (II), which includes Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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) N
I
H
NN

5 R4x (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 10 pharmaceutically acceptable salts thereof;
wherein R4x is independently selected from the group consisting of R4, 0R4, SR4, S(0)R4, S02R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10, CO(0)R10, OC(0)R10 , OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10, NHS(0)2R10, NR10S(0)2R10 , NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10, NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHSO2R10, C(0)NR10S02R10, SO2NH2, SO2NHR10, SO2N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (III), R4x is independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I.
In another embodiment of Formula (III), R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (III), R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (III), R4x is C(0)NHR4. In another embodiment of Formula (III), R4x is 0R4. In another embodiment of Formula (III), R4x is R4.
In one embodiment of Formula (III), R4, at each occurrence, is independently selected 1 0 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, 0R7, SR7, S(0)R7, S02R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, 1 5 NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected 20 from the group consisting of R1 , 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 25 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety 30 represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10 , F, CI, Br and I. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (III), R4, at each occurrence, is heterocyclyl;
wherein the cyclic moiety represented by R4 is independently optionally substituted with one 35 or more substituents independently selected from the group consisting of R10, C(0)C(0)R10 , C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (III), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (III), R7, at each occurrence, is 40 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 R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, sRii, s(0)R11, s02R11, c(0)R11, c0(0)R11 , )1( OC(0)0R11, NH2, NHR11, N(R11)2, 1 0 NHC(0)R11, mis(0)2R11, NR11s(0)2-x11 , NHC(0)0R11,INK 11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2,INR11C(0)NHR11, -rINK'-'11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2 , C(0)NHOH, C(0)NHOR11, C(0)NH502R11, C(0)NR11502-K 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein 1 5 each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 2R12, c(o)R12, co(o)R12, oc(0)-K 12, OC(0)0R12, NH2, NHR12, N(R12)2/
NHC(0)R12, NR12c(o)R12, NHS(0)2R12, (0)2-K 12, NHC(0)0R12, - -12 NK C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12c (0)NHR12, N-K12-L(0)N(R12)2, 20 C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502-K 12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NH-K1 , C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl 25 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 R1 alkyl is optionally substituted with one or more substituents 30 independently selected from the group consisting of R11, 0R11, 5R11, 2 N(Riiµ), NHC(0)R11, OH, F, CI, Br and I; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)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 35 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), R1 , at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group 40 consisting of R11, 0R11, 5R11, ) NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
1 0 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) N
I
H
R4x 10 N

Formula (III);
wherein R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;

R , at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10 , C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, and C(0)R12;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.

Still another embodiment pertains to compounds having Formula (III), which includes Examples 1, 2, 4, 5, 6, 7, 9, 10, 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) Xal X2 H
N Yal Ral Ral 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 .. .
.
.. .
%.
I j%

, or N µµµ
, N =
....
wherein 1-1-1-1,- 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, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), 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, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;

R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of Rs, 0R5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHRs, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5 , NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHRs, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), 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, ORs, 5R8, S(0)R8, 502R8, NHR8, N(R8)2, C(0)R8 , C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHSO2R8, NHC(0)0R8, 502NH2, SO2NHR8, 502N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (0), C(0)0H, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, 5R9, S(0)R9, 502R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, SO2NH2, SO2NHR9, SO2N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, 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 R19, 0R19, 5R19, S(0)R19, C(0)C(0)R19, 502R19, C(0)R19, CO(0)R19, OC(0)R19, OC(0)0R19, NH2, NHR19, N(R19)2, NHC(0)R19, NR19C(0)R19, NHS(0)2R19, NR195(0)2R19, NHC(0)0R19, NR19C(0)0R19, NHC(0)NH2, NHC(0)NHR19, NHC(0)N(R19)2, NR19C(0)NHR19, NR19C(0)N(R19)2, C(0)NH2, C(0)NHR19, C(0)N(R10)2, C(0)NHOH, C(0)NHOR19, C(0)NH502R19, C(0)NR19502R19, 502NH2, 502NHR19, 502N(R19)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR19, C(N)N(R19)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R19, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R19 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R19 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IA), X1 is N and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is N. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, 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, CI, Br and I. In another embodiment of Formula (IA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (IA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, 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 ... .
.
/ .. \
1 N ____________________________ . . .1\I - D N
. .1.. , , or ..
N
=
czzr N , ..
11-11, ..
wherein indicates the point of attachment to the carbonyl and µ=
indicates the point of attachment to the nitrogen containing heteroaryl. In another embodiment of Formula .
_____________________ 2%%%% .
.
Nµ.
1 .
N ____________________ 1-11(. N
(21 (IA), Y1 is Or ;
==
11-1,t. ==
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 ..
1 __ j\
I
=
(N.<N __ , (IA), Y1 is wherein µ1-11-e 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 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, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R2 aryl, 3-membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl;
wherein each R2 -- C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl; wherein each R2 C4-C6-alkyl is -- substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IA), R2 is C4-C6-alkyl;
wherein each R2 C4-C6-alkyl is substituted with one or more R3. In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one or more substituents -- independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN.
In another embodiment of Formula (IA), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (IA), R2 is phenyl; wherein each R2 phenyl is substituted with one 0R4. 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, 0R5, SR5, S(0)R5, -- S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NE12, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, -- CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, -- NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, 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(0)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(0)R6.
In one embodiment of Formula (IA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (IA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R1 , 0R10, SW , S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10 , F, CI, Br and I. In another embodiment of Formula (IA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, c(0)R10, c0(0)1( io, F, CI, Br and I.
In one embodiment of Formula (IA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, c(0)R10, c0(0)1( io, F, CI, Br and I.
In one embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, se, s(0)R11, s02R11, c(0)R11, c0(0)R11, oc(0µ
)1( OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, Nec(0)e, mis(0)2R11, NR11s(o)27 11, NHC(0)0R11,INK'-'11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2,INR11C(0)NHR11, -rINK'-'11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2 , C(0)NHOH, C(0)NHOR11, C(0)NH502R11, C(0)Ne s02K 11, 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5 R12, S(0)R12, 502R12, c(o)R12, co(o)R12, ocos -=-=)K 12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12c(o)R12, NHS(0)2R12, NR12s(0)K 2-12, NHC(0)0R12, -rINK'-'12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12c (0)NHR12, K ¶0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NH-K1 , C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, ) NHC(0)R11, OH, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of K-12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, sRii, 2 N(Rii.), NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IA) H

N

Formula (IA);
wherein X1 is CR1 and X2 is CRi;
... .
. .
/ ..

..
1 ___________________________________________________ N
N
, orN
(221 =
, yl is wherein ..
11-11, i ..
indicates the point of attachment to the carbonyl and µ= 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 R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;
R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of RR), c(o)c(o)Rio, cor io, K and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IA), which include N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(5-fluoropyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-[4-({1-[(25)-2-methylbutanoyl]piperidin-4-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-[4-( {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-l-carboxamide;

3 -(pyridin-3 -y1)-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 -y1)-N-(4- { [1 - (tetrahydro-2H-pyran-4-ylacetyl)pip eridin-4-yl]oxyl phenyl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2S)-2-methylbutanoy1]- 1 ,2,3 ,6-tetrahydropyridin-4-yll phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 - [(2R)-tetrahydro furan-2-ylcarb onyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yll phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbony1]- 1 ,2,3 ,6-tetrahydropyridin-4-yll phenyl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-hydroxy-2-methylpropanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
methyl 4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yl]carbonyll amino)benzoate;
N-(4-cyanopheny1)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
tert-butyl 4- [4-( { [3 -(pyridin-3 -yl)azetidin- 1 -yl]carbonyll amino)butyl]piperidine- 1 -carb oxylate ;
N- {4- [1 -(2,2-dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(3,3 -dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(3,3,3 -trifluoropropanoy1)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl } azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(4,4,4-trifluorobutanoy1)- 1,2,3 ,6-tetrahydropyridin-4-yl]phenyll azetidine- 1 -carboxamide;
N- {4- [1 -(methoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(methylsulfanyl)acety1]- 1,2,3 ,6-tetrahydropyridin-4-yll phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 - (ethoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acety1]- 1 ,2,3 ,6-tetrahydropyridin-4-yll phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1- [3 -(methylsulfanyl)prop anoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-yll phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

N- {4- [1-(cyclopropylcarbony1)-1,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [1-(cyclopropylacety1)-1,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(2-methylpropanoy1)-1,2,3,6-tetrahydropyridin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {1- [(2R)-tetrahydro furan-2-ylc arbonyl] azetidin-3-yl } oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {1- [(2S)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl } oxy)phenyl]azetidine-l-carboxamide;
N-(4- { [1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {1- [(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-2-ylc arb onyl)pip eridin-4-yl]oxy} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-acetylpiperidin-4-yOcarbonyl]piperidin-4-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {1- [(2-methylcyclopropyl)carbonyl]piperidin-4-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]piperidin-4-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {1- [3-(morpholin-4-yl)propanoyl]piperidin-4-y1} oxy)pheny1]-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N- [4-( {1- [3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-y1} oxy)phenyl] -(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {1- [3-(pyrrolidin-1-yl)propanoyl]piperidin-4-y1} oxy)phenyl]azetidine-l-carboxamide;
N-(4- { [1-(cyclopropylacetyl)piperidin-4-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [1-(3-methylpentanoyl)piperidin-4-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [1-(4-methylpentanoyl)piperidin-4-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-{4-[(1-butanoylpiperidin-4-yl)oxy]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(2,2-dimethylpropanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {[1-(ethoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(methoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4-[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]phenyl}azetidine-l-carboxamide;
N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
N- {4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-[4-(1-benzoylpiperidin-4-yl)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;

3-(pyridin-3-y1)-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-l-carboxylate;
tert-butyl 3- [4-( { [3-(pyridin-3-yl)azetidin-1-yl]carbonyl}
amino)phenoxy]azetidine-l-carboxylate;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro-2H-pyran-4-ylac etyl)pyrrolidin-3-yl]phenyl} azetidine-l-carboxamide;
N- {4- [1-(2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-3-ylcarb onyl)pyrro lidin-3-yl]phenyl } azetidine-l-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-b enzoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [1- (cyclopropylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4- (1-butanoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydro furan-3-ylc arb onyl)pyrro lidin-yl]oxy} phenyl)azetidine-l-carboxamide;

N-(4- { [(3R)-1-(cyclopropylacetyl)pyrrolidin-3-y1]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-benzoylpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-1 0 carboxamide;
3-(pyridin-3-y1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-butanoylpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3 -yl]oxy}phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2S)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-yl}oxy)phenyl] azetidine-l-carb oxamide ;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2R)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-yl}oxy)phenyl] azetidine-l-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy}phenyl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(2-hydroxy-2-methylpropanoyOpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-benzoylpyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3S)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-yl}oxy)phenyl]-3-(pyridin-3-4 0 yl)azetidine-l-carboxamide;

N-(4- { [(3S)-1-butanoylpyrrolidin-3-y1] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl} azetidine-l-carboxamide;
N- {4- [1- (2-methylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl } phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl } phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-3-ylcarb onyl) azetidin-3-yl]phenyl } azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)azetidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N- {4- [1- (2-hydroxy-2-methylprop anoyl)azetidin-3-yl]phenyl } -3- (pyridin-3 -yl)azetidine-l-carboxamide;
N- [4- (1-b enzoylazetidin-3-yl)pheny1]-3-(pyridin-3-y1) azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl) azetidin-3-yl]phenyl }
azetidine-l-carboxamide;
N- {4- [1- (cyc lopropylcarb onyl) azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-butanoylazetidin-3-yl)phenyl] -3-(pyridin-3-y1) azetidine-l-carboxamide;
tert-butyl 4- [4-( { [3-(2-chloropyridin-3-yl)azetidin-1 -yl]carbonyl} amino)phenyl]piperidine-l-carboxylate;
tert-butyl 4- [4-( { [3-(4-chloropyridin-3-yl)azetidin-1-yl]carbonyl} amino)phenyl]piperidine-l-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-l-carboxylate;
N- {4- [(1-pentanoylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;

N- [4-( {1- [(2-methoxyethoxy)acetyl]azetidin-3-y1} oxy)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [1-(ethoxyacetyl)azetidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(methoxyacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1 0 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-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,3- 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-y1} oxy)phenyl]-3-(pyridin-3 -yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1- (4,4,4-trifluorobutanoyl)azetidin-3-yl] oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [1-(2-methylpropanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,2- dimethylpropanoyl)azetidin-3-yl] oxy} pheny1)-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- { [142,2- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(3-methylbutanoyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [143,3- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(3,3,3-trifluoropropanoyl)azetidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} oxy)pheny1]-3-(pyridin-3-4 0 yl)azetidine-l-carboxamide;

N-(4- { [1-(2-methylpentanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-y1) azetidine-1-carb oxamide ;
N- {4- [(1-acetylazetidin-3-yl)oxy]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(cyclohexylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [1-(cyclohexylcarbonyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- { [1-(cyclopropylcarbonyl)azetidin-3-yl]oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-c arb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-2-ylc arb onyl)azetidin-3-yl] oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [1-(cyclopentylcarbonyl)azetidin-3-yl]oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- { [1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-c arb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N- [4-( {1- [(3,5-dimethy1-1,2-oxazol-4-y1)carbonyl]azetidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-3-ylc arb onyl)azetidin-3-yl] oxy} phenyl) azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [1-(1,2-oxazo 1-5-ylcarb onyl) azetidin-3-yl] oxy} phenyl)-3 -(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {1- [(4-methylpiperazin-1-yl)acetyl]azetidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1 -carboxamide;
N- [4-( {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(cyclopentylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;

3-(pyridin-3-y1)-N-(4- { [1- (pyrro lidin-l-ylacetyl)azetidin-3-yl]
oxy}phenyl)azetidine-1-carboxamide;
3-(2-fluoropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl}azetidine-l-carboxamide;
N- {4- [1- (2-methylpropy1)-1H-pyrazol-4-yl]pheny11-3- (pyridin-3-y1) azetidine-1-1 0 carboxamide;
N- [4- (1-propy1-1H-pyrazol-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-1-carboxamide;
3-(4-chloropyridin-3-y1)-N-(4- {1- [(3S)-tetrahydro furan-3-ylc arb onyl]pip eridin-4-yl}phenyl)azetidine-l-carboxamide;
3-(2-chloropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl}azetidine-l-carboxamide;
4-(pyridin-3-y1)-N-(4- { [1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy}phenyl)piperazine-l-carboxamide;
N- [4- (1-p entanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)pip eridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)pip eridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(3-ethoxypropanoyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [142,2- dimethylbutanoyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [143,3- dimethylbutanoyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylprop anoyl)pip eridin-4-yl]pheny11-3- (pyridin-3-y1) azetidine-1-carboxamide;
N- [4- (1-butanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)pip eridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(3-methylbutanoyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-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-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylc arb onyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylacetyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pip eridin-4-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyclop entylc arb onyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]piperidin-4-y1} pheny1)-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-ac etylpip eridin-4-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylc arb onyl)pip eridin-4-yl]phenyl}
azetidine-1-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- {4- [1-(morpholin-4-ylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylc arb onyl)pip eridin-4-yl]phenyl }
azetidine-l-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-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-methy1-1H-pyrrol-2-y1)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyc lopropyl)c arb onyl]pip eridin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;

3 -(pyridin-3 -y1)-N- {4- [1 -(pyrrolidin- 1 -ylacetyl)piperidin-4-yl]phenyl}
azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-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)carb onyl] azetidin-3 -y1} pheny1)-3 -(pyridin-3-1 5 yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [( 1 S,4R)-bicyclo [2.2. 1 ]hept-2-ylacetyl] azetidin-3-yl}pheny1)-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 - (ethoxyac etyl)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 -y1} 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 - (cyc lohexylacetyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

3-(pyridin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyc lop entylcarb onyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-ac etylazetidin-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-y1)-N- {4- [1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylazetidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)azetidin-3-yl]phenyl }
azetidine-l-carboxamide;
N- {4- [1- (cyclop entylacetyl)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-carboxamide;

N- {4- [1-(cyclohexylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [143,3- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylp entyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylpropyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-ethylbutyl)pip eridin-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)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-butylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-propylpip eridin-4-yl)pheny1]-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(2-cyclopropylethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl } azetidine-l-carboxamide;
N- {4- [142,2- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclop entylmethyl)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- [143,3- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclopropylmethyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylp entyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-2-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;

N- {4- [1- (2-methylpropyl) azetidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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-y1)-N- {4- [1- (tetrahydro furan-3-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [142,2- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-p entanoylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (3-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]pyrro lidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclop entylacetyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)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-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)pyrrolidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (N,N-dimethyl-beta- alanyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3 -yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)pyrro lidin-3-yl]phenyl } azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-yl} pheny1)-3-(pyridin-yl)azetidine-l-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-carb oxamide ;
N- {4- [1- (4-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4- (1-ac etylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-c arb oxamide ;
N- {4- [1- (cyc lohexylacetyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpyrro lidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- {1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} phenyl)-3- (pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- {1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [142,2- dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} phenyl)-3-(pyridin-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1} phenyl)-3 -(pyridin-3-yl)azetidine-1-carb oxamide;
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-y1} phenyl)-3 - (pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [1- (ethoxyac etyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;

N- {4- [1- (3,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-oxoprop anoyl)pyrrolidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutanoyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclop entylcarb onyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-pentanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(3-methylpentanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(bicyclo [2.2.1] hept-2-ylacetyl)pyrro lidin-3-yl] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -(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} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy} pheny1)-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-l-carboxamide;

3-(pyridin-3-y1)-N-(4- { [(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -1 0 (pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} oxy)phenyl] -(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy} phenyl)-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- {[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3- (pyridin-3-yl)azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
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-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-l-carb oxamide;
N- [4-( {(3R)-1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-2-ylcarb onyl)pyrro lidin-3-4 0 yl]oxy} phenyl)azetidine-l-carboxamide;

N- [4-( {(3R)-1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [3- (pip eridin-l-yl)prop anoyl]pyrro lidin-3-y1} oxy)phenyl]
-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(3,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(2,2-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-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} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(2,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N- [4- (1-b enzoylpip eridin-4-yl)phenyl] -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(2-fluorobenzoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylb enzoyl)pip eridin-4-yl]phenyl } -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylprop anoyl)pip eridin-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-ac etylpip eridin-4-yl)phenyl] -3- (pyridazin-3-y1) azetidine-l-carboxamide;
N- {4- [143,3- dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lobutylcarb onyl)pip eridin-4-yl]phenyl } -3-(pyridazin-3-yl)azetidine-1-carboxamide;

3-(pyridazin-3-y1)-N- {4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]phenyll azetidine-l-carboxamide;
3-(pyridazin-3-y1)-N- {4-[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyll azetidine-l-carboxamide;
N-(4- {1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yll pheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4-[1-(cyclopropylacetyl)piperidin-4-yl]phenyll-3-(pyridazin-3-yl)azetidine-carboxamide;
N- {4- [(1-benzoylpiperidin-4-yl)methyl]phenyll -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(2-fluorobenzoyl)piperidin-4-yl]methyll pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyll pheny1)-3-(pyridazin-yl)azetidine-1-carboxamide;
N-(4- { [1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyll pheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N-(4- { [1-(2-ethylbutanoyl)piperidin-4-yl]methyll pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
3-(pyridazin-3-y1)-N-(4- {[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyllphenyl)azetidine-l-carboxamide;
N-(4- {[1-(2-methylpropanoyl)piperidin-4-yl]methyllpheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4- [(1-acetylpiperidin-4-yl)methyl]phenyll -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-[4-( {1-[(2S)-2-methylbutanoyl]piperidin-4-yllmethyl)pheny1]-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yllmethyl)pheny1]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide; and pharmaceutically acceptable salts thereof.
Embodiments of Formula (HA) In another aspect, the present invention provides compounds of Formula (IIA) N
Xi X2 Ri H
N N
Ri (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, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I;
R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-alkynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R2 C4-C6-alkyl, C4-C6-alkenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting of R3, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (0), 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, 0R4, SR", S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;

R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, 0R5, SR5, S(0)R5, S02R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), 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, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR6, C(N)N(R6)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, ORs, 5R8, S(0)R8, 502R8, NHR8, N(R8)2, C(0)R8 , C(0)NH2, C(0)NHR8, C(0)N(R8)2, NHC(0)R8, NR8C(0)R8, NHSO2R8, NHC(0)0R8, 502NH2, SO2NHR8, 502N(R8)2, NHC(0)NH2, NHC(0)NHR8, OH, (0), C(0)0H, N3, CN, NH2, F, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, 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 R1 , 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NH502R11, C(0)NR11502R11, 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;

R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (HA), X1 is N and X2 is CR1. In another embodiment of Formula (HA), X1 is CR1 and X2 is N. In another embodiment of Formula (HA), X1 is CR1 and X2 is CR1. In another embodiment of Formula (HA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, Cl, Br and I. In -- another embodiment of Formula (HA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (HA), X1 is CR1 and X2 is CR1, and R1, at each occurrence, is hydrogen.
In one embodiment of Formula (HA), R1, at each occurrence, is independently -- selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydoxyalkyl, alkoxy, OH, NH2, CN, NO2, F, CI, Br and I. In another embodiment of Formula (HA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, CI, Br and I. In another embodiment of Formula (HA), R1, at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, F, and Cl.
-- In another embodiment of Formula (HA), R1, at each occurrence, is hydrogen.
In one embodiment of Formula (HA), R2 is independently selected from the group consisting of C4-C6-alkyl, C4-C6-alkenyl, C4-C6-a1kynyl, aryl, 3-12 membered heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R2 C4-C6-alkyl, C4-C6-a1kenyl, and C4-C6-alkynyl is substituted with one or more substituents independently selected from the group consisting -- of R3, 0R3, SR3, S(0)R3, S02R3, C(0)R3, CO(0)R3, OC(0)R3, OC(0)0R3, NH2, NHR3, N(R3)2, NHC(0)R3, NR3C(0)R3, NHS(0)2R3, NR3S(0)2R3, NHC(0)0R3, NR3C(0)0R3, NHC(0)NH2, NHC(0)NHR3, NHC(0)N(R3)2, NR3C(0)NHR3, NR3C(0)N(R3)2, C(0)NH2, C(0)NHR3, C(0)N(R3)2, C(0)NHOH, C(0)NHOR3, C(0)NHSO2R3, C(0)NR3502R3, 502NH2, SO2NHR3, 502N(R3)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR3, C(N)N(R3)2, -- CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R2 aryl, membered heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, -- NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, SO2N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, 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 R2 C4-C6-alkyl is substituted with one or more substituents independently selected from the group consisting of R3, F, CI, Br and I; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IIA), R2 is independently selected from the group consisting of C4-C6-alkyl, and aryl;
wherein each R2 C4-C6-alkyl is substituted with one or more R3; wherein each R2 aryl is optionally substituted with one or more substituents independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IIA), R2 is C4-C6-alkyl;
wherein each R2 C4-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, 0R4, CO(0)R4, C(0)NHR4, and CN.
In another embodiment of Formula (IIA), R2 is aryl; wherein each R2 aryl is substituted with one C(0)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one C(0)NHR4. In another embodiment of Formula (IIA), R2 is phenyl; wherein each R2 phenyl is substituted with one 0R4. 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, 0R5, SR5, S(0)R5, 502R5, C(0)R5, CO(0)R5, OC(0)R5, OC(0)0R5, NH2, NHR5, N(R5)2, NHC(0)R5, NR5C(0)R5, NHS(0)2R5, NR5S(0)2R5, NHC(0)0R5, NR5C(0)0R5, NHC(0)NH2, NHC(0)NHR5, NHC(0)N(R5)2, NR5C(0)NHR5, NR5C(0)N(R5)2, C(0)NH2, C(0)NHR5, C(0)N(R5)2, C(0)NHOH, C(0)NHOR5, C(0)NHSO2R5, C(0)NR5502R5, 502NH2, SO2NHR5, 502N(R5)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R3 aryl, cycloalkyl, cycloalkenyl, and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R6, 0R6, 5R6, S(0)R6, 502R6, C(0)R6, CO(0)R6, OC(0)R6, OC(0)0R6, NH2, NHR6, N(R6)2, NHC(0)R6, NR6C(0)R6, NHS(0)2R6, NR6S(0)2R6, NHC(0)0R6, NR6C(0)0R6, NHC(0)NH2, NHC(0)NHR6, NHC(0)N(R6)2, NR6C(0)NHR6, NR6C(0)N(R6)2, C(0)NH2, C(0)NHR6, C(0)N(R6)2, C(0)NHOH, C(0)NHOR6, C(0)NHSO2R6, C(0)NR6502R6, 502NH2, SO2NHR6, 502N(R6)2, C(0)H, C(0)0H, 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(0)R6, F, CI, Br and I. In another embodiment of Formula (IIA), R3, at each occurrence, is independently heterocyclyl;
wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6.
In one embodiment of Formula (IIA), R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, 0R9, SR9, S(0)R9, S02R9, NHR9, N(R9)2, C(0)R9, C(0)NH2, C(0)NHR9, C(0)N(R9)2, NHC(0)R9, NR9C(0)R9, NHSO2R9, NHC(0)0R9, 502NH2, SO2NHR9, 502N(R9)2, NHC(0)NH2, NHC(0)NHR9, OH, (0), C(0)0H, N3, CN, NH2, CF3, CF2CF3, F, CI, Br and I. In another embodiment of Formula (IIA), R6, at each occurrence, is alkyl.
In one embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R1 , 0R10, SW , S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10 , F, CI, Br and I. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, c(0)R10, c0(0)1( io, F, CI, Br and I.
In one embodiment of Formula (IIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 is independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, c(0)R10, c0(0)1( io, F, CI, Br and I.
In one embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, se, s(0)R11, s02R11, c(0)R11, c0(0)R11, oc(0µ
)1( OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, Nec(0)e, mis(0)2R11, NR11s(o)27 11, NHC(0)0R11,INK 11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2,1NR11C(0)NHR11, -rINK'-'11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2 , C(0)NHOH, C(0)NHOR11, C(0)NH502R11, C(0)Ne s02K 11, 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, c(o)R12, co(o)R12, ocos -=-=)1( 12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12c(o)R12, NHS(0)2R12, NR12s(0)K 2-12, NHC(0)0R12, -rINK'-'12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12c (0)NHR12, K u(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12502-K 12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NH-K1 , C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, ) NHC(0)R11, OH, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, c(o)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another 1 0 embodiment of Formula (IIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
One embodiment of this invention pertains to compounds or pharmaceutically acceptable salts thereof, which are useful as inhibitors of NAMPT, the compounds having Formula (IIA) %
Xi X2 Ri Ri 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-a1kyl, and aryl;
wherein each R2 C4-C6-a1kyl 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, 0R4, CO(0)R4, C(0)NHR4, and CN;
R3, at each occurrence, is heterocyclyl; wherein each R3 heterocyclyl is optionally substituted with one or more CO(0)R6;

R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R6, at each occurrence, is independently alkyl;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, c(o)c(o)Rio, cos¨)1( io, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIA), which include N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(5-fluoropyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-[4-({1-[(25)-2-methylbutanoyl]piperidin-4-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-[4-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)phenyl]azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {[1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- {[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(6-methylpyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- {1- [(25)-2-methylbutanoy1]-1,2,3,6-tetrahydropyridin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydro furan-2-ylcarb onyl] -1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydrofuran-2-ylcarbony1]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)azetidine-1-carboxamide;
N- {4- [1-(2-hydroxy-2-methylprop anoy1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
methyl 4-( { [3-(pyridin-3-yl)azetidin-1-yl]carbonyl}amino)benzoate;
N-(4-cyanopheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
tert-butyl 4- [4-( { [3-(pyridin-3-yl)azetidin-1-yl] carb onyl}amino)butyl]pip eridine-1-carb oxylate ;
N- {4- [1- (2,2-dimethylbutanoy1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [1- (3,3-dimethylbutanoy1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoy1)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoy1)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}azetidine-1-c arb oxamide ;
N- {4- [1- (methoxyac ety1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-yl)azetidine-l-carb oxamide;
N-(4- {1- [(methylsulfanyl)acety1]-1,2,3,6-tetrahydropyridin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (ethoxyacety1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-carb oxamide;
N-(4- {1- [(2-methoxyethoxy)acetyl] -1,2,3,6-tetrahydropyridin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [3-(methylsulfanyl)propanoy1]-1,2,3,6-tetrahydropyridin-4-yl}pheny1)-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(cyclopropylc arb ony1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [1-(cyclopropylac ety1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-carb oxamide;
N- {4- [1-(2-methylpropanoy1)-1,2,3,6-tetrahydropyridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {1- [(2R)-tetrahydro furan-2-ylc arbonyl] azetidin-3-yl}oxy)phenyl]azetidine-l-carboxamide;

3-(pyridin-3-y1)-N- [4-( {1- [(2S)-tetrahydro furan-2-ylcarb onyl] azetidin-3-y1}oxy)phenyl] azetidine-l-carboxamide;
N-(4- { [1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl] oxy}pheny1)-3-(pyridin-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {1- [(2S)-tetrahydro furan-2-ylc arb onyl]pip eridin-yl}oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-3-ylcarbonyl)piperidin-4-yl]oxy}phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-ac etylpip eridin-4-yOcarbonyl]pip eridin-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-methy1-1H-pyrrol-2-y1)c arb onyl]pip eridin-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-y1)-N- [4-( {1- [3-(pyrro lidin-l-yl)prop anoyl]pip eridin-4-yl}oxy)phenyl] azetidine-l-carboxamide;
N-(4- { [1-(cyclopropylacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [1-(3-methylpentanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1 -carboxamide;
N-(4- { [1-(4-methylpentanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [(1-butanoylpiperidin-4-yl)oxy]pheny11-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [142,2- dimethylpropanoyl)piperidin-4-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [143,3- dimethylbutanoyl)piperidin-4-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [1-(ethoxyacetyl)piperidin-4-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;

N-(4- {[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(methoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}
azetidine-1-carboxamide;
3-(pyridin-3-y1)-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]pheny1}-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
N- {4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1 -benzoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -y1) azetidine- 1 -carb oxamide;
3-(pyridin-3-y1)-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-y1)-N-{4-[1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]phenyl}azetidine-1-carboxamide;
N-{4-[1-(2-methylpropanoyl)pyrrolidin-3-yl]pheny1}-3-(pyridin-3-yl)azetidine-l-carboxamide;

3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-3-ylcarb onyl)pyrro lidin-3-yl]phenyl} azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carb oxamide ;
N- {4- [1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-b enzoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]phenyl } azetidine-1-c arb oxamide ;
N- {4- [1- (cyclopropylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4- (1-butanoylpyrro lidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3R)-1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 -yl} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-benzoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;

N-(4- { [(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-y1] oxy } pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-butanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3S)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3S)-1-benzoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)-3-(pyridin-3 -yl)azetidine-l-carboxamide;
N- [4-( {(3S)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-butanoylpyrrolidin-3-yl] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
3-(pyridin-3-y1)-N- {4- [1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl} azetidine-l-carboxamide;
N- {4- [1- (2-methylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl} phenyl)azetidine-l-carboxamide;

3 -(pyridin-3 -y1)-N-(4- {1- [(2R)-tetrahydro furan-2-ylcarb onyl] azetidin-3 -yl } phenyl)azetidine-l-carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1- (tetrahydro furan-3 -ylcarb onyl) azetidin-3 -yl]phenyl } azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)azetidin-3-yl]phenyl} -3 - (pyridin-3 -y1) azetidine-1-carboxamide;
N- {4- [1- (2-hydroxy-2-methylprop anoyl)azetidin-3 -yl]phenyl } -3- (pyridin-yl)azetidine-l-carboxamide;
N- [4- (1-b enzoylazetidin-3 -yl)pheny1]-3 -(pyridin-3 -y1) azetidine-l-carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl) azetidin-3 -yl]phenyl } azetidine-1-carboxamide;
N- {4- [1- (cyc lopropylcarb onyl) azetidin-3 -yl]phenyl } -3 -(pyridin-3 -yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl] azetidin-3 -y1} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carboxamide;
N- [4- (1-butanoylazetidin-3 -yl)phenyl] -3 -(pyridin-3 -y1) azetidine-l-carboxamide;
tert-butyl 4- [4-( { [3 -(2-chloropyridin-3 -yl)azetidin-1-yl] carb onyl } amino)phenyl]piperidine-l-carboxylate;
tert-butyl 4- [4-( { [3 -(4-chloropyridin-3 -yl)azetidin-1-yl] carb onyl } amino)phenyl]piperidine-l-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-l-carboxylate;
N- {4- [(1-pentanoylazetidin-3-yl)oxy]phenyl} -3 -(pyridin-3 -yl)azetidine-1-carboxamide;
N- [4-( {1- [(2-methoxyethoxy)acetyl] azetidin-3 -y1} oxy)phenyl] -3- (pyridin-yl)azetidine-l-carboxamide;
N-(4- { [1-(ethoxyacetyl)azetidin-3-yl]oxy}pheny1)-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 -y1) azetidine-1-carboxamide;

N- [4-( {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl] azetidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,3- 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-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1- (4,4,4-trifluorobutanoyl)azetidin-3-yl] oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [1-(2-methylpropanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,2- dimethylpropanoyl)azetidin-3-yl] oxy} pheny1)-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- { [142,2- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(3-methylbutanoyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [143,3- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(3,3,3-trifluoropropanoyl)azetidin-3 -yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} oxy)pheny1]-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} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(cyclohexylcarbonyl)azetidin-3-yl]oxy} pheny1)-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-y1)-N-(4- { [1-(thiophen-2-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [1-(cyclopentylcarbonyl)azetidin-3-yl]oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- { [1-(morpholin-4-ylacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-5-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N- [4-( {1- [(3,5-dimethy1-1,2-oxazol-4-y1)carbonyl]azetidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(thiophen-3-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-(4- { [1-(1,2-oxazo 1-5-ylcarb onyl) azetidin-3-yl] oxy} phenyl)-3-(pyridin-yl)azetidine-l-carboxamide;
N- [4-( {1- [(4-methylpiperazin-1-yl)acetyl]azetidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(N,N-dimethyl-beta-alanyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(furan-3-ylcarbonyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4-( {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(cyclopentylacetyl)azetidin-3-yl]oxy} phenyl)-3-(pyridin-3-yl)azetidine-1 -carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]oxy} phenyl) azetidine-l-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [1- (pyrro lidin-l-ylacetyl)azetidin-3-yl] oxy}
phenyl)azetidine-1-c arb oxamide ;
3-(2-fluoropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl } azetidine-l-carboxamide;
N- {4- [1- (2-methylpropy1)-1H-pyrazol-4-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carb oxamide ;
N- [4- (1-propy1-1H-pyrazol-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide ;
3-(pyridin-3-y1)-N-(4- {1- [(3S)-tetrahydro furan-3-ylcarb onyl]pip eridin-4-yl } phenyl)azetidine-l-carboxamide;

3-(4-chloropyridin-3-y1)-N-(4- {1- [(3S)-tetrahydrofuran-3-ylcarbonyl]piperidin-4-y1} phenyl)azetidine-l-carboxamide;
3-(2-chloropyridin-3-y1)-N- {4- [1- (2-hydroxy-2-methylprop anoyl)pip eridin-4-yl]phenyl } azetidine-l-carboxamide;
N- [4- (1-p entanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)pip eridin-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- [142,2- 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-dimethylprop anoyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-butanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1-(3-methylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-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-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylc arb onyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylacetyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pip eridin-4-yl]phenyl}
azetidine-1-carboxamide;

N- {4- [1- (cyclopentylc arb onyl)pip eridin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-3-ylcarb onyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-ac etylpip eridin-4-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pip eridin-4-yl]pheny11-3- (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylc arb onyl)pip eridin-4-yl]phenyl}azetidine-1-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carb onyl]pip eridin-4-yl}pheny1)-3-(pyridin-yl)azetidine-l-carboxamide;
N- {4- [1-(morpholin-4-ylacetyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylc arb onyl)pip eridin-4-yl]phenyl}azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carb onyl]pip eridin-4-yl}pheny1)-3-(pyridin-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-2-ylcarb onyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]piperidin-4-y11phenyl)-3-(pyridin-y1)azetidine-1-carboxamide;
N- [4- (1-prop anoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3 -yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)piperidin-4-yl]phenyl}azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-l-carboxamide;
N- {4- [1-(cyclopentylacetyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [142,3- dimethylbutanoyl)piperidin-4-yl]pheny11-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-p entanoylazetidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carb onyl] azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-(4- {1- [(1S,4R)-bicyclo [2.2.1]hept-2-ylacetyl]azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-ethoxyprop anoyl)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-dimethylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)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-y1} pheny1)-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- (cyc lohexylacetyl)azetidin-3-yl] phenyl } -3-(pyridin-3-yl)azetidine-1 -carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyc lop entylcarb onyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-ac etylazetidin-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 -y1)-N- {4- [1 -(thiophen-3 -ylcarbonyl)azetidin-3 -yl]phenyl}
azetidine- 1 -carboxamide;
N-(4- { 1 - [(3 -methylthiophen-2-yl)carb onyl] azetidin-3 -yl} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 - (morpholin-4-ylac etyl)azetidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-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- 1 H-pyrro 1-2-yl)carb onyl] azetidin-3 -yl} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4- (1 -prop anoylazetidin-3-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [(1 -methylcyclopropyl)carb onyl] azetidin-3 -yl} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(1,3 -thiazol-2-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine- 1 -carboxamide;
N- {4- [ 1 - (cyclop entylacetyl)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-methylp entyl)pip eridin-4-yl]phenyl } -3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 - (2-methylpropyl)pip eridin-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)pip eridin-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)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-butylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-propylpip eridin-4-yl)pheny1]-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(2-cyclopropylethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl } azetidine-l-carboxamide;
N- {4- [142,2- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclop entylmethyl)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- [143,3- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclopropylmethyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylp entyl) azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-2-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [1- (2-methylpropyl) azetidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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-y1)-N- {4- [1- (tetrahydro furan-3-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;

N- {4- [142,2- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-p entanoylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (3-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carb oxamide ;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]pyrro lidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- {4- [1- (cyclop entylacetyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carb oxamide ;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)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-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)pyrrolidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (N,N-dimethyl-beta- alanyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carb oxamide ;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)pyrro lidin-3-yl]phenyl } azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} phenyl)-3-(pyridin-yl)azetidine-l-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-carb oxamide ;
N- {4- [1- (4-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carb oxamide ;

N-(4- {1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-ac etylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylacetyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpyrro lidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [142,2- dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-1-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1} 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-y1} phenyl)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (ethoxyac etyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (3,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1 -carboxamide;
N- {4- [1- (2,2-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-oxoprop anoyl)pyrrolidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutanoyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;

N- {4- [ 1 - (cyclop entylcarb onyl)pyrro lidin-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)pyrro lidin-3 -yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopentylacetyl)pyrrolidin-3 -yl]oxy} phenyl)-3 -(pyridin-yl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(2-methylcyclopropyl)carbonyl]pyrrolidin-3 -y1}
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 -y1)-N-(4- { [(3R)- 1 - (pyrro lidin- 1 -ylacetyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(5- oxo-D-pro lyl)pyrro lidin-3 -yl]oxy} phenyl)-3 -(pyridin-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 -y1)-N-(4- { [(3R)- 1 -(1,3 -thiazol-2-ylcarbonyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [(3R)- 1 -(thiophen-3 -ylcarbonyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(1 -methylcyclopropyl)carbonyl]pyrrolidin-3 -y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(3 -methylthiophen-2-yl)carbonyl]pyrrolidin-3 -y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [(3R)- 1 -(4,4,4-trifluorobutanoyl)pyrrolidin-3 -yl]oxy} phenyl)azetidine- 1 -carboxamide;
N- [4-( { (3 R)- 1 - [(4-methylpiperazin- 1 -yl)acetyl]pyrrolidin-3 -y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

N-(4- { [(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-y1]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- {[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3- (pyridin-3-yl)azetidine-l-carb oxamide;
N-(4- { [(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-propanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide ;
N- [4-( {(3R)-1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [3- (pip eridin-l-yl)prop anoyl]pyrro lidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-c arb oxamide ;
N-(4- { [(3R)-1-(3,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(2,2-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;

N-(4- { [(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(3-methylbutanoyl)pyrrolidin-3-yl] oxy}pheny1)-3- (pyridin-3-1 0 yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(cyclopentylcarbonyl)pyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2,3-dimethylbutanoyOpyrrolidin-3-yl] oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4- (1-b enzoylpip eridin-4-yl)phenyl] -3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(2-fluorobenzoyl)piperidin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (2-methylb enzoyl)pip eridin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-1-carb oxamide ;
N- {4- [1- (2,2-dimethylprop anoyl)pip eridin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-1-c arb oxamide ;
N- {4- [1-(cyclopropylcarbonyl)piperidin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- [4- (1-ac etylpip eridin-4-yl)phenyl] -3- (pyridazin-3-yl)azetidine-1-carb oxamide;
N- {4- [143,3- dimethylbutanoyl)piperidin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lobutylcarb onyl)pip eridin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-1-carb oxamide ;
3-(pyridazin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)pip eridin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridazin-3-y1)-N- {4- [1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]phenyl}azetidine-l-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)piperidin-4-yl]pheny11-3-(pyridazin-3-yl)azetidine-l-carboxamide;
N- {4- [(1-benzoylpiperidin-4-yl)methyl]pheny11-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(2- fluorob enzoyl)piperidin-4-yl]methyl}pheny1)-3- (pyridazin-3-4 0 yl)azetidine-l-carboxamide;

N-(4- {[1-(2,2-dimethylpropanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N-(4- { [143,3 -dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-yl)azetidine-l-carboxamide;
N-(4- { [1-(2-ethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 -(pyridazin-3 -1 0 yl)azetidine- 1 -carboxamide;
3 -(pyridazin-3 -y1)-N-(4- {[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]methyl}phenyl)azetidine-l-carboxamide;
N-(4- {[1-(2-methylpropanoyl)piperidin-4-yl]methyl}pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide;
N- {4- [(1-acetylpiperidin-4-yl)methyl]phenyl} -3 -(pyridazin-3 -yl)azetidine-carboxamide;
N- [4-( { 1- [(2S)-2-methylbutanoyl]piperidin-4-y1} methyl)pheny1]-3 -(pyridazin-3 -yl)azetidine-l-carboxamide;
N- [4-( { 1- [(1-methylcyclopropyl)carbonyl]piperidin-4-y1} methyl)pheny1]-3 -(pyridazin-3-yl)azetidine- 1 -carboxamide; and pharmaceutically acceptable salts thereof.
Embodiments of Formula (IIIA) In another a spect, the present invention provides compounds of Formula (IIIA) N

H
R4x 10 NN

(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, 0R4, SR4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NE12, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4S02R4, SO2NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein the cyclic moieties represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10, CO(0)R10, OC(0)R10 , OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10, NHS(0)2R10, NR105(0)2R10 , NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10, NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NH502R10, C(0)NR10502R10, 502NH2, 502NHR10, 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11S02R11, 502NH2, SO2NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR12S(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2/
C(0)NHOH, C(0)NHOR12, C(0)NHSO2R12, C(0)NR12S02R12, 502NH2, 502NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR12, C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I;
R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl.
In one embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, 0R4, 5R4, S(0)R4, 502R4, C(0)R4, CO(0)R4, OC(0)R4, OC(0)0R4, NH2, NHR4, N(R4)2, NHC(0)R4, NR4C(0)R4, NHS(0)2R4, NR4S(0)2R4, NHC(0)0R4, NR4C(0)0R4, NHC(0)NH2, NHC(0)NHR4, NHC(0)N(R4)2, NR4C(0)NHR4, NR4C(0)N(R4)2, C(0)NH2, C(0)NHR4, C(0)N(R4)2, C(0)NHOH, C(0)NHOR4, C(0)NHSO2R4, C(0)NR4502R4, 502NH2, SO2NHR4, 502N(R4)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR4, C(N)N(R4)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I.
In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, CN, F, CI, Br and I. In another embodiment of Formula (IIIA), R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN. In another embodiment of Formula (IIIA), R4x is C(0)NHR4. In another embodiment of Formula (IIIA), R4x is 0R4. 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, 0R7, 5R7, S(0)R7, 502R7, C(0)R7, CO(0)R7, OC(0)R7, OC(0)0R7, NH2, NHR7, N(R7)2, NHC(0)R7, NR7C(0)R7, NHS(0)2R7, NR7S(0)2R7, NHC(0)0R7, NR7C(0)0R7, NHC(0)NH2, NHC(0)NHR7, NHC(0)N(R7)2, NR7C(0)NHR7, NR7C(0)N(R7)2, C(0)NH2, C(0)NHR7, C(0)N(R7)2, C(0)NHOH, C(0)NHOR7, C(0)NHSO2R7, C(0)NR7502R7, 502NH2, SO2NHR7, 502N(R7)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR7, C(N)N(R7)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I; wherein the cyclic moiety represented by R4 is independently optionally substituted with one or more substituents independently selected from the group consisting of R1 , 0R10, Se, S(0)R10, C(0)C(0)R10, 502R10, C(0)R10 , CO(0)R10, OC(0)R10, OC(0)0R10, NH2, NHR10, N(R10)2, NHC(0)R10, NR10C(0)R10 , NHS(0)2R10, NR105(0)2R10, NHC(0)0R10, NR10C(0)0R10, NHC(0)NH2, NHC(0)NHR10 , NHC(0)N(R10)2, NR10C(0)NHR10, NR10C(0)N(R10)2, C(0)NH2, C(0)NHR10, C(0)N(R10)2, C(0)NHOH, C(0)NHOR10, C(0)NHS02R10, C(0)NR10S02R10, SO2NH2, 502NHR10 , 502N(R10)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR10, C(N)N(R10)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is independently selected from the group consisting of alkyl and heterocyclyl;
wherein each R4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, F, CI, Br and I; wherein the cyclic moiety represented by R4 isindependently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10 , F, CI, Br and I. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl. In another embodiment of Formula (IIIA), R4, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R4 isindependently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIIA), R7, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is independently heterocyclyl. In another embodiment of Formula (IIIA), R7, at each occurrence, is heterocyclyl; wherein the cyclic moiety represented by R7 isindependently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, CO(0)R10, F, CI, Br and I.
In one embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R1 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, S(0)R11, 502R11, C(0)R11, CO(0)R11, OC(0)R11, OC(0)0R11, NH2, NHR11, N(R11)2, NHC(0)R11, NR11C(0)R11, NHS(0)2R11, NR11S(0)2R11, NHC(0)0R11, NR11C(0)0R11, NHC(0)NH2, NHC(0)NHR11, NHC(0)N(R11)2, NR11C(0)NHR11, NR11C(0)N(R11)2, C(0)NH2, C(0)NHR11, C(0)N(R11)2, C(0)NHOH, C(0)NHOR11, C(0)NHSO2R11, C(0)NR11502R11, 502NH2, 502NHR11, 502N(R11)2, C(0)H, C(0)0H, C(N)NH2, C(N)NHR11, C(N)N(R11)2, CNOH, CNOCH3, OH, (0), CN, N3, NO2, F, CI, Br and I;
wherein each R1 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, 0R12, 5R12, S(0)R12, 502R12, C(0)R12, CO(0)R12, OC(0)R12, OC(0)0R12, NH2, NHR12, N(R12)2, NHC(0)R12, NR12C(0)R12, NHS(0)2R12, NR125(0)2R12, NHC(0)0R12, NR12C(0)0R12, NHC(0)NH2, NHC(0)NHR12, NHC(0)N(R12)2, NR12C(0)NHR12, NR12C(0)N(R12)2, C(0)NH2, C(0)NHR12, C(0)N(R12)2, C(0)NHOH, C(0)NHOR12, C(0)NH502R12, C(0)NR12s02-K 12, SO2NH2, SO2NHR12, 502N(R12)2, C(0)H, C(0)0H, C(N)NE12, C(N)NH-K12 , C(N)N(R12)2, CNOH, CNOCH3, OH, CN, N3, NO2, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R11 alkyl, alkenyl, and alkynyl is optionally substituted with alkyl or alkoxy; wherein each R11 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with alkyl or alkoxy; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, 2 N(Riis), NHC(0)R11, OH, F, CI, Br and I; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of K-12, C(0)R12, F, CI, Br and I; R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy; wherein each R11 heterocyclyl and cycloalkyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl. In another embodiment of Formula (IIIA), R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, 5R11, ) NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, c(0)K'-'12, 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) N

H
NN

5 R4x Formula (IIIA);
wherein R4x is independently selected from the group consisting of R4, 0R4, CO(0)R4, C(0)NHR4, and CN;
10 R4, at each occurrence, is independently selected from the group consisting of alkyl, and heterocyclyl; wherein each R4 alkyl is optionally substituted with one or more R7;
R7, at each occurrence, is independently heterocyclyl;
wherein the cyclic moiety represented by R4 and R7 are independently optionally substituted with one or more substituents independently selected from the group consisting of R10, C(0)C(0)R10, C(0)R10, and CO(0)R10;
R10, at each occurrence, is independently selected from the group consisting of alkyl, aryl, heterocyclyl, and cycloalkyl; wherein each R1 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R11, 0R11, SR11, N(R11)2, NHC(0)R11, OH, and F; wherein each R1 aryl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of R12, C(0)R12, and F;
R11, at each occurrence, is independently selected from the group consisting of alkyl, heterocyclyl, and cycloalkyl; wherein each R11 alkyl is optionally substituted with alkoxy;
wherein each R11 heterocyclyl is optionally substituted with alkyl; and R12, at each occurrence, is independently selected alkyl.
Still another embodiment pertains to compounds having Formula (IIIA), which include N-[4-({1-[(2S)-2-methylbutanoyl]azetidin-3-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {[1-(tetrahydro-2H-pyran-4-ylacetyl)piperidin-4-yl]oxy} phenyl) azetidine-l-carb oxamide;
N-[4-({1-[(25)-2-methylbutanoyl]piperidin-4-yl}oxy)pheny1]-3-(pyridin-3-yl)azetidine-l-carboxamide;

3 -(pyridin-3 -y1)-N- [4-( { 1 -[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-y1} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-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-methylbutanoy1]- 1 ,2,3 ,6-tetrahydropyridin-4-y1} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 - [(2R)-tetrahydro furan-2-ylcarb onyl] - 1 ,2,3 ,6-tetrahydropyridin-4-y1} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 -[(2S)-tetrahydrofuran-2-ylcarbony1]- 1 ,2,3 ,6-tetrahydropyridin-4-y1} phenyl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-hydroxy-2-methylpropanoy1)- 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-cyanopheny1)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(2,2-dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(3,3 -dimethylbutanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(3,3,3 -trifluoropropanoy1)- 1 ,2,3,6-tetrahydropyridin-4-yl]phenyl } azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(4,4,4-trifluorobutanoy1)- 1,2,3 ,6-tetrahydropyridin-4-yl]phenyl } azetidine- 1 -carboxamide;
N- {4- [1 -(methoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(methylsulfanyl)acety1]- 1,2,3 ,6-tetrahydropyridin-4-y1} phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [ 1 - (ethoxyacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 -[(2-methoxyethoxy)acety1]- 1 ,2,3 ,6-tetrahydropyridin-4-y1}
pheny1)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1- [3 -(methylsulfanyl)prop anoyl] - 1 ,2,3 ,6-tetrahydropyridin-4-y1}
phenyl)-3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(cyclopropylcarbony1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

N- {4- [ 1 -(cyclopropylacety1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-methylpropanoy1)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]phenyl } -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { 1 - [(2R)-tetrahydro furan-2-ylc arbonyl]
azetidin-3 -yl} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { 1- [(2 S)-tetrahydro furan-2-ylcarb onyl]
azetidin-3 -y1} 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 -y1)-N- [4-( { 1- [(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-y1} oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(thiophen-2-ylcarbonyl)piperidin-4-yl]oxy} phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(thiophen-3 -ylc arb onyl)pip eridin-4-yl]oxy} phenyl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [( 1 -acetylpiperidin-4-yOcarbonyl]piperidin-4-y1} oxy)phenyl] -3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(2-methylcyclopropyl)carbonyl]piperidin-4-y1} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(1 -methyl- 1 H-pyrrol-2-yl)c arb onyl]pip eridin-4-y1}
oxy)pheny1]-3- (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [3 -(morpholin-4-yl)propanoyl]piperidin-4-y1} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [3 -(4-methylpiperazin- 1 -yl)propanoyl]piperidin-4-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- [4-( {1- [3-(pyrrolidin-1-yl)propanoyl]piperidin-4-y1} oxy)phenyl]azetidine-l-carboxamide;
N-(4- { [1-(cyclopropylacetyl)piperidin-4-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(3-methylpentanoyl)piperidin-4-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(4-methylpentanoyl)piperidin-4-yl]oxy} pheny1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(3,3-dimethylbutanoyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {[1-(ethoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(cyclopropylcarbonyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[1-(methoxyacetyl)piperidin-4-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-carboxamide;
3-(pyridin-3-y1)-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-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-{4-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]phenyl}azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}phenyl)azetidine-l-carboxamide;
N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4-[1-(2-methylpropanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1 -benzoylpiperidin-4-yl)phenyl] -3 -(pyridin-3 -y1) azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-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]carbony11 amino)phenoxy]azetidine- 1 -carb oxylate ;
3 -(pyridin-3 -y1)-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 -y1)-N-(4- { 1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 -y11 phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1 - [(2R)-tetrahydro furan-2-ylcarb onyl]pyrro lidin-3-y11 phenyl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 - (tetrahydro furan-3 -ylcarbonyl)pyrrolidin-3 -yl]phenyl} azetidine- 1 -carboxamide;
N- {4-[ 1 -(cyclopropylacetyl)pyrrolidin-3 -yl]pheny11 -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N- {4- [1 -(2-hydroxy-2-methylpropanoyl)pyrrolidin-3 -yl]phenyl} -3 -(pyridin-yl)azetidine- 1 -carboxamide;
N- [4- (1 -benzoylpyrrolidin-3 -yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- {4- [1 -(3 ,3 ,3-trifluoroprop anoyl)pyrro lidin-3 -yl]phenyl} azetidine-1 -carboxamide;
N- {4- [ 1 - (cyclopropylcarb onyl)pyrro lidin-3 -yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [(2S)-2-methylbutanoyl]pyrrolidin-3 -y11 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 -y1)-N-(4- { [(3R)- 1 -(tetrahydro-2H-pyran-4-ylacetyl)pyrro lidin-3-yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(2-methylpropanoyl)pyrrolidin-3 -yl]oxy}pheny1)-3 -(pyridin-yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { (3R)- 1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 -y11 oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N- [4-( { (3R)- 1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3 -y11 oxy)phenyl]azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [(3R)- 1 -(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-yl]oxy}phenyl)azetidine- 1 -carboxamide;
N-(4- { [(3R)- 1 -(cyclopropylacetyl)pyrrolidin-3 -yl]oxy}pheny1)-3 -(pyridin-yl)azetidine- 1 -carboxamide;

N-(4- { [(3R)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-y1] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-benzoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(3,3,3-trifluoroprop anoyl)pyrro lidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-butanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydro-2H-pyran-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(2-methylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- [4-( {(3S)-1- [(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-y1} oxy)phenyl]azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(tetrahydrofuran-3-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(cyclopropylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
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} pheny1)-3-(pyridin-3-yl)azetidine-carb oxamide ;
3-(pyridin-3-y1)-N-(4- { [(3S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3S)-1- [(2S)-2-methylbutanoyl]pyrrolidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3S)-1-butanoylpyrrolidin-3-yl] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

3-(pyridin-3-y1)-N- {4- [1-(tetrahydro-2H-pyran-4-ylacetyl)azetidin-3-yl]phenyl} azetidine-l-carboxamide;
N- {4- [1- (2-methylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2S)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- {1- [(2R)-tetrahydro furan-2-ylcarb onyl] azetidin-3-yl } phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-3-ylcarb onyl)azetidin-3-yl]phenyl } azetidine-l-carboxamide;
N- {4- [1-(cyclopropylacetyl)azetidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-hydroxy-2-methylprop anoyl)azetidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-l-carboxamide;
N- [4- (1-b enzoylazetidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (3,3,3-trifluoroprop anoyl)azetidin-3-yl]phenyl }
azetidine-l-carboxamide;
N- {4- [1- (cyc lopropylcarb onyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2S)-2-methylbutanoyl]azetidin-3-y1} pheny1)-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-y1} oxy)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [1-(ethoxyacetyl)azetidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(methoxyacetyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-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-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,3- 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-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1- (4,4,4-trifluorobutanoyl)azetidin-3-yl] oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [1-(2-methylpropanoyl)azetidin-3-yl]oxy} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [142,2- dimethylpropanoyl)azetidin-3-yl] oxy} pheny1)-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- { [142,2- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(3-methylbutanoyl)azetidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [143,3- dimethylbutanoyl)azetidin-3-yl] oxy} phenyl)-3 - (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [1-(3,3,3-trifluoroprop anoyl)azetidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} oxy)pheny1]-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} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [1-(cyclohexylcarbonyl)azetidin-3-yl]oxy} pheny1)-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 -y1)-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 -y1)-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)carb onyl] azetidin-3 -y1}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(thiophen-3-ylcarbonyl)azetidin-3 -yl]oxy} phenyl) azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 -(1,3 -thiazol-4-ylcarbonyl)azetidin-3 -yl]oxy} phenyl) azetidine- 1 -carboxamide;
N-(4- { [1 -( 1 ,2-oxazo 1-5 -ylcarb onyl) azetidin-3 -yl] oxy} phenyl)-3 -(pyridin-3-yl)azetidine- 1 -carboxamide;
N- [4-( { 1 - [(4-methylpiperazin- 1 -yl)acetyl]azetidin-3 -y1} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { [1 -(N,N-dimethyl-beta-alanyl)azetidin-3 -yl]oxy} phenyl)-3 -(pyridin-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)carb onyl] azetidin-3 -y1} 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 -y1)-N-(4- { [1 -(1,3 -thiazol-2-ylcarbonyl)azetidin-3 -yl]oxy} phenyl) azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { [1 - (pyrro lidin- 1 -ylacetyl)azetidin-3 -yl]oxy}
phenyl)azetidine-1 -carboxamide;
N- {4- [1 -(2-methylpropy1)- 1 H-pyrazol-4-yl]phenyl} -3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4-( 1 -propyl- 1 H-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -y1)-N-(4- { 1- [(3 S)-tetrahydrofuran-3 -ylcarb onyl]pip eridin-yl } phenyl)azetidine- 1 -carboxamide;
N- [4-( 1 -p entanoylpip eridin-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;

N-(4- {1- [(2-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)pip eridin-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- [142,2- 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-dimethylprop anoyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-butanoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1-(3-methylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-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-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylc arb onyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylacetyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pip eridin-4-yl]phenyl}
azetidine-1-carboxamide;
N- {4- [1- (cyclop entylc arb onyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]piperidin-4-y1} pheny1)-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-ac etylpip eridin-4-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pip eridin-4-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylc arb onyl)pip eridin-4-yl]phenyl}
azetidine-l-carboxamide;
1 0 N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-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-y1)-N- {4- [1- (thiophen-2-ylc arb onyl)pip eridin-4-yl]phenyl }
azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-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-methy1-1H-pyrrol-2-y1)carbonyl]piperidin-4-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)piperidin-4-yl]phenyl}
azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1-(cyclopentylacetyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [142,3- dimethylbutanoyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-p entanoylazetidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carb onyl] azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1]hept-2-ylacetyl]azetidin-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (4-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylp entanoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;

N- {4- [1- (3-ethoxyprop anoyl)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-dimethylprop anoyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (ethoxyac etyl)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-y1} pheny1)-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- (cyc lohexylacetyl)azetidin-3-yl] phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1-(4,4,4-trifluorobutanoyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (cyc lop entylcarb onyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]azetidin-3-y1} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1-(furan-3-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-ac etylazetidin-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-y1)-N- {4- [1-(thiophen-3-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;

3-(pyridin-3-y1)-N- {4- [1-(thiophen-2-ylcarbonyl)azetidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1-(furan-2-ylcarbonyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylazetidin-3-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]azetidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)azetidin-3-yl]phenyl }
azetidine-l-carboxamide;
N- {4- [1- (cyclop entylacetyl)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-carboxamide;
N- {4- [1-(cyclohexylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [143,3- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylp entyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylpropyl)pip eridin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutyl)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-ethylbutyl)pip eridin-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)pip eridin-4-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-butylpip eridin-4-yl)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-propylpip eridin-4-yl)pheny1]-3- (pyridin-3-yl)azetidine-l-carboxamide;

N- {4- [1-(2-cyclopropylethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydrofuran-3-ylmethyl)piperidin-4-yl]phenyl } azetidine-l-carboxamide;
N- {4- [142,2- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclop entylmethyl)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- [143,3- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (cyclopropylmethyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-methylp entyl)azetidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (tetrahydro furan-2-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [1- (2-methylpropyl)azetidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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-y1)-N- {4- [1- (tetrahydro furan-3-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide;
N- {4- [142,2- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- [4- (1-p entanoylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (3-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1S,4R)-bicyclo [2.2.1] hept-2-ylacetyl]pyrro lidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N- {4- [1- (cyclop entylacetyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-y1) azetidine-1-carboxamide;
N-(4- {1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (morpholin-4-ylac etyl)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-y1)-N- {4- [1-(pyrrolidin-l-ylacetyl)pyrrolidin-3-yl]phenyl}
azetidine-l-carboxamide;
N- {4- [1- (N,N-dimethyl-beta-alanyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (1,3-thiazol-2-ylc arb onyl)pyrro lidin-3-yl]phenyl } azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-3-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (4,4,4-trifluorobutanoyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-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-methylp entanoyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-ac etylpyrro lidin-3-yl)phenyl] -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyc lohexylacetyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4- (1-prop anoylpyrro lidin-3-yl)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-(4- {1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} phenyl)-3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [142,2- dimethylpropanoyl)pyrrolidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N- {4- [1- (thiophen-2-ylcarb onyl)pyrro lidin-3-yl]phenyl}
azetidine-l-carboxamide;
N-(4- {1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1} 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-y1} phenyl)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N- {4- [1- (ethoxyac etyl)pyrro lidin-3-yl]phenyl} -3- (pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (3,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,2-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2-oxoprop anoyl)pyrrolidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (methoxyacetyl)pyrro lidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclohexylcarb onyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (3-methylbutanoyl)pyrro lidin-3-yl]phenyl } -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (cyclop entylcarb onyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N- {4- [1- (2,3-dimethylbutanoyl)pyrro lidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-pentanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;

N-(4- { [(3R)-1-(3-methylpentanoyl)pyrrolidin-3-y1] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [1-(bicyclo [2.2.1] hept-2-ylacetyl)pyrro lidin-3-yl] oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(2-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)-3 -(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(furan-3-ylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(5-oxo-D-prolyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(N,N-dimethyl-beta-alanyl)pyrrolidin-3-yl]oxy} phenyl)-3 -(pyridin-3-yl)azetidine-1-carb oxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(1,3-thiazol-2-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-3-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methylcyclopropyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -(pyridin-3-yl)azetidine-1-carb oxamide;
N- [4-( {(3R)-1- [(3-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(4,4,4-trifluorobutanoyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(4-methylpiperazin-1-yl)acetyl]pyrrolidin-3-y1} oxy)phenyl] -(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(5-oxo-L-prolyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(3-ethoxypropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carb oxamide;
N-(4- { [(3R)-1-(4-methylpentanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;

N- [4-( {(3R)-1- [(1-methylcyclohexyl)carbonyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[(3R)-1-(cyclohexylacetyl)pyrrolidin-3-yl]oxy} pheny1)-3- (pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-(N-acetyl-L-leucyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide;
N-(4- { [(3R)-1-propanoylpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(2-methoxyethoxy)acetyl]pyrrolidin-3-y1} oxy)phenyl] -3-(pyridin-3-yl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [3-(morpholin-4-yl)propanoyl]pyrrolidin-3-yl} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(2,2-dimethylpropanoyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [(5-methylthiophen-2-yl)carbonyl]pyrrolidin-3-y1} oxy)phenyl]

(pyridin-3-yl)azetidine-1-carboxamide;
3-(pyridin-3-y1)-N-(4- { [(3R)-1-(thiophen-2-ylcarbonyl)pyrrolidin-3-yl]oxy} phenyl)azetidine-l-carboxamide;
N- [4-( {(3R)-1- [(1-methy1-1H-pyrrol-2-y1)carbonyl]pyrrolidin-3-y1}
oxy)phenyl] -3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(furan-2-ylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N- [4-( {(3R)-1- [3- (pip eridin-l-yl)prop anoyl]pyrro lidin-3-y1} oxy)pheny1]-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(ethoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(3,3-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(2,2-dimethylbutanoyOpyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(methoxyacetyl)pyrrolidin-3-yl]oxy} pheny1)-3-(pyridin-3-yl)azetidine- 1 -carboxamide;
N-(4 { [(3R)-1-(cyclohexylcarbonyl)pyrrolidin-3-yl]oxy} pheny1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- {[(3R)-1-(2,3-dimethylbutanoyOpyrrolidin-3-yl]oxy}pheny1)-3-(pyridin-3-y1)azetidine- 1 -carboxamide; and pharmaceutically acceptable salts thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of Treatment, and Administration Another embodiment comprises pharmaceutical compositions comprising a compound having Formula (I) and an excipient.
Still another embodiment comprises methods of treating cancer in a mammal comprising administering thereto a therapeutically acceptable amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I).
Still another embodiment pertains to compositions for treating diseases during which NAMPT is expressed, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating disease in a patient during which NAMPT is expressed, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to compositions for treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said methods comprising administering to the patient a therapeutically effective amount of the compound having Formula (I) and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
Metabolites of compounds having Formula (I), produced by in vitro or in vivo metabolic processes, may also have utility for treating diseases associated with NAMPT.
Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula (I) may also have utility for treating diseases associated with NAMPT.
Compounds having Formula (I) may exist as acid addition salts, basic addition salts or zwitterions. Salts of the compounds are prepared during isolation or following purification of the compounds. Acid addition salts of the compounds are those derived from the reaction of the compounds with an acid. For example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate, and undecanoate salts of the compounds are contemplated as being embraced by this invention. Basic addition salts of the compounds are those derived from the reaction of the compounds with the hydroxide, carbonate or bicarbonate of cations such as lithium, sodium, potassium, calcium, and magnesium.
The compounds having Formula (I) may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally or vaginally.
Therapeutically effective amounts of compounds having Formula (I) depend on the recipient of the treatment, the disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. The amount of a compound of this invention having Formula (I) used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without an excipient.
Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
Excipients for preparation of compositions comprising a compound having Formula (I) to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.
Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P.
or isotonic sodium chloride solution, water and mixtures thereof. Excipients for preparation of compositions comprising a compound of this invention having Formula (I) to be administered rectally or vaginally include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof.
Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bc1-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 (Pik) 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-ethyny1-1-0 -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.
Bc1-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE (G3139 or oblimersen (Bc1-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chloro (1,1'-bipheny1)-2-yl)methyl)pip erazin-l-yOb enzoy1)-4-(((1R)-3 -(dimethylamino)- 1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), N-(4-(442-(4-chloropheny1)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoy1)-4-(((lR)-3-(morpholin-4-y1)-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), BM5347070, CELEBREX (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX (deracoxib), JTE-522, 4-methy1-2-(3,4-dimethylpheny1)-1-(4-sulfamoylpheny1-1H-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

trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB (human recombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
Inhibitors of inhibitors of apoptosis proteins include HG51029, 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 DRS) 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 G5K923295A 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, CO.) and Chiron, (Emeryville, CA)) , axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), NEXAVAR (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT (sunitinib, SU-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-la, ACTIMMUNE (interferon gamma-lb) or interferon gamma-nl, combinations thereof and the like. Other agents include ALFAFERONE
,(IFN-a), BAM-002 (oxidized glutathione), BEROMUN (tasonermin), BEXXAR
(tositumomab), CAMPATH (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, 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, sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR
(gemcitabine), TOMUDEX (ratitrexed), TROXATYLTm (triacetyluridine troxacitabine) and the like.
Purine analogs include LANVIS (thioguanine) and PURI-NETHOL
(mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4-hydroxyphenyl)amino)pyridin-3-y1)-4-methoxybenzenesulfonamide, ixabepilone (BMS
247550), paclitaxel, TAXOTERE (docetaxel), PNU100940 (109881), patupilone, (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-methy1-3,17-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); 0: 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-a, interferon-y, 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-methy1-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFERADETm (adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER or ZAVESCA (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX (arsenic trioxide), VIRULIZIN , ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN
(motexafin gadolinium), XIILAYTM (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 50X final concentrations prior to dilution with assay buffer (50 mM HEPES
(NaOH), pH
7.5, 100 mM NaC1, 10 mM MgC12, 1 mM DTT, 1% Glycerol) to 3X and 6% DMSO. Six L

were transferred to 384-well low-volume plates (Owens Corning #3673). To this, 12 L of a 1.5X solution containing enzyme, probe and antibody were added. Final concentrations in the 18 L reactions were 1X 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 1X 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.

TR- TR-TR- FRET TR- FRET
FRET Binding FRET Binding Example Binding - IC50 Example Binding -- IC50 (with - IC50 (with ( M) PRPP) ( M) PRPP) (1M) (1M) 1 0.024900 0.000873 169 0.005360 0.000304 2 0.125000 0.000370 170 0.007070 0.000364 3 1.220000 0.007640 171 0.008740 0.000231 4 0.019700 0.000195 172 0.005650 0.000206 5 0.056800 0.000169 173 0.090400 0.000393 6 0.053400 0.000224 174 0.020800 0.000325 7 0.057800 0.000344 175 0.030700 0.000403 8 0.617000 0.015400 176 0.065500 0.000350 9 0.016300 0.000346 177 0.015800 0.000304 10 0.041500 0.000250 178 0.013900 0.000420 11 0.015800 0.000320 179 0.032500 0.000249 12 0.032100 0.000430 180 0.021300 0.000284 13 0.201000 0.000374 181 0.008060 0.000256 14 0.879000 0.000178 182 0.003680 0.000219 15 0.307000 0.000917 183 0.022000 0.000380 16 nd nd 184 0.018500 0.000305 17 0.016900 0.000568 185 0.003230 0.000228 18 0.036700 0.000294 186 0.002930 0.000345 19 0.153000 0.000860 187 0.039300 0.000292 20 0.068400 0.000500 188 0.002100 0.000188 21 0.032500 0.000381 189 0.022600 0.000210 22 0.143000 0.000630 190 0.002000 0.000282 23 0.097800 0.000551 191 0.004270 0.000291 24 0.170000 0.000988 192 0.023000 0.000255 25 0.037400 0.000362 193 0.014400 0.000243 26 0.073600 0.000724 194 0.248000 0.000592 27 0.013000 0.000243 195 0.004190 0.000281 28 0.077200 0.000218 196 0.015000 0.000281 29 0.053400 0.000243 197 0.017800 0.000505 30 0.069400 0.000255 198 0.064200 0.000341 31 0.040600 0.000330 199 0.128000 0.000356 32 0.018800 0.000209 200 0.036400 0.000382 33 0.056100 0.000430 201 0.043200 0.000313 34 0.050700 0.000264 202 0.051100 0.000327 35 0.089200 0.000492 203 0.250000 0.000427 36 0.027300 0.000169 204 0.048600 0.000349 37 0.085400 0.000174 205 0.042600 0.000242 38 0.034300 0.000201 206 0.049100 0.000260 39 0.090500 0.000338 207 0.451000 0.000370 40 0.050500 0.000419 208 0.048600 0.000473 41 0.076800 0.000448 209 0.024000 0.000694 42 0.043800 0.000270 210 0.206000 0.000356 43 0.023700 0.000234 211 0.055900 0.000341 44 0.044600 0.000315 212 0.040900 0.000464 45 0.034300 0.000223 213 0.087300 0.000352 46 0.093100 0.000226 214 0.075800 0.000289 47 0.030300 0.000268 215 0.027400 0.000294 48 0.206000 0.000169 216 0.018400 0.000256 49 0.150000 0.000245 217 0.278000 0.000320 50 0.015600 0.000169 218 0.171000 0.000451 51 0.017200 0.000303 219 0.019400 0.000290 52 0.038900 0.000169 220 0.010400 0.000340 53 0.076200 0.000194 221 0.152000 0.000319 54 0.117000 0.000169 222 0.010700 0.000183 55 0.029300 0.000169 223 0.021600 0.000391 56 0.027400 0.000169 224 0.026000 0.000333 57 0.006850 0.000222 225 0.014000 0.000268 58 0.017400 0.000169 226 0.169000 0.000440 59 0.038500 0.000364 227 0.069200 0.000294 60 0.055400 0.000169 228 0.019600 0.000310 61 0.020900 0.000310 229 0.040300 0.000314 62 0.091500 0.000467 230 0.038800 0.000305 63 0.044600 0.000390 231 0.421000 0.000225 64 0.052100 0.000171 232 0.352000 0.000181 65 0.056600 0.000169 233 0.653000 0.000335 66 0.086000 0.000169 234 0.760000 0.000529 67 0.173000 0.000171 235 0.649000 0.000213 68 0.086200 0.000169 236 0.667000 0.000210 69 0.044800 0.000169 237 0.581000 0.000257 70 0.092200 0.000421 238 4.010000 0.001410 71 0.020100 0.000184 239 1.680000 0.000200 72 0.065600 0.000211 240 0.603000 0.000466 73 0.156000 0.000663 241 0.359000 0.000255 74 0.031100 0.000357 242 0.374000 0.000225 75 0.103000 0.000169 243 1.270000 0.000326 76 0.083600 0.000169 244 1.170000 0.000516 77 0.061900 0.000169 245 0.317000 0.000169 78 0.137000 0.000226 246 0.437000 0.000213 79 0.092900 0.000169 247 0.871000 0.000304 80 0.122000 0.000169 248 0.990000 0.000228 81 0.030900 0.000169 249 0.193000 0.000169 82 0.009730 0.000169 250 0.865000 0.000679 83 0.007220 0.000169 251 0.382000 0.000365 84 0.059400 0.000169 252 0.526000 0.000296 85 0.117000 0.000325 253 0.538000 0.000207 86 0.027400 0.000244 254 0.246000 0.000174 87 0.019800 0.000169 255 0.271000 0.000173 88 0.269000 0.000580 256 0.830000 0.000169 89 0.227000 0.000169 257 0.598000 0.000223 90 0.404000 0.000196 258 0.052400 0.000359 91 0.320000 0.000169 259 0.054500 0.000452 92 0.387000 0.000169 260 0.038400 0.000302 93 0.138000 0.000169 261 0.033500 0.000194 94 0.488000 0.000213 262 0.060400 0.000252 95 0.079100 0.000169 263 0.143000 0.000239 96 0.265000 0.000169 264 0.040900 0.000188 97 0.168000 0.000169 265 0.191000 0.000169 98 0.616000 0.001190 266 0.096200 0.000169 99 0.223000 0.000414 267 0.022500 0.000297 100 0.108000 0.000309 268 0.036500 0.000225 101 0.143000 0.000629 269 0.020100 0.000169 102 0.095700 0.000286 270 0.008170 0.000196 103 0.296000 0.000287 271 0.046900 0.000279 104 0.188000 0.000389 272 0.090700 0.000241 105 0.068300 0.000208 273 0.203000 0.000169 106 0.204000 0.000553 274 0.082200 0.000264 107 0.012300 0.000342 275 0.038300 0.000363 108 0.122000 0.000411 276 0.012400 0.000347 109 0.306000 0.000596 277 0.076700 0.000169 110 0.035300 0.000421 278 0.019700 0.000213 111 0.053900 0.000292 279 0.092100 0.000204 112 0.043500 0.045900 280 0.101000 0.000169 113 0.075800 0.014700 281 0.065600 0.000169 114 0.015800 0.000189 282 0.026600 0.000219 115 0.009220 0.000169 283 0.033700 0.000266 116 0.026700 0.000744 284 0.018300 0.000204 117 0.018800 0.000327 285 0.017200 0.000169 118 0.036000 0.000324 286 0.009760 0.000169 119 0.117000 0.000978 287 0.030100 0.000189 120 0.145000 0.000689 288 0.117000 0.000227 121 0.018600 0.000497 289 0.029600 0.000204 122 0.016600 0.000588 290 0.011100 0.000224 123 0.014700 0.000169 291 0.025800 0.000207 124 0.014900 0.000375 292 0.268000 0.000259 125 0.029300 0.000271 293 0.056600 0.000210 126 0.014400 0.000401 294 0.044300 0.000200 127 0.093400 0.000603 295 0.050700 0.000272 128 0.030400 0.000519 296 0.026400 0.000243 129 0.040000 0.000401 297 0.056600 0.000236 130 0.084700 0.000559 298 0.035200 0.000169 131 0.007720 0.000491 299 0.064900 0.000451 132 0.019100 0.000634 300 0.052600 0.000341 133 0.013200 0.000358 301 0.059000 0.000243 134 0.054200 0.000317 302 0.337000 0.000393 135 0.028100 0.000376 303 0.040500 0.000595 136 0.015000 0.000544 304 0.594000 0.000343 137 0.098800 0.000440 305 0.435000 0.000211 138 0.011400 0.000596 306 0.507000 0.000169 139 0.014400 0.000442 307 0.024300 0.000197 140 0.043000 0.000181 308 0.024200 0.000293 141 0.017600 0.000249 309 0.032800 0.000262 142 0.024600 0.000339 310 0.004540 0.000297 143 0.136000 0.000763 311 0.144000 0.000592 144 0.025600 0.000313 312 0.311000 0.000290 145 0.090500 0.000600 313 0.369000 0.000187 146 0.015100 0.000270 314 0.110000 0.000178 147 0.016700 0.000169 315 0.048700 0.000169 148 0.027700 0.000321 316 0.013600 0.000169 149 0.022100 0.000219 317 0.029900 0.000207 150 0.435000 0.002850 318 0.125000 0.000419 151 0.020800 0.000169 319 0.070600 0.000426 152 0.005180 0.000420 320 0.208000 0.000407 153 0.012400 0.000436 321 0.176000 0.000246 154 0.024000 0.000169 322 0.034900 0.000169 155 0.399000 0.000425 323 0.041400 0.000194 156 0.002710 0.000237 324 0.020700 0.000360 157 0.022600 0.000169 325 0.018800 0.000362 158 0.026300 0.000169 326 0.032200 0.000294 159 0.032400 0.000169 327 0.450000 0.000169 160 0.034700 0.004270 328 0.159000 0.000344 161 0.008620 0.005790 329 0.030400 0.000276 162 0.357000 0.000574 330 0.021900 0.000364 163 0.007230 0.000295 331 0.081000 0.000351 164 0.015900 0.000313 332 0.061700 0.000474 165 0.014400 0.000389 333 0.056100 0.000416 166 0.017200 0.000337 334 0.094900 0.000449 167 0.008410 0.000319 335 0.045700 0.000495 168 0.028900 0.000503 nd = no data NAMPT cell proliferation assay PC3 cells were seeded in 96-well black plates (Corning #3904) at 500 cells/well in 90 1 of RPMI media containing 10% heat-inactivated FBS and incubated overnight at 37 C and 5% CO2 to allow cells to attach to wells. The following day, test compounds were serially diluted in neat DMSO to 1000X final concentrations prior to dilution with RPMI
media to 10X and 1% DMSO. Ten L of the 10X compounds were then transferred to wells containing cells to produce a dose response of 10-fold dilutions from 10 M to 1 x 10-5 M.
Cells were incubated for 5 days at 37 C and 5% CO2, then cell viability was measured using Cell Titer Glo reagent (Promega #G7571). Percent inhibition values were calculated and fitted to a sigmoidal dose response curves using Assay Explorer software to determine IC50s.
To assess whether inhibition of cell viability was due to NAMPT inhibition, the proliferation assay was also performed in the presence of 0.3 mM nicotinamide mononucleotide.
Table 2 shows the results of the cell proliferation assay.
Table 2 Cell Titer- Cell Titer-Example Glo - IC50 Example Glo - IC50 (1M) (1M) 1 0.0117 180 0.0677 2 0.0349 181 0.0243 3 4.68 182 0.00695 4 0.014 183 0.0633 0.0283 184 0.0612 6 0.0306 185 0.00918 7 0.0385 186 0.00345 8 7.03 187 0.0863 9 0.00682 188 0.00225 0.0389 189 0.0217 11 0.00933 190 0.00583 12 0.0101 191 0.00746 13 0.514 192 0.0632 14 6.68 193 0.0137 0.0999 194 0.69 16 nd 195 0.00866 17 0.0368 196 0.0646 18 0.0658 197 0.0227 19 0.192 198 0.0476 0.123 199 nd 21 0.0337 200 0.017 22 0.276 201 nd 23 0.195 202 0.0655 24 0.113 203 nd 0.0271 204 0.0604 26 0.172 205 nd 27 0.0092 206 0.0634 28 0.0642 207 nd 29 0.0661 208 0.0737 0.125 209 nd 31 0.0389 210 0.218 32 0.0587 211 nd 33 0.0687 212 0.0206 34 0.0624 213 nd 0.0902 214 0.0437 36 0.0595 215 nd 37 0.0729 216 0.0205 38 0.0836 217 nd 39 0.115 218 0.188 0.0264 219 nd 41 0.0698 220 0.00415 42 0.10 221 nd 43 0.028 222 0.0119 44 0.0385 223 nd 0.0634 224 0.0207 46 0.0442 225 nd 47 0.064 226 0.20 48 0.0958 227 nd 49 0.0801 228 nd 0.00857 229 nd 51 0.00178 230 nd 52 0.00678 231 0.361 53 0.0138 232 nd 54 0.0589 233 0.97 55 0.00806 234 nd 56 0.00883 235 0.993 57 0.00358 236 nd 58 0.00786 237 0.346 59 0.0685 238 0.746 60 0.0749 239 1.51 61 0.0307 240 nd 62 0.0697 241 0.252 63 0.012 242 nd 64 0.0711 243 1.31 65 0.0622 244 nd 66 0.0822 245 0.617 67 0.0785 246 0.622 68 0.0591 247 0.471 69 0.0613 248 1.38 70 0.0731 249 0.541 71 0.0107 250 0.664 72 0.0777 251 0.212 73 0.0845 252 0.401 74 0.0153 253 0.622 75 0.0693 254 nd 76 0.0224 255 0.734 77 0.0173 256 nd 78 0.056 257 nd 79 0.0414 258 0.0683 80 0.0632 259 0.0647 81 0.0178 260 0.0949 82 0.00724 261 0.0713 83 0.00685 262 0.0516 84 0.022 263 0.365 85 0.0489 264 0.0351 86 0.00548 265 0.691 87 0.00604 266 0.207 88 0.109 267 0.0178 89 0.18 268 0.0228 90 0.686 269 0.0167 91 0.111 270 0.0195 92 0.608 271 0.06037 93 0.0876 272 0.22243 94 0.598 273 7.27 95 0.0662 274 0.0685 96 0.171 275 0.0345 97 0.0767 276 0.01 98 0.0709 277 0.0631 99 0.0493 278 0.0306 100 0.0273 279 0.0476 101 0.0681 280 0.114 102 0.0679 281 0.125 103 0.0981 282 0.0143 104 0.0951 283 0.0617 105 0.0609 284 0.0223 106 0.576 285 0.0265 107 0.00599 286 0.00766 108 0.0815 287 0.0374 109 0.11 288 0.084 110 0.0118 289 0.0352 111 0.0292 290 0.0103 112 0.906 291 0.15 113 0.113 292 0.0878 114 0.00811 293 0.0705 115 0.00611 294 0.0609 116 0.135 295 0.0665 117 0.00983 296 0.0198 118 0.0777 297 0.0182 119 0.0769 298 0.0112 120 0.078 299 0.0146 121 0.00773 300 0.0171 122 0.00881 301 0.0219 123 0.00881 302 0.141 124 0.00775 303 0.0135 125 0.00812 304 0.262 126 0.00738 305 1.82 127 0.071 306 0.298 128 0.00836 307 0.00987 129 0.0113 308 0.00961 130 0.0787 309 0.0111 131 0.00818 310 0.00276 132 0.00777 311 0.0471 133 0.00443 312 0.211 134 0.0283 313 4.59 135 0.00869 314 0.0839 136 0.00742 315 0.05416 137 0.0516 316 0.0173 138 0.00838 317 0.0554 139 0.00781 318 0.156 140 0.0263 319 0.0307 141 0.00833 320 0.155 142 0.00791 321 0.119 143 0.0822 322 0.01251 144 0.00904 323 0.051 145 0.0739 324 0.00624 146 0.00907 325 0.0113 147 0.00513 326 0.0165 148 0.0167 327 0.189 149 0.0765 328 0.0527 150 1.05 329 0.0145 151 0.0154 330 0.0123 152 0.00604 331 0.0424 153 0.00803 332 0.0222 154 0.00789 333 0.0224 155 0.13 334 0.0324 156 0.0747 335 0.0158 157 0.0378 336 0.222 158 0.0365 337 0.0555 159 0.0745 338 0.587 160 0.639 339 0.668 161 0.905 340 2.45 162 0.269 341 8.94 163 0.0344 342 0.39 164 0.0259 343 0.831 165 0.0619 344 7.67 166 0.0664 345 1.13 167 0.0235 346 0.843 168 0.045 347 1.55 169 0.00798 348 0.803 170 0.0148 349 0.772 171 0.022 350 0.743 172 0.0345 351 0.655 173 0.0564 352 0.607 174 0.0244 353 nd 175 0.0675 354 0.994 176 0.0889 355 7.31 177 0.074 356 0.791 178 0.075 357 0.703 179 0.0769 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, Waldenstrom'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-I3 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-phthalazinediy1 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; DMS0 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=HCImeans 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride; Fmoc means fluorenylmethoxycarbonyl; HATU
means 0-(7-azabenzotriazol-1-y1)-N,N'N'N'-tetramethyluronium hexafluorophosphate;
HMPA
means hexamethylphosphoramide; IPA means isopropyl alcohol; MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS
means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine;
PPh3 means triphenylphosphine.
The following schemes are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
Schemes Scheme 1 .NH2 x1 N'X2 X1 N'X2 R2 ))L
(2) 1"-7 -- X)YLR1 -ON 11 R1 HN-M1 Ri R2- N y (1) (3) 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 -y1) carbonate and a base such as but not limited to diisopropylethylamine to provide compounds of formula (3).
The reaction is typically performed at ambient temperature in a solvent such as but not limited to acetonitrile.

Scheme 2 xl N' X2 X1 N' X2 Y)-CC\X R1 H X R1 is NH2 HN -01 Ri =N y N -01 R1 (1) 0 (4) _ >h_r N OyN

X1 Rio N' X2 IIOH X1 N' X2 H X R1 0 (6) H 0-CC\X R1 ___________ . NN--011 Ri ___________ > si N y N -011 R1 II
SI 0 (5) 0 (7) HN Rio N
Rio H
Y

0(8) , X1 N' X2 H )< R1 is N y N -OWN R1 Rio N (9) 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 -y1) 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 R1 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-dimethylaminopropy1)-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 R1 is as described herein, to provide compounds of formula (9), which are representative of compounds of Formula (I). The reaction is typically performed in the presence of a reducing agent such as but not limited to sodium triacetoxyborohydride and acetic acid in a solvent such as but not limited to methanol and may be performed at an elevated temperature.
Scheme 3 x.?N. x2 X1 N, X2 0 HN -40 R1 0 csICX y-R1 Nr-A = NH2 (1) 401 Ny"-" R1 0 (10) X1 N .X2 X1 N X2 0 (6) =N N.** R1 Nyõ,,,, R1 1-111¨\ A R10 N30 = 0 (12) (11) 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 -y1) 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 R1 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-dimethylaminopropy1)-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 April 2011), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw0 Ver. 9Ø7 (CambridgeSoft, Cambridge, MA).
Experimentals Example 1 N- [4-( {1- [(2S)-2-methylbutanoyl]azetidin-3-y1} oxy)pheny1]-3 -(pyridin-3 -yl)azetidine- 1-carb oxamide Example lA
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't 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 (1g, 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-y1) 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-yOpyridine 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)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide To a 20 mL vial was added tert-butyl 3-(4-(3-(pyridin-3-34)azetidine-1-carboxamido)phenoxy) azetidine-l-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 lE
(S)-N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide N-(4-(azetidin-3-yloxy)pheny1)-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-dimethylaminopropy1)-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)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) 6 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) .
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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.62 - (ESI(+)) (4- {[1-(tetrahydro- 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)azetidi 7H), 3.64 - 3.53 (m, 1H), 3.09 - 2.85 (m, ne-l-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) 6 8.49 (d, J
(ESI(+)) y1)-N-(4-{[1- = 2.8 Hz, 1H), 8.46 (t, J= 1.8 Hz, 1H), 8.37 m/e 497 (tetrahydro-2H- (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)azetidi 7H), 3.25 - 3.14 (m, 2H), 2.27 (d, J= 1.4 ne-l-carboxamide Hz, 1H), 2.00 - 1.77 (m, 3H), 1.66 - 1.33 (m, 4H), 1.32 - 1.04 (m, 2H) 4 N-[4-({1-[(25)-2- 1H NMR (300 MHz, DMSO-d6) 6 8.59 -(ESI(+)) methylbutanoyl]piper 8.46 (m, 2H), 8.36 (s, 1H), 7.86 (dt, J= 7.9, m/e 437 idin-4- 2.0 Hz, 1H), 7.45 - 7.35 (m, 3H), 6.92 -(M+H) yl}oxy)pheny1]-3- 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), 1.99 - 1.79 carboxamide (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) 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) [4-({1-[(2R)- = 2.4 Hz, 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), 4.56 - 4.44 yl}oxy)phenyl]azetidi (m, 1H), 4.36 (t, J = 8.1 Hz, 1H), 3.99 -ne-l-carboxamide 3.66 (m, 7H), 2.11 - 1.69 (m, 6H), 1.64 -1.38 (m, 2H) 6 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.59 - (ESI(+)) (4-{[1-(3,3,3- 8.45 (m, 2H), 8.37 (s, 1H), 7.86 (dt, J = 7.9, m/e 463 trifluoropropanoyl)pi 2.0 Hz, 1H), 7.45 - 7.35 (m, 3H), 6.92 - (M+H) peridin-4- 6.85 (m, 2H), 4.58 - 4.42 (m, 1H), 4.36 (t, J
yl]oxy}phenyl)azetidi = 8.1 Hz, 1H), 4.01 - 3.74 (m, 4H), 3.66 (q, ne-l-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) 6 16.84 - (ESI(+)) 2- 16.76 (m, 1H), 8.56 (d, J= 2.3 Hz, 1H), m/e 439 methylpropanoyl)pip 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.37 (s, 1H), (M+H) eridin-4- 7.86 (dt, J = 7.9, 2.0 Hz, 1H), 7.45 - 7.35 yl]oxy}pheny1)-3- (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) 6 8.41 (d, J (ESI(+)) y1)-N-(4-{[1- = 2.4 Hz, 1H), 8.35 (s, 1H), 7.75 (dd, J = m/e (tetrahydro-2H- 8.0, 2.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.27 (M+H) pyran-4- (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)azetidi 2H), 3.99 - 3.57 (m, 9H), 2.45 (s, 1H), 2.27 ne-l-carboxamide (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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J
(ESI(+)) [4-({1-[(2R)- = 2.3 Hz, 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]azetidi 1H), 4.43 - 4.24 (m, 4H), 4.20 - 4.07 (m, ne-l-carboxamide 1H), 4.09 - 3.63 (m, 6H), 2.16 - 1.70 (m, 4H) 29 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J
(ESI(+)) [4-({1-[(25)- = 2.4 Hz, 1H), 8.51 - 8.39 (m, 2H), 8.40 (s, m/e tetrahydrofuran-2- 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.62 - (M+H) ylcarbonyl]azetidin- 7.37 (m, 3H), 6.79 - 6.72 (m, 2H), 5.02 -3- 4.91 (m, 1H), 4.73 - 4.60 (m, 1H), 4.42 -yl}oxy)phenyl]azetidi 4.25 (m, 4H), 4.19 - 4.09 (m, 1H), 4.02 -ne-l-carboxamide 3.63 (m, 6H), 2.14 - 1.70 (m, 4H) 30 N-(4- {[1-(2-hydroxy- 1H NMR (300 MHz, DMSO-d6) 6 8.58 - (ESI(+)) 2- 8.45 (m, 1H), 8.40 (s, 1H), 7.86 (dt, J= 7.9, m/e methylpropanoyl)azet 2.0 Hz, 1H), 7.45 - 7.35 (m, 3H), 6.78 - (M+H) idin-3- 6.71 (m, 2H), 5.13 (s, 1H), 5.00 - 4.73 (m, yl]oxy}pheny1)-3- 2H), 4.36 (d, J = 15.9 Hz, 2H), 4.29 - 4.22 (pyridin-3- (m, 2H), 3.98 - 3.85 (m, 3H), 3.78 - 3.69 yl)azetidine- 1- (m, 1H), 1.25 (s, 6H) carboxamide 31 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) [4-({1-[(2S)- = 2.3 Hz, 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 =
yl}oxy)phenyl]azetidi 3.1 Hz, 1H), 4.36 (d, J= 15.9 Hz, 2H), 4.01 ne-l-carboxamide - 3.67 (m, 7H), 2.11 - 1.68 (m, 6H), 1.65 -1.33 (m, 2H) 32 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) (4- {[1-(thiophen-2- = 2.2 Hz, 1H), 8.59 - 8.45 (m, 2H), 8.38 (s, m/e ylcarbonyl)piperidin- 1H), 7.86 (dt, J = 7.9, 2.0 Hz, 1H), 7.80 - (M+H) 4- 7.69 (m, 1H), 7.45 - 7.36 (m, 4H), 7.12 yl]oxy}phenyl)azetidi (ddd, J = 5.0, 3.6, 0.5 Hz, 1H), 6.94 - 6.87 ne-l-carboxamide (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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) (4- {[1-(thiophen-3- = 2.1 Hz, 1H), 8.59 - 8.45 (m, 2H), 8.37 (s, m/e 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 yl]oxy}phenyl)azetidi Hz, 1H), 7.45 - 7.35 (m, 3H), 7.21 (dd, J =
ne-l-carboxamide 4.9, 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) 6 8.56 (d, J (ESI(+)) acetylpiperidin-4- = 2.2 Hz, 1H), 8.59 - 8.45 (m, 2H), 8.37 (s, m/e yl)carbonyl]piperidin 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.45 - (M+H) -4-y1} oxy)pheny1]-3- 7.35 (m, 3H), 6.92 - 6.85 (m, 2H), 4.56 -(pyridin-3- 4.42 (m, 1H), 4.36 (t, J= 7.9 Hz, 3H), 4.02 yl)azetidine- 1- - 3.71 (m, 6H), 3.15 - 3.02 (m, 1H), 2.98 -carboxamide 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) 6 8.56 (d, J (ESI(+)) methylcyclopropyl)ca = 2.0 Hz, 1H), 8.59 - 8.46 (m, 2H), 8.36 (s, m/e 435 rbonyl]piperidin-4- 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.45 - (M+H) yl}oxy)pheny1]-3- 7.36 (m, 3H), 6.92 - 6.85 (m, 2H), 4.56 -(pyridin-3- 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), 2.03 -carboxamide 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) 6 8.56 (d, J (ESI(+)) 1H-pyrrol-2- = 2.3 Hz, 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-y1} oxy)pheny1]-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), 6.02 yl)azetidine- 1- (dd, J = 3.7, 2.5 Hz, 1H), 4.54 (p, J = 3.8 carboxamide Hz, 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) 6 8.57 (dd, (ESI(+)) (morpholin-4- J= 6.8, 1.7 Hz, 1H), 8.52 - 8.42 (m, 1H), m/e yl)propanoyl]piperidi 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), (M+H) n-4-yl}oxy)pheny1]- 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) 6 8.56 (d, J (ESI(+)) methylpiperazin-1- = 2.4 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 505 yl)propanoyl]piperidi 1H), 8.37 (s, 1H), 7.94 - 7.82 (m, 1H), 7.49 (M+H) n-4-yl}oxy)pheny1]- - 7.20 (m, 4H), 6.91 - 6.84 (m, 2H), 4.55 -3-(pyridin-3- 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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J
(ESI(+)) [4-({1-[3-(pyrrolidin- = 2.3 Hz, 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]piperidi 1H), 7.49 - 7.33 (m, 4H), 6.93 - 6.81 (m, n-4- 3H), 4.54 - 4.28 (m, 4H), 3.98 - 3.64 (m, yl}oxy)phenyl]azetidi 7H), 2.71 -2.62 (m, 2H), 1.98 - 1.79 (m, ne-l-carboxamide 3H), 1.75 - 1.61 (m, 5H), 1.62 - 1.39 (m, 3H) 40 N-(4- {[1- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) (cyclopropylacetyl)pi = 2.1 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, m/e 435 peridin-4- 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, (M+H) yl]oxy}pheny1)-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 yl)azetidine-1- Hz, 2H), 3.98 - 3.79 (m, 4H), 3.76 - 3.59 carboxamide (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) 6 8.56 (d, J (ESI(+)) methylpentanoyl)pipe = 2.2 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 451 ridin-4- 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, (M+H) yl]oxy}pheny1)-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), 3.77 carboxamide - 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) 6 8.56 (d, J (ESI(+)) methylpentanoyl)pipe = 2.2 Hz, 1H), 8.48 (dd, J= 4.7, 1.5 Hz, m/e 451 ridin-4- 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, (M+H) yl]oxy}pheny1)-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), 3.76 carboxamide ¨ 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) 6 8.56 (d, J (ESI(+)) butanoylpiperidin-4- = 2.0 Hz, 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 carboxamide Hz, 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) 6 8.56 (d, J (ESI(+)) dimethylpropanoyl)pi = 2.0 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, m/e 437 peridin-4- 1H), 8.37 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, (M+H) yl]oxy}pheny1)-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 yl)azetidine-1- Hz, 2H), 3.99 ¨ 3.77 (m, 5H), 1.99 ¨ 1.83 carboxamide (m, 2H), 1.62 ¨ 1.35 (m, 2H), 1.20 (s, 9H) 45 N-(4- {[1-(3,3- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) dimethylbutanoyl)pip = 2.0 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, m/e 451 eridin-4- 1H), 8.36 (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, (M+H) yl]oxy}pheny1)-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 yl)azetidine-1- Hz, 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) 6 8.56 (d, J (ESI(+)) (ethoxyacetyl)piperid = 2.1 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, m/e 439 in-4-yl]oxy}pheny1)- 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 carboxamide Hz, 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) 6 8.58 ¨ (ESI(+)) (cyclopropylcarbonyl 8.45 (m, 2H), 8.36 (s, 1H), 7.86 (dt, J= 7.9, m/e 421 )piperidin-4- 2.0 Hz, 1H), 7.44 ¨ 7.35 (m, 3H), 6.92 ¨ (M+H) yl]oxy}pheny1)-3- 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), 3.58 yl)azetidine-1- ¨ 3.38 (m, 1H), 3.28 ¨ 3.08 (m, 1H), 2.05 ¨
carboxamide 1.79 (m, 3H), 1.49 (bs, 2H), 0.77 ¨ 0.63 (m, 4H) 48 N-(4- {[1- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J (ESI(+)) (methoxyacetyl)piper = 2.2 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 425 idin-4- 1H), 8.37 (s, 1H), 7.94 ¨ 7.78 (m, 1H), 7.49 (M+H) yl]oxy}pheny1)-3- ¨ 7.31 (m, 3H), 6.96 ¨ 6.81 (m, 2H), 4.59 ¨
(pyridin-3- 4.44 (m, 1H), 4.35 (t, J= 8.0 Hz, 1H), 4.09 yl)azetidine-1- (s, 2H), 4.01 ¨ 3.73 (m, 4H), 3.57 (d, J=

carboxamide 12.9 Hz, 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-y1)-N- (ESI(+)) (4-{[(3R)-1- m/e 465 (tetrahydro-2H- (M+H) pyran-4-ylacetyl)pyrrolidin-3-y1]oxy}phenyl)azetidi ne-l-carboxamide 77 N-(4-{[(3R)-1-(2- (ESI(+)) methylpropanoyl)pyrr m/e 409 olidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 78 3-(pyridin-3-y1)-N- (ESI(+)) [4-({(3R)-1-[(2S)- m/e 437 tetrahydrofuran-2- (M+H) ylcarbonyl]pyrrolidin yl}oxy)phenyl]azetidi ne-l-carboxamide 79 3-(pyridin-3-y1)-N- (ESI(+)) [4-({(3R)-1-[(2R)- m/e 437 tetrahydrofuran-2- (M+H) ylcarbonyl]pyrrolidin yl}oxy)phenyl]azetidi ne-l-carboxamide 80 3-(pyridin-3-y1)-N- (ESI(+)) (4-{[(3R)-1- m/e 437 (tetrahydrofuran-3- (M+H) ylcarbonyl)pyrrolidin yl]oxy}phenyl)azetidi ne-l-carboxamide 81 N-(4-{[(3R)-1- (ESI(+)) (cyclopropylacetyl)py m/e 421 rrolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 82 N-(4-{[(3R)-1-(2- (ESI(+)) hydroxy-2- m/e 424 methylpropanoyl)pyrr (M+H) olidin-3-yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 83 N-(4-{[(3R)-1- (ESI(+)) benzoylpyrrolidin-3- m/e 443 yl]oxy}pheny1)-3- (M+H) (pyridin-3-yl)azetidine-l-carboxamide 84 3-(pyridin-3-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, Temp (ESI(+)) (4-{[(3R)-1-(3,3,3- =90 C) 6 8.73 (d, J= 2.1 Hz, 1H), 8.64 (d, m/e trifluoropropanoyl)py J= 4.4 Hz, 1H), 8.33 ¨ 8.26 (m, 1H), 7.83 ¨ (M+H) rrolidin-3- 7.76 (m, 1H), 7.42 ¨ 7.35 (m, 2H), 6.89 ¨
yl]oxy}phenyl)azetidi 6.81 (m, 2H), 5.01 ¨ 4.90 (m, 1H), 4.47 ¨
ne-l-carboxamide 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) 6 8.76 (bs, (ESI(+)) (cyclopropylcarbonyl 1H), 8.69 ¨ 8.62 (m, 1H), 8.41 (s, 1H), 8.26 m/e 407 )pyrrolidin-3- (dd, J= 5.0, 3.0 Hz, 1H), 7.73 (ddd, J= 7.6, (M+H) yl]oxy}pheny1)-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), 4.08 carboxamide ¨ 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) 6 8.80 ¨ (ESI(+)) 2- 8.64 (m, 2H), 8.68 (d, J= 4.3 Hz, 1H), 8.41 m/e methylbutanoyl]pyrro (s, 1H), 8.34 ¨ 8.25 (m, 1H), 7.77 (ddd, J= (M+H) lidin-3- 7.9, 5.3, 2.5 Hz, 1H), 7.45 ¨ 7.37 (m, 2H), yl}oxy)pheny1]-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), 2.20 ¨
carboxamide 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) 6 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}pheny1)-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), 6.90 ¨ 6.80 yl)azetidine-1- (m, 2H), 4.95 (d, J= 22.7 Hz, 1H), 4.45 ¨
carboxamide 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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.76 (s, (ESI(+)) (4-{[(35)-1- 1H), 8.66 (d, J= 4.5 Hz, 1H), 8.41 (s, 1H), m/e (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), 4.80 ¨ 4.39 yl]oxy}phenyl)azetidi (m, 4H), 4.38 (q, J= 5.7 Hz, 3H), 4.10 ¨
ne-l-carboxamide 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-{[(35)-1-(2- 1H NMR (300 MHz, DMSO-d6) 6 8.78 (bs, (ESI(+)) methylpropanoyl)pyrr 1H), 8.68 (d, J= 4.9 Hz, 1H), 8.41 (s, 1H), m/e 409 olidin-3- 8.35 ¨ 8.27 (m, 1H), 7.82 ¨ 7.73 (m, 1H), (M+H) yl]oxy}pheny1)-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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.79 (bs, (ESI(+)) [4-({(3S)-1-[(2S)- 1H), 8.68 (d, J= 5.3 Hz, 1H), 8.41 (s, 1H), m/e 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]azetidi 3H), 4.08 - 3.92 (m, 3H), 3.86 - 3.44 (m, ne-l-carboxamide 6H), 2.28 - 1.70 (m, 6H) 91 3-(pyridin-3-y1)-N- (ESI(+)) [4-({(35)-1-[(2R)- m/e 437 tetrahydrofuran-2- (M+H) ylcarbonyl]pyrrolidin yl} oxy)phenyl]azetidi ne-l-carboxamide 92 3-(pyridin-3-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.81 (bs, (ESI(+)) (4-{[(35)-1- 1H), 8.70 (d, J= 5.4 Hz, 1H), 8.42 (s, 1H), m/e (tetrahydrofuran-3- 8.36 (dd, J= 9.0, 2.5 Hz, 1H), 7.86 - 7.77 (M+H) ylcarbonyl)pyrrolidin (m, 1H), 7.45 - 7.38 (m, 2H), 6.94 - 6.72 -3- (m, 2H), 5.75 (s, 1H), 5.03 - 4.89 (m, 1H), yl]oxy}phenyl)azetidi 4.40 - 4.33 (m, 2H), 4.07 - 3.73 (m, 6H), ne-l-carboxamide 3.55 - 3.49 (m, 2H), 3.43 - 3.09 (m, 2H), 2.29 - 1.86 (m, 5H) 93 N-(4-{[(35)-1- 1H NMR (300 MHz, DMSO-d6) 6 8.80 (bs, (ESI(+)) (cyclopropylacetyl)py 1H), 8.69 (d, J= 5.3 Hz, 1H), 8.41 (s, 1H), m/e 421 rrolidin-3- 8.38 - 8.29 (m, 1H), 7.79 (ddd, J= 7.9, 5.4, (M+H) yl]oxy}pheny1)-3- 2.3 Hz, 1H), 7.44 - 7.37 (m, 2H), 6.91 -(pyridin-3- 6.76 (m, 2H), 6.71 - 5.35 (m, 2H), 5.01 -yl)azetidine-1- 4.88 (m, 1H), 4.40 - 4.33 (m, 2H), 4.06 -carboxamide 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- {[(35)-1-(2- 1H NMR (300 MHz, DMSO-d6) 6 8.78 (d, J (ESI(+)) hydroxy-2- = 2.1 Hz, 1H), 8.67 (dd, J= 5.2, 1.4 Hz, m/e 425 methylpropanoyl)pyrr 1H), 8.41 (s, 1H), 8.34 - 8.26 (m, 1H), 7.81 (M+H) olidin-3- - 7.73 (m, 1H), 7.31 (dd, J= 56.7, 9.0 Hz, yl]oxy}pheny1)-3- 2H), 6.89 - 6.81 (m, 2H), 4.92 (d, J= 25.9 (pyridin-3- Hz, 1H), 4.43 -4.31 (m, 2H), 4.13 - 3.92 yl)azetidine-1- (m, 4H), 3.87 - 3.56 (m, 2H), 3.44 (dd, J=
carboxamide 22.1, 12.9 Hz, 2H), 2.15 - 1.90 (m, 2H), 1.34 - 1.23 (m, 4H), 1.20 (s, 1H) 95 N-(4-{[(35)-1- 1H NMR (300 MHz, DMSO-d6) 6 8.80 - (ESI(+)) benzoylpyrrolidin-3- 8.74 (m, 1H), 8.70 - 8.63 (m, 1H), 8.45 - m/e yl]oxy}pheny1)-3- 8.36 (m, 1H), 8.33 - 8.24 (m, 1H), 7.81 - (M+H) (pyridin-3- 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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 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 trifluoropropanoyl)py 8.30 - 8.22 (m, 1H), 7.78 - 7.69 (m, 1H), (M+H) rrolidin-3- 7.45 - 7.38 (m, 2H), 6.91 - 6.81 (m, 2H), yl]oxy}phenyl)azetidi 4.97 (d, J = 20.8 Hz, 2H), 4.40 - 4.32 (m, ne-l-carboxamide 2H), 4.04 - 3.91 (m, 3H), 3.83 - 3.20 (m, 5H), 2.29 - 1.97 (m, 2H) 97 N-(4-{[(35)-1- 1H NMR (300 MHz, DMSO-d6) 6 8.78 (s, (ESI(+)) (cyclopropylcarbonyl 1H), 8.68 (d, J= 5.3 Hz, 1H), 8.41 (s, 1H), m/e 407 )pyrrolidin-3- 8.34 - 8.26 (m, 1H), 7.81 - 7.72 (m, 1H), (M+H) yl]oxy}pheny0-3- 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-({(35)-1-[(25)- 1H NMR (300 MHz, DMSO-d6) 6 8.78 (bs, (ESI(+)) 2- 1H), 8.68 (d, J= 5.3 Hz, 1H), 8.41 (s, 1H), m/e methylbutanoyl]pyrro 8.35 - 8.27 (m, 1H), 7.82 - 7.73 (m, 2H), (M+H) lidin-3- 7.40 (t, J= 6.2 Hz, 2H), 6.90 - 6.80 (m, yl}oxy)pheny1]-3- 2H), 4.95 (d, J = 24.2 Hz, 2H), 4.43 - 4.32 (pyridin-3- (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-{[(35)-1- 1H NMR (300 MHz, DMSO-d6) 6 8.80 (bs, (ESI(+)) butanoylpyrrolidin-3- 1H), 8.69 (d, J= 5.3 Hz, 1H), 8.42 (s, 1H), m/e 409 yl]oxy}pheny0-3- 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), 7.01 -yl)azetidine-1- 6.71 (m, 2H), 5.03 -4.89 (m, 2H), 4.43 -carboxamide 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/D20) (ESI(+)) (cyclopropylacetyl)az ppm 8.56 (d, J=1.83 Hz, 1 H) 8.48 (dd, m/e 407 etidin-3- J=4.58, 1.53 Hz, 1 H) 8.40 (s, 1 H) 7.84 - (M+H) yl]oxy}pheny0-3- 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) 4.51 yl)azetidine-1- (dd, J=9.00, 6.87 Hz, 1 H) 4.36 (t, J=8.24 carboxamide Hz, 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/D20) (ESI(+)) ylcarbonyl)azetidin- ppm 8.58 (s, 1 H) 8.50 (d, J=4.27 Hz, 1 H) m/e 419 3-yl]oxy}pheny1)-3- 8.41 (s, 1 H) 7.84 - 7.91 (m, 2 H) 7.42 - (M+H) (pyridin-3- 7.46 (m, 3 H) 7.07 - 7.08 (m, 1 H) 6.76 -yl)azetidine-1- 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/D20 (ESI(-0) pentanoylazetidin-3- Temp=90 C) 6 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/D20, (ESI(-0) methoxyethoxy)acety Temp=90 C) 6 ppm 8.61 ¨ 8.40 (m, 2H), m/e 441 1]azetidin-3- 7.90 ¨ 7.73 (m, 1H), 7.51 ¨ 7.31 (m, 3H), (M+H) yl}oxy)pheny1]-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), 3.52 ¨
carboxamide 3.40 (m, 2H) 119 N-(4-{[1- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(-0) (ethoxyacetyl)azetidi Temp=90 C) 6 ppm 8.66 ¨ 8.29 (m, 2H), m/e 411 n-3-yl]oxy}pheny1)- 7.81 (dt, J= 7.9, 2.0 Hz, 1H), 7.57 ¨ 7.35 (M+H) 3 -(pyridin-3 - (m, 3H), 6.84 ¨ 6.65 (m, 2H), 5.19 ¨ 4.85 yl)azetidine- 1- (m, 1H), 4.39 (t, J= 8.4 Hz, 4H), 4.06 ¨
carboxamide 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/D20, (ESI(-0) (methoxyacetyl)azeti Temp=90 C) 6 ppm 8.65 ¨ 8.38 (m, 2H), m/e 397 din-3- 7.91 ¨ 7.72 (m, 1H), 7.49 ¨ 7.32 (m, 3H), (M+H) yl]oxy}pheny1)-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/D20, (ESI(-0) methylpentanoyl)azet Temp=90 C) 6 ppm 8.61 ¨ 8.52 (m, 1H), m/e 423 idin-3- 8.52 ¨ 8.41 (m, 1H), 7.88 ¨ 7.72 (m, 1H), (M+H) yl]oxy}pheny1)-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/D20, (ESI( )) bicyclo[2.2.1]hept-2- Temp=90 C) 6 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)pheny1]-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/D20, (ESI(-0) dimethylbutanoyl)aze Temp=90 C) 6 ppm 8.54 (t, J= 3.5 Hz, 1H), m/e 423 tidin-3- 8.48 ¨ 8.41 (m, 1H), 7.95 ¨ 7.69 (m, 1H), (M+H) yl]oxy}pheny1)-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/D20, (ESI(+)) methylpentanoyl)azet Temp=90 C) 6 ppm 8.55 (t, J= 3.7 Hz, 1H), m/e 423 idin-3- 8.49 ¨ 8.40 (m, 1H), 7.92 ¨ 7.72 (m, 1H), (M+H) yl]oxy}pheny1)-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 carboxamide Hz, 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/D20, (ESI(+)) methylcyclopropyl)ca Temp=90 C) 6 ppm 8.54 (t, J= 3.8 Hz, 1H), m/e 407 rbonyl]azetidin-3- 8.52 ¨ 8.43 (m, 1H), 7.89 ¨ 7.74 (m, 1H), (M+H) yl}oxy)pheny1]-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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4-{[1-(4,4,4- Temp=90 C) 6 ppm 8.55 (t, J= 3.6 Hz, 1H), m/e 449 trifluorobutanoyl)azet 8.52 ¨ 8.39 (m, 1H), 7.89 ¨ 7.74 (m, 1H), (M+H) idin-3- 7.43 ¨ 7.28 (m, 3H), 6.83 ¨ 6.69 (m, 2H), yl]oxy}phenyl)azetidi 5.10 ¨ 4.88 (m, 1H), 4.48 ¨ 4.30 (m, 3H), ne-l-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/D20, (ESI(+)) methylpropanoyl)azet Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 395 idin-3- 1H), 8.51 ¨ 8.38 (m, 1H), 7.88 ¨ 7.76 (m, (M+H) yl]oxy}pheny1)-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 yl)azetidine- 1- Hz, 4H), 3.97 (dd, J= 8.0, 6.0 Hz, 3H), 3.93 carboxamide ¨ 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/D20, (ESI(+)) dimethylpropanoyl)az Temp=90 C) 6 ppm 8.55 (dd, J= 6.6, 1.8 m/e 409 etidin-3- Hz, 1H), 8.52 ¨ 8.43 (m, 1H), 7.88 ¨ 7.74 (M+H) yl]oxy}pheny1)-3- (m, 1H), 7.47 ¨ 7.27 (m, 3H), 6.85 ¨ 6.60 (pyridin-3- (m, 2H), 5.05 ¨ 4.91 (m, 1H), 4.66 ¨ 4.46 yl)azetidine- 1- (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/D20, (ESI(+)) butanoylazetidin-3- Temp=90 C) 6 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/D20, (ESI(+)) propanoylazetidin-3- Temp=90 C) 6 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/D20, (ESI(-0) dimethylbutanoyl)aze Temp=90 C) 6 ppm 8.54 (t, J= 2.6 Hz, 1H), m/e 423 tidin-3- 8.51 ¨ 8.38 (m, 1H), 7.92 ¨ 7.73 (m, 1H), (M+H) yl]oxy}pheny1)-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/D20, (ESI( )) methylbutanoyl)azeti Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 409 din-3- 1H), 8.46 (dd, J= 4.7, 1.4 Hz, 1H), 7.89 ¨ (M+H) yl]oxy}pheny1)-3- 7.73 (m, 1H), 7.48 ¨ 7.30 (m, 3H), 6.87 ¨
(pyridin-3- 6.74 (m, 2H), 5.00 ¨ 4.89 (m, 1H), 4.39 (t, J
yl)azetidine-1- = 8.4 Hz, 4H), 4.08 ¨ 3.79 (m, 5H), 1.99 ¨
carboxamide 1.86 (m, 3H), 1.02 ¨ 0.85 (m, 6H) 133 N-(4-{[1-(3,3- 1H NMR (400 MHz, DMSO-d6/D20, (ESI( )) dimethylbutanoyl)aze Temp=90 C) 6 ppm 8.54 (d, J= 2.0 Hz, m/e 423 tidin-3- 1H), 8.46 (dd, J= 4.8, 1.4 Hz, 1H), 7.94 ¨ (M+H) yl]oxy}pheny1)-3- 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), 4.39 yl)azetidine-1- (t, J= 8.3 Hz, 3H), 3.96 (dd, J= 16.5, 8.5 carboxamide Hz, 3H), 3.88 (dd, J= 14.3, 6.0 Hz, 2H), 1.98 (s, 2H), 0.99 (s, 9H) 134 3-(pyridin-3-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(-0) (4- {[1-(3,3,3- Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 435 trifluoropropanoyl)az 1H), 8.51 ¨ 8.38 (m, 1H), 7.97 ¨ 7.74 (m, (M+H) etidin-3- 1H), 7.52 ¨ 7.27 (m, 3H), 6.87 ¨ 6.68 (m, yl]oxy}phenyl)azetidi 2H), 5.12 ¨ 4.93 (m, 1H), 4.58 (s, 1H), 4.44 ne-l-carboxamide ¨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/D20, (ESI(-0) methylcyclopropyl)ca Temp=90 C) 6 ppm 8.62 ¨ 8.52 (m, 1H), m/e 407 rbonyl]azetidin-3- 8.52 ¨ 8.36 (m, 1H), 7.90 ¨ 7.72 (m, 1H), (M+H) yl}oxy)pheny1]-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/D20, (ESI( )) methylpentanoyl)azet Temp=90 C) 6 ppm 8.54 (s, 1H), 8.46 (d, J m/e 423 idin-3- = 4.7 Hz, 1H), 7.81 (d, J= 7.9 Hz, 1H), (M+H) yl]oxy}pheny1)-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 carboxamide Hz, 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/D20, (ESI( )) acetylazetidin-3- Temp=90 C) 6 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), 7.85 ¨ (M+H) (pyridin-3- 7.77 (m, 1H), 7.46 ¨ 7.33 (m, 3H), 6.81 ¨
yl)azetidine-1- 6.69 (m, 2H), 5.05 ¨4.84 (m, 1H), 4.39 (t, J

carboxamide = 8.4 Hz, 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/D20, (ESI(+)) (cyclohexylacetyl)aze Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 449 tidin-3- 1H), 8.52 ¨ 8.36 (m, 1H), 7.85 ¨ 7.73 (m, (M+H) yl]oxy}pheny1)-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
carboxamide = 6.8 Hz, 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/D20, (ESI(+)) (cyclohexylcarbonyl) Temp=90 C) 6 ppm 8.54 (d, J= 2.2 Hz, m/e 435 azetidin-3- 1H), 8.51 ¨ 8.42 (m, 1H), 7.88 ¨ 7.74 (m, (M+H) yl]oxy}pheny1)-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 yl)azetidine-1- Hz, 4H), 4.04 ¨ 3.82 (m, 5H), 2.31 ¨ 2.15 carboxamide (m, 1H), 1.76 ¨ 1.57 (m, 6H), 1.38 ¨ 1.24 (m, 4H) 140 N-(4-{[1- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (cyclopropylcarbonyl Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 393 )azetidin-3- 1H), 8.49 ¨ 8.30 (m, 1H), 7.91 ¨ 7.72 (m, (M+H) yl]oxy}pheny1)-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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4- {[1-(thiophen-2- Temp=90 C) 6 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)azetidi 1H), 7.53 (dd, J= 3.7, 1.0 Hz, 1H), 7.49 ¨
ne-l-carboxamide 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/D20, (ESI(+)) (cyclopentylcarbonyl) Temp=90 C) 6 ppm 8.54 (d, J= 2.1 Hz, m/e 421 azetidin-3- 1H), 8.46 (dd, J= 4.8, 1.5 Hz, 1H), 7.81 (dt, (M+H) yl]oxy}pheny1)-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/D20, (ESI(+)) 4-ylacetyl)azetidin-3- Temp=90 C) 6 ppm 8.68 ¨ 8.50 (m, 1H), m/e 452 yl]oxy}pheny1)-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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4-{[1-(1,3-thiazol-5- Temp=90 C) 6 ppm 9.19 (s, 1H), 8.55 (d, J m/e 436 ylcarbonyl)azetidin- = 2.1 Hz, 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)azetidi 7.49 ¨ 7.32 (m, 3H), 6.87 ¨ 6.72 (m, 2H), ne-l-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/D20, (ESI(+)) dimethy1-1,2-oxazol- Temp=90 C) 6 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-y1} oxy)pheny1]-3- 5.03 (tt, J= 6.4, 4.1 Hz, 1H), 4.50 ¨ 4.36 (pyridin-3- (m, 4H), 4.06 ¨ 3.92 (m, 4H), 3.92 ¨ 3.82 yl)azetidine-1- (m, 1H), 3.20 (s, 1H), 2.44 (s, 3H), 2.24 (s, carboxamide 3H) 146 3-(pyridin-3-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4- {[1-(thiophen-3- Temp=90 C) 6 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)azetidi 7.55 (dd, J= 5.1, 2.9 Hz, 1H), 7.43 ¨ 7.34 ne-l-carboxamide (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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4- {[1-(1,3-thiazol-4- Temp=90 C) 6 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= (M+H) 3- 4.8, 1.5 Hz, 1H), 8.28 (d, J= 2.1 Hz, 1H), yl]oxy}phenyl)azetidi 7.91 ¨ 7.73 (m, 1H), 7.50 ¨ 7.30 (m, 3H), ne-l-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/D20, (ESI(+)) 5- Temp=90 C) 6 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= (M+H) 3-yl]oxy}pheny1)-3- 4.7, 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/D20, (ESI(+)) methylpiperazin-1- Temp=90 C) 6 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)pheny1]-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/D20, (ESI(+)) dimethyl-beta- Temp=90 C) 6 ppm 8.54 (s, 1H), 8.46 (d, J m/e 424 alanyl)azetidin-3- = 4.8 Hz, 1H), 7.80 (d, J= 7.8 Hz, 1H), (M+H) yl]oxy}pheny1)-3- 7.45 ¨ 7.29 (m, 3H), 6.76 (dd, J= 11.5, 4.7 (pyridin-3- Hz, 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), 4.05 ¨

carboxamide 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) 6 ppm 8.57 (d, J= 2.1 Hz, m/e 419 3-yl]oxy}pheny1)-3- 1H), 8.54 ¨ 8.47 (m, 1H), 8.43 (s, 1H), 8.19 (M+H) (pyridin-3- (s, 1H), 7.92 ¨ 7.84 (m, 1H), 7.76 (t, J= 1.6 yl)azetidine-1- Hz, 1H), 7.48 ¨ 7.40 (m, 3H), 6.80 ¨ 6.75 carboxamide (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/D20, (ESI(+)) methylcyclohexyl)car Temp=90 C) 6 ppm 8.60 ¨ 8.53 (m, 1H), m/e 449 bonyl]azetidin-3- 8.52 ¨ 8.42 (m, 1H), 7.81 (ddd, J= 7.9, 4.7, (M+H) yl}oxy)pheny1]-3- 1.5 Hz, 1H), 7.46 ¨ 7.32 (m, 3H), 6.80 ¨
(pyridin-3- 6.71 (m, 3H), 4.98 ¨ 4.90 (m, 1H), 4.56 ¨
yl)azetidine-1- 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/D20, (ESI(+)) (cyclopentylacetyl)az Temp=90 C) 6 ppm 8.54 (d, J= 2.2 Hz, m/e 435 etidin-3- 1H), 8.46 (dd, J= 4.8, 1.5 Hz, 1H), 7.81 (dt, (M+H) yl]oxy}pheny1)-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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4- {[1-(1,3-thiazol-2- Temp=90 C) 6 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 (M+H) 3- Hz, 1H), 7.92 (d, J= 3.2 Hz, 1H), 7.81 (dt, yl]oxy}phenyl)azetidi J= 7.9, 1.9 Hz, 1H), 7.48 ¨ 7.38 (m, 3H), ne-l-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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20, (ESI(+)) (4-{[1-(pyrrolidin-1- Temp=90 C) 6 ppm 8.54 (s, 1H), 8.46 (d, J m/e 436 ylacetyl)azetidin-3- = 4.3 Hz, 1H), 7.81 (dd, J= 7.9, 1.9 Hz, (M+H) yl]oxy}phenyl)azetidi 1H), 7.49 ¨ 7.34 (m, 3H), 6.81 ¨ 6.72 (m, ne-l-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}pheny1)-3- (M+H) (pyridin-3-yl)azetidine-1-carboxamide 298 N-(4-{[(3R)-1-(3- (ESI(+)) methylpentanoyl)pyrr m/e 437 olidin-3- (M+H) y1]oxy}pheny1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 300 N-(4-{[(3R)-1- (ESI(+)) (cyclopentylacetyl)py m/e 449 rrolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 301 N-[4-({(3R)-1-[(2- (ESI(+)) methylcyclopropyl)ca m/e 421 rbonyl]pyrrolidin-3- (M+H) yl} oxy)pheny1]-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}pheny1)-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}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 304 3-(pyridin-3-y1)-N- (ESI(+)) (4- { [(3R)-1- m/e 450 (pyrrolidin-1- (M+H) ylacetyl)pyrrolidin-3-yl]oxy}phenyl)azetidi ne-l-carboxamide 305 N-(4-{[(3R)-1-(5- (ESI(+)) oxo-D- m/e 450 prolyl)pyrrolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-l-carboxamide 306 N-(4- { [(3R)-1-(N,N- (ESI(+)) dimethyl-b eta- m/e 438 alanyl)pyrrolidin-3- (M+H) y1] oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 307 3 -(pyridin-3 -y1)-N- (ESI(+)) (4- { [(3R)-1-(1,3- m/e 450 thiazol-2- (M+H) ylcarbonyl)pyrrolidin yl] oxy} phenyl)azetidi ne-l-carboxamide 308 3 -(pyridin-3 -y1)-N- (ESI(+)) (4- { [(3R)-1- m/e 449 (thiophen-3- (M+H) ylcarbonyl)pyrrolidin yl] oxy} phenyl)azetidi ne-l-carboxamide 309 N-[4-( {(3R)-1-[(1- (ESI(+)) methylcyclopropyl)ca m/e 421 rbonyl]pyrrolidin-3- (M+H) yl} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 310 N-[4-( {(3R)-1-[(3- (ESI(+)) methylthiophen-2- m/e 463 yl)carbonyl]pyrrolidi (M+H) n-3-yl} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 311 3 -(pyridin-3 -y1)-N- (ESI(+)) (4- { [(3R)-1-(4,4,4- m/e 463 trifluorobutanoyl)pyrr (M+H) olidin-3-yl]oxy} phenyl)azetidi ne-l-carboxamide 312 N-[4-( {(3R)-1-[(4- (ESI(+)) methylpiperazin-1- m/e 479 yl)acetyl]pyrrolidin- (M+H) 3-y1} oxy)pheny1]-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 313 N-(4- { [(3R)-1-(5- (ESI(+)) oxo-L- m/e 450 pro lyl)pyrro lidin-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3-yl)azetidine-l-carboxamide 314 N-(4- { [(3R)-1-(3- (ESI(+)) ethoxypropanoyl)pyrr m/e 439 olidin-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 315 N-(4- { [(3R)-1-(4- (ESI(+)) methylpentanoyl)pyrr m/e 437 olidin-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 316 N- [4-( {(3R)-1- [(1- (ESI(+)) methylcyclohexyl)car m/e 463 bonyl]pyrrolidin-3- (M+H) yl} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 317 N-(4- { [(3R)-1- (ESI(+)) (cyclohexylacetyl)pyr m/e 463 rolidin-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 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-carb oxamide 319 N-(4- { [(3R)-1- (ESI(+)) prop anoylpyrro lidin- m/e 395 3 -yl] oxy} pheny1)-3- (M+H) (pyridin-3-yl)azetidine-l-carboxamide 320 N- [4-( {(3R)-1- [(2- (ESI(+)) methoxyethoxy)acety m/e 455 l]pyrrolidin-3- (M+H) yl} oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 321 N- [4-( {(3R)-1- [3- (ESI(+)) (morpholin-4- m/e 480 yl)prop anoyl]pyrro lid (M+H) in-3 -y1} oxy)pheny1]-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 322 N-(4- { [(3R)-1-(2,2- (ESI(+)) dimethylpropanoyl)p m/e 423 yrrolidin-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 323 N- [4-( {(3R)-1- [(5- (ESI(+)) methylthiophen-2- m/e 463 yl)carbonyl]pyrrolidi (M+H) n-3 -yl } oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 324 3 -(pyridin-3 -y1)-N- (ESI(+)) (4- { [(3R)-1- m/e 449 (thiophen-2- (M+H) ylcarbonyl)pyrrolidin yl] oxy} phenyl)azetidi ne-l-carboxamide 325 N-[4-( {(3R)-1- [(1- (ESI(+)) methyl-1H-pyrrol-2- m/e 446 yl)carbonyl]pyrrolidi (M+H) n-3 -yl } oxy)phenyl] -3 -(pyridin-3 -yl)azetidine-1-carb oxamide 326 N-(4- { [(3R)-1-(furan- (ESI(+)) 2- m/e 433 ylcarbonyl)pyrrolidin (M+H) -3-yl]oxy} pheny1)-3-(pyridin-3 -yl)azetidine-1-carb oxamide 327 N- [4-( {(3R)-1- [3- (ESI(+)) (pip eridin-1- m/e 478 yl)prop anoyl]pyrro lid (M+H) in-3 -yl } oxy)pheny1]-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 328 N-(4- { [(3R)-1- (ESI(+)) (ethoxyacetyl)pyrroli m/e 425 din-3- (M+H) yl]oxy} phenyl)-3 -(pyridin-3 -yl)azetidine-1-carb oxamide 329 N-(4- { [(3R)-1-(3,3- (ESI(+)) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 330 N-(4-{[(3R)-1-(2,2- (ESI(-0) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 331 N-(4-{[(3R)-1- (ESI(-0) (methoxyacetyl)pyrro m/e 411 lidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 332 N-(4-{[(3R)-1- (ESI(-0) (cyclohexylcarbonyl) m/e 449 pyrrolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 333 N-(4-{[(3R)-1-(3- (ESI(-0) methylbutanoyl)pyrro m/e 423 lidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 334 N-(4-{[(3R)-1- (ESI(-0) (cyclopentylcarbonyl) m/e 435 pyrrolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 335 N-(4-{[(3R)-1-(2,3- (ESI(-0) dimethylbutanoyl)pyr m/e 437 rolidin-3- (M+H) yl]oxy}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide Example 9 N-(4- {1-[(25)-2-methylbutanoy1]-1,2,3,6-tetrahydropyridin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide Example 9A

tert-butyl 4-(4-nitropheny1)-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-tetramethy1-1,3,2-dioxaborolan-2-y1)-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 m1). 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-aminopheny1)-5,6-dihydropyridine-1(2H)-carboxylate The title compound was prepared as described in Example 1B, substituting tert-butyl 4-(4-nitropheny1)-5,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 3-(4-nitrophenoxy)azetidine-l-carboxylate.
Example 9C
tert-butyl 4-(4-(3-(pyridin-3-yl)azetidine-1-carboxamido)pheny1)-5,6-dihydropyridine-1(2H)-carboxylate The title compound was prepared as described in Example 1C, substituting tert-butyl 4-(4-aminopheny1)-5,6-dihydropyridine-1(2H)-carboxylate for tert-butyl 3-(4-aminophenoxy)azetidine-1-carboxylate.
Example 9D
3-(pyridin-3-y1)-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-l-carboxylate.
Example 9E
N-(4- {1-[(2S)-2-methylbutanoy1]-1,2,3,6-tetrahydropyridin-4-yl}pheny1)-3-(pyridin-3-y0azetidine-l-carboxamide The title compound was prepared as described in Example 1E, substituting 3-(pyridin-3-y1)-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) 6 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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J
(ESI(+)) (4-{1-[(2R)- = 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e tetrahydrofuran-2- 1H), 7.87 (dt, J= 7.9, 2.0 Hz, 1H), 7.54 -(M+H) ylcarbony1]-1,2,3,6- 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
yl}phenyl)azetidine- = 16.9, 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-y1)-N- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J
(ESI(+)) (4-{1-[(25)- = 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e tetrahydrofuran-2- 1H), 7.87 (dt, J= 7.9, 2.0 Hz, 1H), 7.55 -(M+H) ylcarbony1]-1,2,3,6- 7.27 (m, 5H), 6.09 (bs, 1H), 4.77 - 4.63 (m, tetrahydropyridin-4- 1H), 4.39 (t, J= 8.2 Hz, 2H), 4.23 - 3.48 yl}phenyl)azetidine- (m, 2H), 2.19 - 1.72 (m, 4H) 1-carboxamide 12 N-{4-[1-(2-hydroxy- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J
(ESI(+)) 2-methylpropanoy1)- = 2.3 Hz, 2H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 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), 6.14 yl]phenyl} -3- - 6.08 (m, 1H), 5.43 (s, 1H), 4.38 (t, J= 8.2 (pyridin-3- Hz, 2H), 4.22 - 3.76 (m, 6H), 1.40 - 1.23 yl)azetidine-1- (m, 6H) carboxamide 16 N-{4-[1-(2,2- 1H NMR (400 MHz, DMSO-d6/D20 (APCI(+) dimethylbutanoy1)- Temp=90 C) ppm 8.47 - 8.61 (m, 2 H) ) m/e 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) 4.12 - 4.19 (pyridin-3- (m, 2 H) 3.88 - 4.06 (m, 3 H) 3.74 (t, J=5.80 yl)azetidine-1- Hz, 2 H) 2.93 (d, J=4.58 Hz, 2 H) 1.56 -carboxamide 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/D20 (APCI(+) dimethylbutanoy1)- Temp=90 C) ppm 8.61 (d, 2 H) 7.95 (d, ) m/e 1,2,3,6- 1 H) 7.50 - 7.58 (m, J=12.82 Hz, 1 H) 7.43 -(M+H) tetrahydropyridin-4- 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-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20 (APCI(+) {4-[1-(3,3,3- Temp=90 C) ppm 8.61 (d, 2 H) 7.96 (d, ) m/e trifluoropropanoy1)- 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) 3.49 -yl]phenyl}azetidine- 3.75 (m, 4 H) 2.93 (s, 2 H) 1-carboxamide 19 3-(pyridin-3-y1)-N- 1H NMR (400 MHz, DMSO-d6/D20 (APCI(+) {4-[1-(4,4,4- Temp=90 C) ppm 8.61 (d, 2 H) 7.95 (d, ) m/e 459 trifluorobutanoy1)- 1 H) 7.50 - 7.57 (m, 1 H) 7.47 (d, J=8.54 (M+H) 1,2,3,6- Hz, 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, 4H) 20 N-{4-[1- 1H NMR (400 MHz, DMSO-d6/D20) (APCI(+) (methoxyacety1)- ppm 8.64 (d, 2 H) 8.02 (d, 1 H) 7.55 - 7.61 ) m/e 407 1,2,3,6- (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) 2.92 yl)azetidine-1- (s, 2 H) carboxamide 21 N-(4- {1- 1H NMR (400 MHz, DMSO-d6) ppm (APCI(+) [(methylsulfanyl)acet 8.64 (d, 2 H) 8.03 (d, J=8.24 Hz, 1 H) 7.53 - ) m/e 423 y1]-1,2,3,6- 7.61 (m, J=12.82 Hz, 1 H) 7.47 (d, J=8.54 (M+H) tetrahydropyridin-4- Hz, 2 H) 7.27 - 7.37 (m, 2 H) 6.07 (s, 1 H) yl}pheny1)-3- 4.43 (t, J=8.24 Hz, 2 H) 4.14 (s, 2 H) 3.94 -(pyridin-3- 4.06 (m, 3 H) 3.68 (t, J=5.65 Hz, 2 H) 3.42 yl)azetidine-1- (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(+) (ethoxyacety1)- 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) 4.43 yl]phenyl} -3- (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) 1.10 -carboxamide 1.20 (m, 3 H) 23 N-(4-{1-[(2- 1H NMR (400 MHz, DMSO-d6) ppm (APCI(+) methoxyethoxy)acety 8.63 (d, 2 H) 8.00 (d, 1 H) 7.52 - 7.60 (m, 1 ) m/e 451 1]-1,2,3,6- H) 7.46 (d, J=8.85 Hz, 2 H) 7.32 (d, J=8.85 (M+H) tetrahydropyridin-4- Hz, 2 H) 6.06 (s, 1 H) 4.43 (t, J=8.24 Hz, 2 yl}pheny1)-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)prop 8.61 (d, 2 H) 7.96 (d, 1 H) 7.50 - 7.56 (m, 1 ) m/e anoy1]-1,2,3,6- H) 7.47 (d, J=8.54 Hz, 2 H) 7.32 (d, J=8.54 (M+H) tetrahydropyridin-4- Hz, 2 H) 6.06 (s, 1 H) 4.42 (t, J=8.39 Hz, 2 yl}pheny1)-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) 2.65 - 2.76 yl)azetidine-1- (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) 7.32 (M+H) tetrahydropyridin-4- (d, 2 H) 6.08 (s, 1 H) 4.43 (t, J=8.24 Hz, 2 yl]phenyl} -3- H) 4.22 (s, 2 H) 3.91 - 4.07 (m, 3 H) 3.78 (s, (pyridin-3- 2 H) 2.93 (s, 2 H) 1.90 - 2.01 (m, 1 H) 0.71 yl)azetidine-1- - 0.82 (m, 4 H) carboxamide 26 N-{4-[1- 1H NMR (400 MHz, DMSO-d6) PPm (APCI(+) (cyclopropylacety1)- 8.62 (d, 2 H) 7.96 (d, 1 H) 7.50 - 7.55 (m, ) m/e 417 1,2,3,6- J=12.21 Hz, 1 H) 7.46 (d, J=8.54 Hz, 2 H) (M+H) tetrahydropyridin-4- 7.32 (d, J=8.54 Hz, 2 H) 6.06 (s, 1 H) 4.42 yl]phenyl} -3- (t, J=8.24 Hz, 2 H) 4.08 - 4.12 (m, J=2.44 (pyridin-3- Hz, 2 H) 3.90 - 4.04 (m, 3 H) 3.66 (t, yl)azetidine-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) 6 8.57 (d, J (ESI(+)) methylpropanoy1)- = 2.4 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, m/e 1,2,3,6- 1H), 7.87 (dt, J= 7.9, 2.0 Hz, 1H), 7.54 -(M+H) tetrahydropyridin-4- 7.30 (m, 5H), 6.10 (bs, 1H), 4.39 (t, J= 8.2 yl]phenyl} -3- Hz, 2H), 4.23 - 4.15 (m, 1H), 4.11 - 4.04 (pyridin-3- (m, 1H), 4.01 - 3.86 (m, 3H), 3.72 - 3.63 yl)azetidine-1- (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 I). 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) 6 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-cyanopheny1)-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) 6 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) 6 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-y1)-N- {4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-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)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide and 4-aminobenzoic acid for (S)-2-methylbutanoic acid.
Example 49B
3-(pyridin-3-y1)-N-{4-[(tetrahydrofuran-3-ylmethyl)carbamoyl]phenyl}azetidine-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/D20 Temp=90 C) 6 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 -y1)-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)pheny1)-3-(pyridin-3-y1)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-l-carboxylate.

Example 50C
N-(4- {1-[(2S)-2-methylbutanoy1]-1,2,3,6-tetrahydropyridin-4-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide The title compound was prepared as described in Example 1E, substituting N-(4-(piperidin-4-yl)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)pheny1)-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) 6 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) 6 8.56 (d, J=
(ESI(+)) hydroxy-2- 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.45 m/e 423 methylpropanoyl) (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.46 - (M+H) piperidin-4- 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-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J= (ESI(+)) N-(4-{1-[(25)- 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.45 m/e 435 tetrahydrofuran- (s, 1H), 7.86 (dt, J= 7.9, 1.9 Hz, 1H), 7.46 -(M+H) 2- 7.37 (m, 3H), 7.14 - 7.07 (m, 2H), 4.68 (dd, J=
ylcarbonyl]piperi 7.5, 5.7 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.37 (t, J
din-4- = 8.1 Hz, 2H), 4.15 - 4.05 (m, 1H), 4.03 - 3.68 yl}phenyl)azetidi (m, 5H), 3.17 - 2.98 (m, 1H), 2.80 - 2.59 (m, ne- 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-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J= (ESI(+)) N-{4-[1- 2.3 Hz, 1H), 8.52 - 8.37 (m, 1H), 7.86 (dt, J=
m/e 435 (tetrahydrofuran- 7.9, 2.0 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.15 - (M+H) 3- 7.08 (m, 2H), 4.59 - 4.48 (m, 1H), 4.37 (t, J=
ylcarbonyl)piperi 8.1 Hz, 2H), 4.11 - 4.01 (m, 1H), 4.00 - 3.80 din-4- (m, 4H), 3.78 - 3.62 (m, 3H), 3.46 - 3.34 (m, yl]phenyl}azetidi 1H), 3.20 - 3.02 (m, 1H), 2.77 - 2.59 (m, 2H), ne- 1- 2.10 - 1.91 (m, 2H), 1.93 - 1.70 (m, 2H), 1.61 -carboxamide 1.29 (m, 2H) 54 3-(pyridin-3-y1)- 1H NMR (400 MHz, DMSO-d6) 6 8.56 (d, J= (ESI(+)) N-(4-{1-[(2R)- 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.45 m/e tetrahydrofuran- (s, 1H), 7.86 (dt, J= 7.9, 1.9 Hz, 1H), 8.05 -(M+H) 2- 7.64 (m, 2H), 7.46 - 7.38 (m, 4H), 7.14 - 7.07 ylcarbonyl]piperi (m, 3H), 4.68 (dd, J= 7.6, 5.7 Hz, 1H), 4.52 -din-4- 4.44 (m, 1H), 4.37 (t, J= 8.3 Hz, 3H), 4.14 -yl}phenyl)azetidi 4.05 (m, 1H), 4.02 - 3.68 (m, 7H), 3.17 - 3.00 ne- 1- (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) 6 8.45 (d, J= (ESI(+)) (cyclopropylacet 2.3 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.34 (s, 1H), m/e yl)piperidin-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), 2.17 carboxamide (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) 6 8.56 (d, J= (ESI(+)) methylpropanoyl) 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.44 m/e 407 piperidin-4- (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.47 -(M+H) yl]phenyl} -3- 7.36 (m, 3H), 7.15 - 7.07 (m, 2H), 4.60 - 4.49 (pyridin-3- (m, 1H), 4.37 (d, J= 16.2 Hz, 2H), 4.13 - 3.81 yl)azetidine-1- (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) 6 8.56 (d, J= (ESI(+)) benzoylpiperidin- 2.3 Hz, 1H), 8.48 (dd, J= 4.7, 1.6 Hz, 1H), 8.44 m/e 441 4-yl)pheny1]-3- (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.52 -(M+H) (pyridin-3- 7.36 (m, 8H), 7.19 - 7.11 (m, 2H), 4.76 - 4.48 yl)azetidine-1- (m, 1H), 4.37 (d, J= 16.2 Hz, 2H), 4.03 - 3.81 carboxamide (m, 3H), 3.77 - 3.50 (m, 1H), 3.23 - 2.63 (m, 3H), 1.97 - 1.46 (m, 4H) 58 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J= (ESI(+)) N-{4-[1-(3,3,3- 2.1 Hz, 1H), 8.48 (dd, J= 4.8, 1.6 Hz, 1H), 8.44 m/e trifluoropropanoy (s, 1H), 7.86 (dt, J= 7.9, 2.0 Hz, 1H), 7.50 - (M+H) 1)piperidin-4- 7.35 (m, 3H), 7.14 - 7.07 (m, 2H), 4.56 - 4.46 yl]phenyl}azetidi (m, 1H), 4.37 (d, J= 16.2 Hz, 2H), 4.03 - 3.81 ne- 1- (m, 4H), 3.65 (q, J= 11.0 Hz, 1H), 3.20 - 3.04 carboxamide (m, 1H), 2.77 - 2.57 (m, 2H), 1.82 - 1.72 (m, 2H), 1.64 - 1.22 (m, 2H) 64 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.77 (d, J= (ESI(+)) N-{4-[1- 2.1 Hz, 1H), 8.67 (dd, J= 5.2, 1.4 Hz, 1H), 8.51 m/e (tetrahydro-2H- (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 ylacetyl)pyrrolidi Hz, 2H), 7.17 (t, J= 8.6 Hz, 2H), 4.47 -4.31 n-3- (m, 2H), 4.06 - 3.90 (m, 3H), 3.92 - 3.72 (m, yl]phenyl}azetidi 3H), 3.69 - 3.41 (m, 2H), 3.39 - 3.20 (m, 4H), ne- 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) 6 8.57 (d, J= (ESI(+)) methylpropanoyl) 2.3 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e 393 pyrrolidin-3- 7.9, 2.0 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.23 - (M+H) yl]phenyl} -3- 7.12 (m, 2H), 4.38 (t, J= 8.1 Hz, 2H), 4.04 -(pyridin-3- 3.79 (m, 4H), 3.80 - 3.64 (m, 1H), 3.62 - 3.46 yl)azetidine-1- (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-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J= (ESI(+)) N-(4-{1-[(2S)- 2.4 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e tetrahydrofuran- 7.9, 2.0 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.21 - (M+H) 2- 7.12 (m, 2H), 4.58 - 4.48 (m, 1H), 4.38 (t, J=
ylcarbonyl]pyrrol 8.1 Hz, 2H), 4.07 - 3.38 (m, 9H), 3.25 - 3.05 idin-3- (m, 1H), 2.31 -2.08 (m, 1H), 2.11 - 1.71 (m, yl}phenyl)azetidi 5H) ne- 1-carb oxamide 67 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J= (ESI(+)) N-(4-{1-[(2R)- 2.4 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e tetrahydrofuran- 7.9, 2.0 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.21 - (M+H) 2- 7.12 (m, 2H), 4.58 - 4.48 (m, 1H), 4.38 (t, J=
ylcarbonyl]pyrrol 8.1 Hz, 2H), 4.07 - 3.38 (m, 9H), 3.25 - 3.05 idin-3- (m, 1H), 2.31 -2.08 (m, 1H), 2.11 - 1.71 (m, yl}phenyl)azetidi 5H) ne- 1-carb oxamide 68 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.57 (d, J= (ESI(+)) N- {4- [1- 2.4 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e (tetrahydrofuran- 7.9, 2.0 Hz, 1H), 7.52 - 7.37 (m, 3H), 7.23 - (M+H) 3- 7.13 (m, 2H), 4.38 (t, J= 8.1 Hz, 2H), 4.04 -ylcarbonyl)pyrrol 3.40 (m, 10H), 3.24 - 2.87 (m, 2H), 2.33 -2.11 idin-3- (m, 1H), 2.12 - 1.79 (m, 3H) yl]phenyl}azetidi ne- 1-carb oxamide 69 N-{4-[1- 1H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J= (ESI(+)) (cyclopropylacet 2.3 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e yl)pyrrolidin-3- 7.9, 2.0 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.21 - (M+H) yl]phenyl} -3- 7.12 (m, 2H), 4.38 (d, J= 16.3 Hz, 2H), 4.04 -(pyridin-3- 3.75 (m, 4H), 3.66 - 3.40 (m, 2H), 3.24 - 2.96 yl)azetidine-1- (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) 6 8.57 (d, J= (ESI(+)) hydroxy-2- 2.4 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J= m/e methylpropanoyl) 7.9, 2.0 Hz, 1H), 7.50 - 7.38 (m, 3H), 7.21 - (M+H) pyrrolidin-3- 7.13 (m, 2H), 5.14 (d, J= 3.3 Hz, 1H), 4.43 -yl]pheny1}-3- 4.23 (m, 3H), 4.12 - 3.81 (m, 4H), 3.75 - 3.39 (pyridin-3- (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) 6 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)pheny1]-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-y1)- 1H NMR (400 MHz, DMSO-d6) 6 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 m/e trifluoropropanoy Hz, 1H), 7.51 -7.34 (m, 3H), 7.17 (dd, J= 8.3, (M+H) 1)pyrrolidin-3- 5.2 Hz, 2H), 4.38 (t, J = 8.3 Hz, 2H), 4.04 -yl]phenyl}azetidi 3.75 (m, 4H), 3.74 - 3.46 (m, 4H), 3.30 - 3.13 ne- 1- (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) 6 8.57 (d, J = (ESI(+)) (cyclopropylcarb 2.4 Hz, 1H), 8.51 - 8.45 (m, 2H), 7.86 (dt, J = m/e 391 onyl)pyrrolidin- 7.9, 1.9 Hz, 1H), 7.51 - 7.37 (m, 3H), 7.19 (dd, (M+H) 3-yl]phenyl} -3- J= 12.4, 8.4 Hz, 2H), 4.38 (t, J= 8.1 Hz, 2H), (pyridin-3- 4.12 - 3.75 (m, 5H), 3.71 - 3.37 (m, 2H), 3.25 -yl)azetidine-1- 3.04 (m, 2H), 2.34 - 1.66 (m, 3H), 0.80 - 0.63 carboxamide (m, 4H) 74 N-(4-{1-[(25)-2- 1H NMR (300 MHz, DMSO-d6) 6 8.75 (bs, 1H), (ESI(+)) methylbutanoyl]p 8.65 (d, J= 5.3 Hz, 1H), 8.51 (d, J= 2.1 Hz, m/e 467 yrrolidin-3- 1H), 8.24 (dd, J= 8.5, 2.3 Hz, 1H), 7.76 - 7.67 (M+H) yl}pheny1)-3- (m, 1H), 7.46 (dd, J= 8.5, 3.1 Hz, 2H), 7.23 -(pyridin-3- 7.12 (m, 2H), 4.47 - 4.30 (m, 3H), 4.06 - 3.88 yl)azetidine-1- (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(+)) butanoylpyrrolidi m/e 393 n-3 -yl)phenyl] -3 - (M+H) (pyridin-3-yl)azetidine- 1-carboxamide 100 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.77 (d, J = (ESI(+)) N-{4-[1- 2.2 Hz, 1H), 8.66 (dd, J= 5.2, 1.5 Hz, 1H), 8.55 m/e (tetrahydro-2H- (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), 7.30 - 7.11 ylacetyl)azetidin- (m, 2H), 4.47 (dd, J = 14.6, 6.5 Hz, 2H), 4.43 -3- 4.32 (m, 1H), 4.30 - 4.11 (m, 1H), 4.12 - 3.92 yl]phenyl}azetidi (m, 4H), 3.86 - 3.65 (m, 4H), 3.34 - 3.22 (m, ne- 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/D20 Temp = (ESI(+)) methylpropanoyl) 90 C) 6 8.73 (d, J= 2.2 Hz, 1H), 8.64 (dd, J = m/e 379 azetidin-3- 5.3, 1.4 Hz, 1H), 8.31 - 8.24 (m, 1H), 7.77 (dd, (M+H) yl]pheny1}-3- J = 8.0, 5.3 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.24 -(pyridin-3- 7.18 (m, 2H), 4.51 -4.15 (m, 4H), 4.15 - 3.72 yl)azetidine-1- (m, 6H), 3.89 - 3.70 (m, 1H), 1.02 (d, J = 6.8 carboxamide Hz, 6H) 102 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.78 (d, J= (ESI(+)) N-(4-{1-[(25)- 2.1 Hz, 1H), 8.68 (dd, J= 5.2, 1.4 Hz, 1H), 8.55 m/e tetrahydrofuran- (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.77 (dd, J =
(M+H) 2- 8.0, 5.2 Hz, 1H), 7.52 (t, J= 9.0 Hz, 2H), 7.27 -ylcarbonyl]azetid 7.20 (m, 2H), 4.67 - 4.55 (m, 1H), 4.45 - 4.30 in-3- (m, 3H), 4.31 - 4.11 (m, 3H), 4.07 - 3.93 (m, yl}phenyl)azetidi 4H), 3.86 - 3.65 (m, 1H), 2.11 - 1.92 (m, 2H), ne- 1- 1.92- 1.74 (m, 3H) carboxamide 103 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.76 (t, J= (ESI(+)) N-(4-{1-[(2R)- 6.1 Hz, 1H), 8.66 (dt, J= 9.5, 4.8 Hz, 1H), 8.57 m/e 407 tetrahydrofuran- (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 ylcarbonyl]azetid Hz, 2H), 7.23 (d, J= 8.3 Hz, 2H), 4.69 - 4.46 in-3- (m, 1H), 4.47 - 4.29 (m, 3H), 4.31 - 4.09 (m, yl}phenyl)azetidi 3H), 4.08 - 3.88 (m, 3H), 3.88 - 3.58 (m, 3H), ne- 1- 2.29 - 1.72 (m, 4H) carboxamide 104 3-(pyridin-3-y1)- 1H NMR (300 MHz, DMSO-d6) 6 8.75 (d, J= (ESI(+)) N-{4-[1- 2.0 Hz, 1H), 8.64 (dd, J= 5.2, 1.4 Hz, 1H), 8.55 m/e (tetrahydrofuran- (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.71 (dd, J= (M+H) 3- 8.0, 5.2 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.24 ylcarbonyl)azetid (d, J= 8.4 Hz, 2H), 4.53 (dd, J= 15.0, 8.1 Hz, in-3- 2H), 4.47 - 4.33 (m, 2H), 4.16 (ddd, J= 14.1, yl]phenyl}azetidi 10.1, 4.6 Hz, 3H), 4.08 - 3.93 (m, 3H), 3.91 -ne- 1- 3.71 (m, 3H), 3.71 - 3.56 (m, 2H), 3.14 - 2.93 carboxamide (m, 1H), 2.10 - 1.87 (m, 2H) 105 N-{4-[1- 1H NMR (300 MHz, DMSO-d6) 6 8.71 (d, J= (ESI(+)) (cyclopropylacet 1.9 Hz, 1H), 8.61 (dd, J= 5.1, 1.5 Hz, 1H), 8.54 m/e yl)azetidin-3- (s, 1H), 8.17 (d, J= 8.0 Hz, 1H), 7.66 (dd, J=
(M+H) yl]phenyl} -3- 8.0, 5.1 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.23 (d, J
(pyridin-3- = 8.5 Hz, 2H), 4.53 -4.31 (m, 2H), 4.20 (dd, J
yl)azetidine-1- = 14.1, 6.7 Hz, 1H), 4.09 - 3.90 (m, 2H), 3.85 -carboxamide 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) 6 8.75 (d, J= (ESI(+)) hydroxy-2- 2.2 Hz, 1H), 8.64 (dd, J= 5.2, 1.5 Hz, 1H), 8.54 m/e methylpropanoyl) (s, 1H), 8.27 - 8.20 (m, 1H), 7.71 (dd, J= 8.0, (M+H) azetidin-3- 5.2 Hz, 1H), 7.57 - 7.40 (m, 2H), 7.28 - 7.14 yl]phenyl} -3- (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) 6 8.76 (d, J= (ESI(+)) benzoylazetidin- 2.1 Hz, 1H), 8.66 (dd, J= 5.2, 1.5 Hz, 1H), 8.55 m/e 3-yl)pheny1]-3- (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-y1)- 1H NMR (400 MHz, DMSO-d6/D20 Temp = (ESI(+)) N-{4-[1-(3,3,3- 90 C) 6 8.69 (d, J= 2.2 Hz, 1H), 8.63 - 8.54 (m, m/e trifluoropropanoy 1H), 8.24 - 7.99 (m, 1H), 7.77 - 7.55 (m, 1H), (M+H) 1)azetidin-3- 7.55 - 7.44 (m, 2H), 7.30 - 7.19 (m, 2H), 4.62 -yl]phenyl}azetidi 4.24 (m, 6H), 4.21 - 3.63 (m, 6H) ne- 1-carboxamide 109 N-{4-[1- 1H NMR (300 MHz, DMSO-d6) 6 8.76 (d, J= (ESI(+)) (cyclopropylcarb 2.2 Hz, 1H), 8.66 (dd, J= 5.2, 1.5 Hz, 1H), 8.55 m/e 377 onyl)azetidin-3- (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), 7.33 - 7.11 (pyridin-3- (m, 2H), 4.62 (t, J= 8.1 Hz, 1H), 4.54 ¨ 4.31 yl)azetidine-1- (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) 6 8.78 ¨ 8.68 (ESI(+)) methylbutanoyfla (m, 1H), 8.67 ¨ 8.61 (m, 1H), 8.54 (s, 1H), 8.27 m/e 393 zetidin-3- ¨ 8.19 (m, 1H), 7.75 ¨ 7.67 (m, 1H), 7.54 ¨ 7.47 (M+H) yl}pheny1)-3- (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), 3.84 ¨
yl)azetidine-1- 3.75 (m, 2H), 2.36 ¨ 2.22 (m, 1H), 1.60 ¨ 1.43 carboxamide (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) 6 8.75 (d, J = (ESI(+)) butanoylazetidin- 2.2 Hz, 1H), 8.65 (dd, J= 5.2, 1.5 Hz, 1H), 8.55 m/e 379 3-yl)pheny1]-3- (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), 7.20 yl)azetidine-1- (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) 6 8.44 (s, 1H), (ESI(+)) fluoropyridin-3- 8.14 (dt, J = 4.8, 1.5 Hz, 1H), 8.09 ¨ 7.98 (m, m/e y1)-N- {44142- 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) 4.08 ¨ 3.92 (m, 4H), 3.23 ¨ 2.59 (m, 3H), 1.80 ¨
piperidin-4- 1.70 (m, 2H), 1.71 ¨ 1.36 (m, 2H), 1.33 (s, 6H) yl]phenyl}azetidi ne- 1-carb oxamide 159 3-(pyridin-3-y1)- 1H NMR (500 MHz, DMSO-d6) 6 8.57 (d, J= (ESI(+)) N-(4-{1-[(35)- 2.3 Hz, 1H), 8.49 (dd, J= 4.8, 1.6 Hz, 1H), 8.47 m/e tetrahydrofuran- (s, 1H), 7.88 (dt, J = 7.9, 1.9 Hz, 1H), 7.46 ¨
(M+H) 3- 7.40 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H), 4.57 ¨
ylcarbonyl]piperi 4.50 (m, 1H), 4.37 (t, J = 8.3 Hz, 2H), 4.09 ¨
din-4- 4.02 (m, 1H), 3.98 ¨ 3.92 (m, 2H), 3.93 ¨ 3.79 yl}phenyl)azetidi (m, 2H), 3.81 ¨ 3.52 (m, 2H), 3.16 ¨ 3.04 (m, ne- 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) 6 8.70 (s, 1H), (ESI(+)) chloropyridin-3- 8.58 ¨ 8.38 (m, 2H), 7.57 (d, J= 5.2 Hz, 1H), m/e y1)-N-(4- {1- 7.44 ¨ 7.39 (m, 2H), 7.14 ¨ 7.08 (m, 2H), 4.57 ¨ (M+H) [(3S)- 4.50 (m, 1H), 4.45 ¨ 4.33 (m, 2H), 4.20 ¨ 4.00 tetrahydrofuran- (m, 4H), 3.88 (dt, J= 12.2, 8.1 Hz, 1H), 3.78 ¨
3- 3.63 (m, 3H), 3.20 ¨ 3.04 (m, 1H), 2.75 ¨ 2.56 ylcarbonyl]piperi (m, 2H), 2.10 ¨ 1.94 (m, 2H), 1.82 ¨ 1.71 (m, din-4- 2H), 1.56 ¨ 1.32 (m, 2H) yl}phenyl)azetidi ne- 1-carb oxamide 161 3-(2- 1H NMR (500 MHz, DMSO-d6) 6 8.46 (s, 1H), (ESI(+)) chloropyridin-3- 8.41 ¨ 8.30 (m, 1H), 8.01 (dd, J= 7.7, 1.8 Hz, m/e y1)-N- {44142- 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), 5.03 - 4.45 methylpropanoyl) (m, 2H), 4.42 - 4.30 (m, 2H), 4.12 - 3.99 (m, piperidin-4- 3H), 3.29 - 2.58 (m, 3H), 1.79 - 1.72 (m, 2H), yl]phenyl}azetidi 1.63 - 1.40 (m, 2H), 1.33 (s, 6H) ne-l-carboxamide 163 N-[4-(1- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) pentanoylpiperidi C) ppm 8.88 (s, 1 H) 8.78 (d, J=5.19 Hz, 1 m/e 421 n-4-yl)pheny1]-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) 4.42 carboxamide (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/D20 Temp=25 (ESI(+)) methylcycloprop C) ppm 8.87 (s, 1 H) 8.76 (d, J=5.49 Hz, 1 m/e 419 yl)carbonyl]piper H) 8.56 (d, J=7.93 Hz, 1 H) 7.99 (dd, J=8.09, (M+H) idin-4- 5.65 Hz, 1 H) 7.41 (d, J=8.54 Hz, 2 H) 7.13 (d, yl}pheny1)-3- J=8.54 Hz, 2 H) 4.28 - 4.54 (m, 4 H) 3.98 - 4.13 (pyridin-3- (m, 3 H) 3.09 - 3.22 (m, 1 H) 2.73 (t, J=11.90 yl)azetidine-1- Hz, 1 H) 2.66 (t, 1 H) 1.68 - 1.92 (m, 3 H) 1.32 -carboxamide 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/D20 Temp=25 (ESI(+)) [(1S,4R)- C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.19 Hz, 1 m/e 473 bicyclo[2.2.1]hep H) 8.58 (d, J=7.94 Hz, 1 H) 8.01 (dd, J=7.93, (M+H) t-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) 4.42 -4-yl}pheny1)-3- (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) 2.54 -yl)azetidine-1- 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/D20 Temp=25 (ESI(+)) methylpentanoyl) C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 435 piperidin-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 yl)azetidine-1- Hz, 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, 2 H) 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/D20 Temp=25 (ESI(+)) methylpentanoyl) C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 435 piperidin-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) 4.42 yl)azetidine-1- (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/D20 Temp=25 (ESI(+)) ethoxypropanoyl) C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.19 Hz, 1 m/e 437 piperidin-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) 4.42 y1)azetidine-1- (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, 3H) 169 N-{4-[1-(2,2- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) dimethylbutanoyl C) ppm 8.85 (s, 1 H) 8.75 (d, J=5.19 Hz, 1 m/e 435 )piperidin-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) 3.99 -yl)azetidine-1- 4.10 (m, 3 H) 2.85 (t, J=12.97 Hz, 2 H) 2.68 -carboxamide 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/D20 Temp=25 (ESI(+)) dimethylbutanoyl C) ppm 8.87 (s, 1 H) 8.76 (d, J=5.49 Hz, 1 m/e 435 )piperidin-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) 4.42 yl)azetidine-1- (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/D20 Temp=25 (ESI(+)) dimethylpropano C) ppm 8.86 (s, 1 H) 8.76 (d, J=5.49 Hz, 1 m/e 421 yl)piperidin-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) 1.79 carboxamide (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/D20 Temp=25 (ESI(+)) butanoylpiperidin C) ppm 8.88 (s, 1 H) 8.78 (d, J=5.49 Hz, 1 m/e 407 -4-yl)pheny1]-3- H) 8.59 (d, J=8.24 Hz, 1 H) 8.01 (dd, J=8 .0 9 , (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) 4.42 carboxamide (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/D20 Temp=25 (ESI(+)) (ethoxyacetyl)pip C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 423 eridin-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) 3.88 - 4.20 yl)azetidine-1- (m, 6 H) 3.43 - 3.54 (m, 2 H) 3.07 (t, J=12.21 carboxamide Hz, 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- 1I-1 NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) methylbutanoyl)p C) ppm 8.88 (s, 1 H) 8.78 (d, J=5.19 Hz, 1 m/e 421 iperidin-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) 4.42 yl)azetidine-1- (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, 2 H) 1.32 - 1.53 (m, 2 H) 0.92 (dd, J=6.56, 1.98 Hz, 6 H) 175 N-{4-[1-(N- 1I-1 NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) acetyl-L- C) 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]pheny1}-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 yl)azetidine-1- Hz, 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- 1I-1 NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) methoxyethoxy)a C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 453 cetyl]piperidin-4- H) 8.58 (d, J=8.24 Hz, 1 H) 8.01 (dd, J=8.09, (M+H) yl}pheny1)-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) 3.99 - 4.25 yl)azetidine-1- (m, 5 H) 3.89 (d, J=12.82 Hz, 1 H) 3.51 - 3.64 carboxamide (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- 1I-1 NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) (cyclohexylcarbo C) ppm 8.85 (s, 1 H) 8.75 (d, J=5.19 Hz, 1 m/e 447 nyl)piperidin-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 yl)azetidine-1- Hz, 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- 1I-1 NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) (cyclohexylacetyl C) ppm 8.83 (s, 1 H) 8.73 (d, J=5.19 Hz, 1 m/e 461 )piperidin-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) 4.36 yl)azetidine-1- - 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-y1)- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) N-{4-[1-(4,4,4- C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 461 trifluorobutanoyl) H) 8.58 (d, J=8.24 Hz, 1 H) 8.01 (dd, J=8.09, (M+H) piperidin-4- 5.65 Hz, 1 H) 7.41 (d, J=8.54 Hz, 2 H) 7.13 (d, yl]phenyl}azetidi J=8.85 Hz, 2 H) 4.52 (d, J=12.82 Hz, 1 H) 4.42 ne- 1- (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/D20 Temp=25 (ESI(+)) (cyclopentylcarb C) ppm 8.89 (s, 1 H) 8.78 (d, J=5.49 Hz, 1 m/e 433 onyl)piperidin-4- H) 8.56 - 8.63 (m, 1 H) 8.03 (dd, J=8 .09 , 5.65 (M+H) yl]phenyl} -3- 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, J=12.82 Hz, 1 H) 4.42 yl)azetidine-1- (t, J=8.24 Hz, 2 H) 4.00 - 4.15 (m, 4 H) 2.95 -carboxamide 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/D20 Temp=25 (ESI(+)) methylcyclohexyl C) ppm 8.85 (s, 1 H) 8.75 (d, J=5.49 Hz, 1 m/e 461 )carbonyl]piperid H) 8.54 (d, J=7.93 Hz, 1 H) 7.97 (dd, J=7.93, (M+H) in-4-yl}pheny1)- 5.49 Hz, 1 H) 7.41 (d, J=8.24 Hz, 2 H) 7.12 (d, 3 -(pyridin-3 - J=8.54 Hz, 2 H) 4.41 (t, J=7.93 Hz, 4 H) 3.97 -yl)azetidine-1- 4.18 (m, 3 H) 2.67 - 2.97 (m, 3 H) 1.97 (d, carboxamide 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/D20 Temp=25 (ESI(+)) ylcarbonyl)piperi C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 431 din-4-yl]pheny1}- 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/D20 Temp=25 (ESI(+)) acetylpiperidin-4- C) ppm 8.88 (s, 1 H) 8.78 (d, J=5.49 Hz, 1 m/e 379 yl)pheny1]-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) 4.42 carboxamide (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, 2 H) 1.47 - 1.60 (m, 1 H) 1.32 - 1.45 (m, 1 H) 184 N-{4-[1- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) (methoxyacetyl)p C) ppm 8.88 (s, 1 H) 8.78 (d, J=5.49 Hz, 1 m/e 409 iperidin-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) 3.97 - 4.20 yl)azetidine-1- (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-y1)- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 (ESI(+)) N-{4-[1- C) 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)piperi 5.65 Hz, 1 H) 7.77 (d, J=1.83 Hz, 1 H) 7.61 (dd, din-4- J=4.88, 3.05 Hz, 1 H) 7.43 (d, 2 H) 7.20 - 7.25 yl]phenyl}azetidi (m, 1 H) 7.16 (d, J=8.54 Hz, 2 H) 4.58 (s, 1 H) ne-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/D20 Temp=25 (ESI(+)) methylthiophen- C) 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]piper 5.49 Hz, 1 H) 7.55 (d, J=5.19 Hz, 1 H) 7.42 (d, idin-4- J=8.85 Hz, 2 H) 7.14 (d, J=8.54 Hz, 2 H) 6.95 yl}pheny1)-3- (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/D20 Temp=25 (ESI(+)) (morpholin-4- C) 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]pheny1}-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) 3.92 - 4.12 yl)azetidine-1- (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-y1)- 1H NMR (500 MHz DMSO-d6/D20 Temp=25 (ESI(+)) N-{4-[1- C) 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)piperi 5.49 Hz, 1 H) 7.69 - 7.80 (m, 1 H) 7.39 - 7.46 din-4- (m, 3 H) 7.10 - 7.19(m, 3 H) 4.19 - 4.57 (m, 4 yl]phenyl}azetidi H) 3.99 - 4.13 (m, 3 H) 2.92 - 3.38 (m, 2 H) ne-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/D20 Temp=25 (ESI(+)) methylthiophen- C) 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]piper 5.65 Hz, 1 H) 7.42 (d, J=8.54 Hz, 2 H) 7.23 (d, idin-4- J=3.66 Hz, 1 H) 7.16 (d, J=8.54 Hz, 2 H) 6.83 yl}pheny1)-3- (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) 2.71 -yl)azetidine-1- 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/D20 Temp=25 (ESI(+)) ylcarbonyl)piperi C) ppm 8.87 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 431 din-4-yl]pheny1}- 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/D20 Temp=25 (ESI(+)) methyl-1H- C) 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]piper 5.80 Hz, 1 H) 7.42 (d, J=8.54 Hz, 2 H) 7.16 (d, idin-4- J=8.85 Hz, 2 H) 6.88 (d, J=1.83 Hz, 1 H) 6.33 yl}pheny1)-3- (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) 4.01 -yl)azetidine-1- 4.10 (m, 3 H) 3.66 - 3.67 (m, 3 H) 2.96 - 3.08 carboxamide (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/D20 Temp=25 (ESI(+)) propanoylpiperidi C) ppm 8.89 (s, 1 H) 8.78 (d, J=5.49 Hz, 1 m/e 393 n-4-yl)pheny1]-3- H) 8.53 - 8.65 (m, 1 H) 8.03 (dd, J=8.09, 5.65 (M+H) (pyridin-3- Hz, 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, 2 H) 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/D20 Temp=25 (ESI(+)) methylcycloprop C) ppm 8.89 (s, 1 H) 8.78 (d, J=5.19 Hz, 1 m/e 419 yl)carbonyl]piper H) 8.60 (t, J=7.93 Hz, 1 H) 8.03 (dd, J=7.93, (M+H) idin-4- 5.80 Hz, 1 H) 7.41 (d, J=8.54 Hz, 2 H) 7.14 (d, yl}pheny1)-3- J=8.54 Hz, 2 H) 4.30 - 4.49 (m, 4 H) 3.99 - 4.18 (pyridin-3- (m, 3 H) 2.65 - 3.18 (m, 3 H) 1.79 (d, J=12.51 yl)azetidine-1- Hz, 2 H) 1.33 - 1.57 (m, 2 H) 1.25 (s, 3 H) 0.78 carboxamide - 0.88 (m, 2 H) 0.50 - 0.60 (m, 2 H) 194 3-(pyridin-3-y1)- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 -- (ESI(+)) N-{4-[1- C) 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) 3.97 - 4.10 yl]phenyl}azetidi (m, 3 H) 3.64 - 3.67 (m, 1 H) 3.59 (d, J=6.41 ne-1- Hz, 2 H) 2.96 - 3.24(m, 3 H) 2.76 (t, J=12.36 carboxamide Hz, 2 H) 1.77 - 2.09 (m, 6 H) 1.36 - 1.66 (m, 2 H) 195 3-(pyridin-3-y1)- 1H NMR (500 MHz, DMSO-d6/D20 Temp=25 -- (ESI(+)) N-{4-[1-(1,3- C) 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)piperi 7.42 (d, J=8.54 Hz, 2 H) 7.16 (d, J=8.85 Hz, 2 din-4- H) 5.35 (d, J=12.82 Hz, 1 H) 4.61 (d, J=11.90 yl]phenyl}azetidi Hz, 1 H) 4.42 (t, J=7.93 Hz, 2 H) 3.99 - 4.10 ne-1- (m, 3 H) 3.27 (t, J=12.66 Hz, 1 H) 2.78 - 2.99 carboxamide (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/D20 Temp=25 (ESI(+)) (cyclopentylacety C) ppm 8.88 (s, 1 H) 8.77 (d, J=5.49 Hz, 1 m/e 447 1)piperidin-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) 4.42 yl)azetidine-1- (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/D20 Temp=25 (ESI(+)) dimethylbutanoyl C) ppm 8.87 (s, 1 H) 8.76 (d, J=5.19 Hz, 1 m/e 435 )piperidin-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) 7.06 - 7.16 (pyridin-3- (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/D20 Temp=90 (ESI(+)) pentanoylazetidin C) ppm 8.71 (d, J=2.14 Hz, 1 H) 8.60 - 8.65 m/e 393 -3-yl)pheny1]-3- (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/D20 Temp=90 (ESI(+)) methylcycloprop C) ppm 8.71 (d, J=1.83 Hz, 1 H) 8.62 (d, m/e 391 yl)carbonyl]azeti J=5.19 Hz, 1 H) 8.23 (d, J=8.24 Hz, 1 H) 7.74 (M+H) din-3-yl}pheny1)- (dd, J=7.93, 5.49 Hz, 1 H) 7.48 (d, J=8 .5 4 Hz, 2 3-(pyridin-3- H) 7.19 - 7.25 (m, 2 H) 4.36 - 4.50 (m, 4 H) yl)azetidine-1- 3.92 - 4.11 (m, 4 H) 3.76 - 3.89 (m, 2 H) 1.25 -carboxamide 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/D20 Temp=90 (ESI(+)) [(1S,4R)- C) ppm 8.71 (d, J=1.83 Hz, 1 H) 8.59 - 8.66 m/e 445 bicyclo[2.2.1]hep (m, 1 H) 8.24 (d, J=7.93 Hz, 1 H) 7.74 (dd, (M+H) t-2- J=7.93, 5.19 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 7.20 ylacetyl]azetidin- (d, J=8.85 Hz, 2 H) 4.31 - 4.61 (m, 4 H) 3.92 -3-yl}pheny1)-3- 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) 1.75 -yl)azetidine-1- 1.86 (m, 1 H) 1.37 - 1.52 (m, 3 H) 1.29 - 1.35 carboxamide (m, 1 H) 1.00 - 1.22 (m, 4 H) 201 N-{4-[1-(4- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methylpentanoyl) C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.63 (dd, m/e 407 azetidin-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 (pyridin-3- Hz, 2 H) 7.21 (d, J=8.54 Hz, 2 H) 4.25 - 4.58 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) methylpentanoyl) C) ppm 8.71 (d, J=1.83 Hz, 1 H) 8.58 - 8.64 m/e 407 azetidin-3- (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) 1.99 -carboxamide 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/D20 Temp=90 (ESI(+)) ethoxypropanoyl) C) ppm 8.70 (d, J=1.83 Hz, 1 H) 8.57 - 8.65 m/e 409 azetidin-3- (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/D20 Temp=90 (ESI(+)) dimethylbutanoyl C) ppm 8.71 (d, J=2.14 Hz, 1 H) 8.63 (dd, m/e 407 )azetidin-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 (pyridin-3- Hz, 2 H) 7.20 (d, J=8.54 Hz, 2 H) 4.33 - 4.64 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) dimethylbutanoyl C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.63 (dd, m/e 407 )azetidin-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 (pyridin-3- Hz, 2 H) 7.20 (d, J=8.54 Hz, 2 H) 4.19 - 4.62 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) dimethylpropano C) ppm 8.73 (d, J=1.83 Hz, 1 H) 8.64 (d, m/e 393 yl)azetidin-3- J=5.49 Hz, 1 H) 8.28 (d, J=7.93 Hz, 1 H) 7.78 (M+H) yl]phenyl} -3- (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/D20 Temp=90 (ESI(+)) (ethoxyacetyl)aze C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.63 (d, m/e 395 tidin-3- J=5.19 Hz, 1 H) 8.26 (d, J=7.93 Hz, 1 H) 7.76 (M+H) yl]phenyl} -3- (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) 4.21 -yl)azetidine-1- 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/D20 Temp=90 (ESI(+)) methylbutanoyl)a C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.61 - 8.65 m/e 393 zetidin-3- (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) 1.92 -carboxamide 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/D20 Temp=90 (ESI(+)) acetyl-L- C) ppm 8.73 (d, J=2.14 Hz, 1 H) 8.62 - 8.65 m/e 464 leucyl)azetidin-3- (m, 1 H) 8.28 (d, J=8.24 Hz, 1 H) 7.73 - 7.79 (M+H) yl]phenyl} -3- (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) 3.91 - 4.21 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) methoxyethoxy)a C) ppm 8.71 (d, J=1.83 Hz, 1 H) 8.62 (dd, m/e 425 cetyl]azetidin-3- J=5.19, 1.22 Hz, 1 H) 8.24 (d, J=7.93 Hz, 1 H) (M+H) yl}pheny1)-3- 7.74 (dd, J=7.93, 5.19 Hz, 1 H) 7.47 (d, J=8.54 (pyridin-3- Hz, 2 H) 7.22 (d, J=8.54 Hz, 2 H) 4.20 - 4.80 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) (cyclohexylcarbo C) ppm 8.72 (d, J=1.53 Hz, 1 H) 8.63 (d, m/e 419 nyl)azetidin-3- J=4.27 Hz, 1 H) 8.26 (d, J=7.93 Hz, 1 H) 7.73 - (M+H) yl]phenyl} -3- 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) 3.90 - 4.15 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) (cyclohexylacetyl C) ppm 8.74 (d, J=1.83 Hz, 1 H) 8.61 - 8.68 m/e 433 )azetidin-3- (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) 1.97 carboxamide (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-y1)- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) N-{4-[1-(4,4,4- C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.63 (d, m/e trifluorobutanoyl) J=4.27 Hz, 1 H) 8.26 (d, J=7.93 Hz, 1 H) 7.76 (M+H) azetidin-3- (dd, J=7.93, 5.19 Hz, 1 H) 7.47 (d, J=8.54 Hz, 2 yl]phenyl}azetidi H) 7.22 (d, J=8.54 Hz, 2 H) 4.18 - 4.81 (m, 4 H) ne- 1- 3.96 - 4.16 (m, 4 H) 3.73 - 3.89 (m, 2 H) 2.42 -carboxamide 2.50 (m, 2 H) 2.32 - 2.40 (m, 2 H) 214 N-{4-[1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) (cyclopentylcarb C) ppm 8.74 (d, J=1.83 Hz, 1 H) 8.65 (d, m/e 405 onyl)azetidin-3- J=5.49 Hz, 1 H) 8.31 (d, J=7.93 Hz, 1 H) 7.80 (M+H) yl]phenyl} -3- (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) 2.61 -carboxamide 2.73 (m, 1 H) 1.38 - 1.87 (m, 8 H) 215 N-(4-{1-[(1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methylcyclohexyl C) ppm 8.73 (d, J=1.83 Hz, 1 H) 8.64 (d, m/e 433 )carbonyl]azetidi J=5.19 Hz, 1 H) 8.28 (d, J=7.93 Hz, 1 H) 7.78 (M+H) n-3-yl}pheny1)-3- (dd, J=8.09, 5.34 Hz, 1 H) 7.47 (d, J=8 .5 4 Hz, 2 (pyridin-3- H) 7.20 (d, J=8.54 Hz, 2 H) 4.35 - 4.68 (m, 4 H) yl)azetidine-1- 3.89 - 4.13 (m, 5 H) 3.70 - 3.80 (m, 1 H) 1.88 -carboxamide 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/D20 Temp=90 (ESI(+)) ylcarbonyl)azetid C) ppm 8.72 (d, J=2.14 Hz, 1 H) 8.62 - 8.66 m/e 403 in-3-yl]pheny1}- (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 carboxamide Hz, 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/D20 Temp=90 (ESI(+)) acetylazetidin-3- C) ppm 8.73 (d, J=1.83 Hz, 1 H) 8.60 - 8.67 m/e 351 yl)pheny1]-3- (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, 3H) 218 N-{4-[1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) (methoxyacetyl)a C) ppm 8.72 (d, J=2.14 Hz, 1 H) 8.63 (dd, m/e 381 zetidin-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 (pyridin-3- Hz, 2 H) 7.22 (d, J=8.54 Hz, 2 H) 4.33 - 4.52 yl)azetidine-1- (m, 4 H) 3.96 - 4.11 (m, 5 H) 3.92 (s, 2 H) 3.80 carboxamide - 3.89 (m, 1 H) 3.31 (s, 3 H) 219 3-(pyridin-3-y1)- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) N-{4-[1- C) 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)azetid 7.97 (dd, J=3.05, 1.22 Hz, 1 H) 7.78 (dd, in-3- J=8.09, 5.34 Hz, 1 H) 7.54 (dd, J=5.04, 2.90 yl]phenyl}azetidi Hz, 1 H) 7.48 (d, J=8.54 Hz, 2 H) 7.39 (dd, ne-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/D20 Temp=90 (ESI(+)) methylthiophen- C) 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]azeti 7.78 (dd, J=8.09, 5.34 Hz, 1 H) 7.56 (d, J=5.19 din-3-yl}pheny1)- Hz, 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) 4.53 yl)azetidine-1- (t, J=9.00 Hz, 2 H) 4.38 - 4.48 (m, 2 H) 3.96 -carboxamide 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/D20 Temp=90 (ESI(+)) (morpholin-4- C) 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]pheny1}-3- 7.68 (dd, J=7.93, 5.19 Hz, 1 H) 7.49 (d, J=8.54 (pyridin-3- Hz, 2 H) 7.24 (d, J=8.54 Hz, 2 H) 4.27 - 5.16 yl)azetidine-1- (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-y1)- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) N-{4-[1- C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.61 - 8.65 m/e 419 (thiophen-2- (m, 1 H) 8.27 (d, J=7.93 Hz, 1 H) 7.71 - 7.80 (M+H) ylcarbonyl)azetid (m, 2 H) 7.54 (d, J=2.75 Hz, 1 H) 7.49 (d, in-3- J=8.54 Hz, 2 H) 7.26 (d, J=8.54 Hz, 2 H) 7.16 yl]phenyl}azetidi (dd, J=4.88, 3.66 Hz, 1 H) 4.65 (s, 2 H) 4.39 -ne-1- 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/D20 Temp=90 (ESI(+)) methylthiophen- C) 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) 7.75 (M+H) yl)carbonyl]azeti (dd, J=7.93, 5.19 Hz, 1 H) 7.48 (d, J=8.54 Hz, 2 din-3-yl}pheny1)- 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 yl)azetidine-1- Hz, 2 H) 4.37 - 4.48 (m, 2 H) 4.18 (t, J=6.41 carboxamide Hz, 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/D20 Temp=90 (ESI(+)) ylcarbonyl)azetid C) ppm 8.73 (d, J=2.14 Hz, 1 H) 8.64 (dd, m/e 403 in-3-yl]pheny1}- 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, 1H) 225 N-(4-{1-[(1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methyl-1H- C) 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) 7.76 (M+H) yl)carbonyl]azeti (dd, J=8.09, 5.34 Hz, 1 H) 7.48 (d, J=8.54 Hz, 2 din-3-yl}pheny1)- 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/D20 Temp=90 (ESI(+)) propanoylazetidi C) ppm 8.72 (d, J=1.83 Hz, 1 H) 8.64 (dd, m/e 365 n-3-yl)pheny1]-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 yl)azetidine-1- Hz, 2 H) 7.21 (d, J=8.54 Hz, 2 H) 4.19 - 4.68 carboxamide (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, 3H) 227 N-(4-{1-[(1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methylcycloprop C) ppm 8.73 (d, J=2.14 Hz, 1 H) 8.64 (d, m/e 391 yl)carbonyl]azeti J=5.19 Hz, 1 H) 8.29 (d, J=7.93 Hz, 1 H) 7.75 - (M+H) din-3-yl}pheny1)- 7.80 (m, 1 H) 7.48 (d, J=8.54 Hz, 2 H) 7.21 (d, 3-(pyridin-3- J=8.54 Hz, 2 H) 4.37 - 4.52 (m, 4 H) 3.97 - 4.12 yl)azetidine-1- (m, 5 H) 3.72 - 3.87 (m, 1 H) 1.27 (s, 3 H) 0.88 carboxamide - 0.97 (m, 2 H) 0.44 - 0.53 (m, 2 H) 228 3-(pyridin-3-y1)- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) N-{4-[1-(1,3- C) 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)azetid 7.99 (d, J=3.05 Hz, 1 H) 7.91 (d, J=3.05 Hz, 1 in-3- H) 7.76 (dd, J=7.93, 5.19 Hz, 1 H) 7.49 (d, yl]phenyl}azetidi J=8.54 Hz, 2 H) 7.24 - 7.30 (m, 2 H) 5.01 (s, 1 ne-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/D20 Temp=90 (ESI(+)) (cyclopentylacety C) ppm 8.71 (d, J=1.83 Hz, 1 H) 8.63 (dd, m/e 419 1)azetidin-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 (pyridin-3- Hz, 2 H) 7.20 (d, J=8.54 Hz, 2 H) 4.14 - 4.78 yl)azetidine-1- (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/D20 Temp=90 (ESI(+)) dimethylbutanoyl C) ppm 8.73 (d, J=1.83 Hz, 1 H) 8.62 - 8.67 m/e 407 )azetidin-3- (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) 2.01 -carboxamide 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(+)) pentanoylpyrrolid m/e 407 in-3-yl)pheny1]- (M+H) 3-(pyridin-3-yl)azetidine-l-carboxamide 259 N-{4-[1-(3- (ESI(+)) methylpentanoyl) m/e 421 pyrrolidin-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]hep (M+H) t-2-ylacetyl]pyrrolidi n-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 261 N- {4- [1- (ESI(+)) (cyclopentylacety m/e 433 1)pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 262 N-(4-{1-[(2- (ESI(+)) methylcycloprop m/e 405 yl)carbonyl]pyrro (M+H) lidin-3-yl} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 263 N-{4-[1- (ESI(+)) (morpholin-4- m/e 450 ylacetyl)pyrrolidi (M+H) n-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 264 N- {4-[1-(furan-3- (ESI(+)) ylcarbonyl)pyrrol m/e 417 idin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 265 3-(pyridin-3-y1)- (ESI(+)) N-{4-[1- m/e 434 (pyrrolidin-1- (M+H) ylacetyl)pyrrolidi n-3-yl]phenyl} azetidi ne-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-y1)- (ESI(+)) N-{4-[1-(1,3- m/e 434 thiazol-2- (M+H) ylcarbonyl)pyrrol idin-3-yl]phenyl} azetidi ne-l-carboxamide 268 3-(pyridin-3-y1)- (ESI(+)) N-{4-[1- m/e 433 (thiophen-3- (M+H) ylcarbonyl)pyrrol idin-3-yl]phenyl} azetidi ne-l-carboxamide 269 N-(4-{1-[(1- (ESI(+)) methylcycloprop m/e 405 yl)carbonyl]pyrro (M+H) lidin-3-yl} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 270 N-(4-{1-[(3- (ESI(+)) methylthiophen- m/e 447 2- (M+H) yl)carbonyl]pyrro lidin-3-yl} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 271 3-(pyridin-3-y1)- (ESI(+)) N-{4-[1-(4,4,4- m/e 447 trifluorobutanoyl) (M+H) pyrrolidin-3-yl]phenyl} azetidi ne-l-carboxamide 272 N-(4-{1-[(4- (ESI(+)) methylpiperazin-m/e 463 1- (M+H) yl)acetyl]pyrrolid in-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-l-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) m/e 421 pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 276 N-(4-{1-[(1- (ESI(+)) methylcyclohexyl m/e 447 )carbonyl]pyrroli (M+H) din-3-yl}pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 277 N-[4-(1- (ESI(+)) acetylpyrrolidin- m/e 365 3-yl)pheny1]-3- (M+H) (pyridin-3-yl)azetidine-l-carboxamide 278 N-{4-[1- (ESI(+)) (cyclohexylacetyl m/e 447 )pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 279 N-[4-(1- (ESI(+)) propanoylpyrroli m/e 379 din-3-yl)pheny1]- (M+H) 3-(pyridin-3-yl)azetidine-1-carboxamide 280 N-(4-{1-[(2- (ESI(+)) methoxyethoxy)a m/e 439 cetyl]pyrrolidin- (M+H) 3-y1} pheny1)-3-(pyridin-3-yl)azetidine- 1-carb oxamide 281 N-(4- {1- [3- (ESI(+)) (morpholin-4- m/e 464 yl)propanoyl]pyrr (M+H) o lidin-3-yl } pheny1)-3 -(pyridin-3 -yl)azetidine- 1-carb oxamide 282 N- {4- [1- (2,2- (ESI(+)) dimethylpropano m/e 407 yl)pyrrolidin-3- (M+H) yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1-carb oxamide 283 N-(4- {1- [(5- (ESI(+)) methylthiophen- m/e 447 2- (M+H) yl)carbonyl]pyrro lidin-3-yl} pheny1)-3 -(pyridin-3 -yl)azetidine- 1-carb oxamide 284 3 -(pyridin-3 -y1)- (ESI(+)) N- {4- [1- m/e 433 (thiophen-2- (M+H) ylcarbonyl)pyrrol idin-3-yl]phenyl} azetidi ne- 1-carb oxamide 285 N-(4- {1- [(1- (ESI(+)) methyl-1H- m/e 430 pyrrol-2- (M+H) yl)carbonyl]pyrro lidin-3-yl} pheny1)-3 -(pyridin-3 -yl)azetidine- 1-carb oxamide 286 N- {4- [1- (furan-2- (ESI(+)) ylcarbonyl)pyrrol m/e 417 idin-3- (M+H) yl]phenyl} -3 -(pyridin-3 -yl)azetidine- 1-carb oxamide 287 N-(4- {1- [3- (ESI(+)) (pip eridin-1- m/e 462 yl)propanoyl]pyrr (M+H) olidin-3-yl} pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide 288 N-{4-[1- (ESI(+)) (ethoxyacetyl)pyr m/e 409 rolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 289 N-{4-[1-(3,3- (ESI(+)) dimethylbutanoyl m/e 421 )pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 290 N-{4-[1-(2,2- (ESI(+)) dimethylbutanoyl m/e 421 )pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 291 N-{4-[1-(2- (ESI(+)) oxopropanoyl)py m/e 393 rrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 292 N-{4-[1- (ESI(+)) (methoxyacetyl)p m/e 395 yrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 293 N-{4-[1- (ESI(+)) (cyclohexylcarbo m/e 433 nyl)pyrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 294 N-{4-[1-(3- (ESI(+)) methylbutanoyl)p m/e 407 yrrolidin-3- (M+H) yl]phenyl} -3-(pyridin-3-yl)azetidine-1-carboxamide 295 N-{4-[1- (ESI(+)) (cyclopentylcarb m/e 419 onyl)pyrrolidin- (M+H) 3-yl]phenyl{ -3-(pyridin-3-yl)azetidine- 1-carb oxamide 296 N-{4-[1-(2,3- (ESI(+)) dimethylbutanoyl m/e 421 )pyrrolidin-3- (M+H) yl]phenyl{ -3-(pyridin-3-yl)azetidine- 1-carb oxamide 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) 6 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-l-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) 6 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) 6 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-l-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) 6 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) 6 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]c arb onyl }
amino)phenyl]pip eridine- 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-y1)-2-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) 6 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]c arb onyl }
amino)phenyl]pip eridine- 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-y1)-4-chloropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) 6 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-y1)-2-fluoropyridine for 3-(azetidin-3-yl)pyridine bis hydrochloride. 1H NMR (300 MHz, DMSO-d6) 6 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-methylpropy1)-1H-pyrazol-4-yl]pheny1}-3-(pyridin-3-y1)azetidine-1-carboxamide Example 157A
N-(4-bromopheny1)-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-methylpropy1)-1H-pyrazol-4-yl]pheny1}-3-(pyridin-3-y1)azetidine-1-carboxamide The title compound was prepared as described in Example 9A, substituting 1-isobuty1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole for tert-butyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6-dihydropyridine-1(2H)-carboxylate and N-(4-bromopheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide for 1-bromo-4-nitrobenzene. 1H
NMR (300 MHz, DMSO-d6) 6 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-propy1-1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-yl)azetidine-l-carboxamide The title compound was prepared as described in Example 157, substituting 1-propyl-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole for 1-isobuty1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole in Example 157B. 1H NMR (500 MHz, DMSO-d6) 6 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-y1)-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-l-carboxylate.
Example 162B
1-(4-(4-aminophenoxy)piperidin-1-y1)-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)pheny1)-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-y1)-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-y1)-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/D20) 6 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]pheny1}-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)pheny1)-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-l-carboxylate.
Example 231C

N-{4-[1-(cyclopentylmethyl)piperidin-4-yl]pheny1}-3-(pyridin-3-yl)azetidine-1-carboxamide In a 20 mL vial was added N-(4-(piperidin-4-yl)pheny1)-3-(pyridin-3-y1)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 1..iL, 1.2 mmol). The reaction mixture was shaken for 1 hour at 70C. 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-D20 Temp=90 C) 6 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/D20 Temp=90 C) (ESI(+)) (cyclohexylm ppm 8.55 (dd, J=4.58, 1.53 Hz, 1 H) 8.40 - 8.46 m/e 433 ethyl)piperidi (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56 - 7.60 (m, 1 (M+H) n-4- H) 7.21 (d, J=8.54 Hz, 2 H) 7.16 - 7.18 (m, 1 H) yl]pheny1}-3- 4.46 (t, J=8.24 Hz, 2 H) 4.05 - 4.15 (m, J=7.93, 5.80 (pyridin-3- Hz, 2 H) 3.64 - 3.74 (m, 1 H) 3.16 (d, 2 H) 2.48 -yl)azetidine- 2.62 (m, 1 H) 2.37 - 2.43 (m, 2 H) 2.24 - 2.37 (m, 2 1- H) 1.94 -2.11 (m, 2 H) 1.76 - 1.90(m, 4 H) 1.53 -carboxamide 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/D20 Temp=90 C) (ESI(+)) dimethylbuty ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.46 - 8.51 m/e 421 1)piperidin-4- (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) 3.64 -yl)azetidine- 3.75 (m, 1 H) 3.44 (d, J=12.21 Hz, 2 H) 2.82 - 2.96 1- (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/D20 Temp=90 C) (ESI(+)) methylpentyl ppm 8.55 (dd, J=4.58, 1.53 Hz, 1 H) 8.42 (s, 1 H) m/e 421 )piperidin-4- 7.75 (d, J=8.54 Hz, 2 H) 7.55 - 7.60 (m, 1 H) 7.20 (M+H) yl]pheny1}-3- (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 yl)azetidine- Hz, 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/D20 Temp=90 C) (ESI(+)) methylpropyl ppm 8.55 (dd, J=4.73, 1.68 Hz, 1 H) 8.41 - 8.43 m/e )piperidin-4- (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56 - 7.61 (m, 1 (M+H) yl]pheny1}-3- H) 7.20 (d, J=8.54 Hz, 2 H) 7.16 - 7.18 (m, J=4.58 (pyridin-3- Hz, 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/D20 Temp=90 C) (ESI(+)) methylbutyl) ppm 8.55 (dd, J=4.88, 1.53 Hz, 1 H) 8.44 - 8.49 m/e piperidin-4- (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56 - 7.60 (m, 1 (M+H) yl]pheny1}-3- H) 7.21 (d, J=8.54 Hz, 2 H) 7.16 - 7.18 (m, J=4.88 (pyridin-3- Hz, 1 H) 4.46 - 4.48 (m, 2 H) 4.10 (dd, J=7.93, 5.80 yl)azetidine- Hz, 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) 2.41 -carboxamide 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/D20 Temp=90 C) (ESI(+)) ethylbutyl)pi ppm 8.55 (dd, J=4.58, 1.53 Hz, 1 H) 8.40 - 8.48 m/e peridin-4- (m, 1 H) 7.75 (d, J=8.54 Hz, 2 H) 7.56 - 7.61 (m, 1 (M+H) yl]pheny1}-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) 1.93 -carboxamide 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(+)) dimethylprop m/e 407 yl)piperidin- (M+H) 4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide 239 N-{4-[1-(2- 1H NMR (500 MHz, pyridine-d5/D20 Temp=90 C) (ESI(+)) methylbutyl) ppm 8.55 (d, J=4.58 Hz, 1 H) 8.42 (s, 1 H) 7.75 m/e piperidin-4- (d, J=8.54 Hz, 2 H) 7.56 - 7.61 (m, 1 H) 7.31 - 7.36 (M+H) yl]pheny1}-3- (m, 1 H) 7.20 (d, J=8.54 Hz, 2 H) 4.46 (t, J=8.39 (pyridin-3- Hz, 2 H) 4.07 - 4.12 (m, J=8.09, 5.95 Hz, 2 H) 3.63 yl)azetidine- - 3.76 (m, 1 H) 2.90 - 3.02 (m, 2 H) 2.42 - 2.52 (m, 1- 1 H) 2.16 - 2.27 (m, 1 H) 1.95 - 2.13 (m, 3 H) 1.73 -carboxamide 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/D20 Temp=90 C) (ESI(+)) butylpiperidi ppm 8.55 (dd, J=4.58, 1.53 Hz, 1 H) 8.42 - 8.48 m/e n-4- (m, 1 H) 7.75 (d, J=8.24 Hz, 2 H) 7.56 - 7.61 (m, 1 (M+H) yl)pheny1]-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) 1.78 -carboxamide 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/D20 Temp=90 C) (ESI(+)) propylpiperid ppm 8.55 (dd, J=4.58, 1.53 Hz, 1 H) 8.44 - 8.49 m/e in-4- (m, 1 H) 7.76 (d, J=8.70 Hz, 2 H) 7.56 - 7.62 (m, 1 (M+H) yl)pheny1]-3- H) 7.20 (d, J=8.54 Hz, 2 H) 7.16 - 7.18 (m, J=5.49 (pyridin-3- Hz, 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) 2.43 -1- 2.72 (m, 5 H) 2.04 - 2.20 (m, 2 H) 1.85 (d, 2 H) 1.57 carboxamide - 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/D20 Temp=90 C) (ESI(+)) cyclopropylet ppm 8.55 (dd, J=4.73, 1.37 Hz, 1 H) 8.43 - 8.48 m/e hyl)piperidin- (m, 1 H) 7.75 (d, J=8.24 Hz, 2 H) 7.58 (d, J=7.93 (M+H) 4-yl]pheny1}- Hz, 1 H) 7.18 (d, 2 H) 7.16 - 7.17 (m, 1 H) 4.33 -3-(pyridin-3-4.38 (m, 2 H) 4.05 - 4.14 (m, J=8.09, 5.95 Hz, 2 H) yl)azetidine- 3.62 - 3.77 (m, 1 H) 3.23 - 3.35 (m, 2 H) 2.75 - 2.86 1- (m, 2 H) 2.42 - 2.64 (m, 3 H) 2.00 - 2.18 (m, 2 H) carboxamide 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/D20 Temp=90 C) (ESI(+)) y1)-N- {441- ppm 8.55 (dd, J=4.88, 1.53 Hz, 1 H) 8.43 (s, 1 H) m/e 421 (tetrahydrofu 7.75 (d, J=8.24 Hz, 2 H) 7.56 - 7.62 (m, 1 H) 7.20 (M+H) ran-3- (d, J=8.54 Hz, 2 H) 7.16 - 7.17 (m, 1 H) 4.46 (t, ylmethyl)pip J=8.24 Hz, 2 H) 4.10 (dd, J=7.93, 5.80 Hz, 2 H) eridin-4- 3.87 - 3.93 (m, J=8.24, 6.71 Hz, 1 H) 3.76 - 3.85 yl]phenyl} az (m, 1 H) 3.65 - 3.73 (m, 2 H) 3.57 (dd, J=8.39, 5.65 etidine-1 - Hz, 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/D20 Temp=90 C) (ESI(+)) dimethylbuty ppm 8.55 (dd, J=4.88, 1.53 Hz, 1 H) 8.42 (s, 1 H) m/e 421 1)piperidin-4- 7.76 (d, J=8.54 Hz, 2 H) 7.56 - 7.62 (m, 1 H) 7.20 (M+H) yl]pheny1}-3- (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) 3.65 -yl)azetidine- 3.75 (m, 1 H) 2.90 (d, J=11.90 Hz, 2 H) 2.40 - 2.45 1- (m, 1 H) 2.25 - 2.37 (m, 2 H) 2.12 (s, 2 H) 1.67 -carboxamide 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/D20 Temp=90 C) (ESI(+)) (cyclopentyl ppm 8.60 (d, J=2.14 Hz, 1 H) 8.52 (dd, J=5.04, m/e methyl)azetid 1.37 Hz, 1 H) 7.94 (d, J=7.63 Hz, 1 H) 7.48 - 7.54 (M+H) in-3- (m, 3 H) 7.27 (d, J=8.54 Hz, 2 H) 3.88 - 4.54 (m, 10 yl]phenyl} -3- H) 3.18 - 3.23 (m, 2 H) 2.09 (d, J=7.63 Hz, 1 H) (pyridin-3- 1.78 (s, 2 H) 1.47 - 1.69 (m, 4 H) 1.15 - 1.29 (m, 2 yl)azetidine- H) carboxamide 246 N-{4-[1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) (cyclohexylm ppm 8.62 (d, J=2.14 Hz, 1 H) 8.54 (dd, J=4.88, m/e ethyl)azetidin 1.22 Hz, 1 H) 7.99 (d, J=7.93 Hz, 1 H) 7.47 - 7.59 (M+H) -3- (m, 3 H) 7.26 (d, J=8.54 Hz, 2 H) 3.73 - 4.68 (m, 10 yl]pheny1}-3- H) 3.11 (s, 2 H) 1.54- 1.78 (m, 6 H) 1.10- 1.37(m, (pyridin-3- 3 H) 0.92 - 1.07 (m, J=9.77 Hz, 2 H) yl)azetidine-carboxamide 247 N-{4-[1-(3,3- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) dimethylbuty ppm 8.64 (d, J=2.14 Hz, 1 H) 8.56 (d, J=4.88 Hz, m/e 393 1)azetidin-3- 1 H) 8.05 (d, J=7.93 Hz, 1 H) 7.60 (dd, J=7 .7 8 , 5.04 (M+H) yl]pheny1}-3- Hz, 1 H) 7.51 (d, J=8.54 Hz, 2 H) 7.26 (t, J=7.78 (pyridin-3- Hz, 2 H) 3.88 - 4.53 (m, 10 H) 3.12 - 3.24 (m, 2 H) yl)azetidine- 1.35 - 1.47 (m, 2 H) 0.93 (s, 9 H) carboxamide 248 N-{4-[1- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) (cyclopropyl ppm 8.63 (d, J=2.14 Hz, 1 H) 8.52 - 8.55 (m, 1 m/e methyl)azetid H) 7.95 - 8.04 (m, 1 H) 7.57 (dd, J=7.93, 5.19 Hz, 1 (M+H) in-3- H) 7.51 (d, J=8.54 Hz, 2 H) 7.27 (d, J=8.54 Hz, 2 yl]pheny1}-3- H) 3.90 - 4.51 (m, 10 H) 3.13 (s, 2 H) 0.95 - 1.07 (pyridin-3- (m, 1 H) 0.58 - 0.67 (m, 2 H) 0.35 - 0.43 (m, yl)azetidine- J=5.04, 5.04 Hz, 2 H) carboxamide 249 N-{4-[1-(2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) methylpentyl ppm 8.60 (d, J=2.44 Hz, 1 H) 8.49 - 8.53 (m, 1 m/e )azetidin-3- H) 7.95 (d, J=7.93 Hz, 1 H) 7.45 - 7.56 (m, 3 H) (M+H) yl]pheny1}-3- 7.23 - 7.31 (m, 2 H) 4.23 - 4.59 (m, 5 H) 3.86 - 4.24 (pyridin-3- (m, 6 H) 2.98 - 3.24 (m, 1 H) 1.72 - 1.87 (m, 1 H) yl)azetidine- 1.10 - 1.46 (m, 4 H) 0.83 - 0.96 (m, 6 H) carboxamide 250 3 -(pyridin-3 - (ESI(+)) y1)-N-{4-[1- m/e 393 (tetrahydrofu (M+H) ran-2-ylmethyl)azet idin-3-yl]phenyl} az etidine-1 -carb oxamide 251 N-{4-[1-(2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) methylpropyl ppm 8.60 (d, J=2.14 Hz, 1 H) 8.50 - 8.53 (m, 1 m/e )azetidin-3- H) 7.92 - 7.97 (m, 1 H) 7.47 - 7.56 (m, 3 H) 7.27 (d, (M+H) yl]pheny1}-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) carboxamide 252 N-{4-[1-(3- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) methylbutyl) ppm 8.61 (d, J=2.14 Hz, 1 H) 8.53 (d, J=4.58 Hz, m/e 379 azetidin-3- 1 H) 7.98 (d, J=7.93 Hz, 1 H) 7.47 - 7.57 (m, 3 H) (M+H) yl]pheny1}-3- 7.26 (d, J=8.54 Hz, 2 H) 3.86 - 4.53 (m, 10 H) 3.16 (pyridin-3- - 3.22 (m, 2 H) 1.56 - 1.74 (m, 1 H) 1.37 - 1.48 (m, yl)azetidine- 2 H) 0.92 (d, J=6.71 Hz, 6 H) carboxamide 253 N-{4-[1-(2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) ethylbutyl)az ppm 8.66 (d, J=2.14 Hz, 1 H) 8.57 (dd, J=5.04, m/e 393 etidin-3- 1.37 Hz, 1 H) 8.09 (d, J=7.93 Hz, 1 H) 7.63 (dd, (M+H) yl]pheny1}-3- J=8.09, 5.04 Hz, 1 H) 7.51 (d, J=8.54 Hz, 2 H) 7.26 (pyridin-3- (t, J=8.09 Hz, 2 H) 3.88 - 4.54 (m, 10 H) 3.09 - 3.24 yl)azetidine- (m, 2 H) 1.50 - 1.62 (m, 1 H) 1.27 - 1.45 (m, 4 H) 1- 0.88 (t, J=7.48 Hz, 6 H) carboxamide 254 N-{4-[1-(2,2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) dimethylprop ppm 8.66 (d, J=2.14 Hz, 1 H) 8.58 (dd, J=5.04, m/e 379 yl)azetidin-3- 1.37 Hz, 1 H) 8.10 (d, J=7.93 Hz, 1 H) 7.64 (dd, (M+H) yl]pheny1}-3- J=7.93, 5.19 Hz, 1 H) 7.43 - 7.58 (m, 2 H) 7.20 -(pyridin-3- 7.33 (m, 2 H) 4.29 - 4.65 (m, 5 H) 3.85 - 4.19 (m, 5 yl)azetidine- H) 3.13 - 3.20 (m, 2 H) 1.00 (s, 9 H) carboxamide 255 N-{4-[1-(2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) methylbutyl) C) ppm 8.57 (d, J=1.83 Hz, 1 H) 8.49 (d, m/e 379 azetidin-3- J=3.66 Hz, 1 H) 7.84 - 7.90 (m, 1 H) 7.42 - 7.53 (m, (M+H) yl]pheny1}-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) 1.11 - 1.49 yl)azetidine- (m, J=64.70 Hz, 2 H) 0.85 - 0.97 (m, 6 H) carboxamide 256 3-(pyridin-3- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 (ESI(+)) y1)-N-{4-[1- C) ppm 8.66 (d, J=2.14 Hz, 1 H) 8.58 (dd, m/e (tetrahydrofu J=5.04, 1.37 Hz, 1 H) 8.10 (d, J=8.24 Hz, 1 H) 7.64 (M+H) ran-3- (dd, J=8.09, 5.04 Hz, 1 H) 7.51 (d, J=8.24 Hz, 2 H) ylmethyl)azet 7.27 (d, J=8.54 Hz, 2 H) 3.94 - 4.60 (m, 10 H) 3.72 idin-3- - 3.84 (m, 2 H) 3.62 - 3.70 (m, 1 H) 3.38 - 3.47 (m, yl]phenyl} az 1 H) 3.31 (d, J=7.02 Hz, 2 H) 2.39 - 2.50 (m, 1 H) etidine-1- 2.00 - 2.16 (m, 1 H) 1.54 - 1.72 (m, 1 H) carboxamide 257 N-{4-[1-(2,2- 1H NMR (400 MHz, DMSO-d6/D20 Temp=90 C) (ESI(+)) dimethylbuty ppm 8.70 (d, J=1.83 Hz, 1 H) 8.61 (d, J=5.19 Hz, m/e 393 1)azetidin-3- 1 H) 8.19 (d, J=7.94 Hz, 1 H) 7.72 (dd, J=7.78, 5.34 (M+H) yl]pheny1}-3- Hz, 1 H) 7.50 (s, 2 H) 7.28 (d, J=8.54 Hz, 2 H) 3.93 (pyridin-3- - 4.63 (m, 10 H) 3.18 (s, 2 H) 1.32 (q, J=7.43 Hz, 2 yl)azetidine- H) 0.95 (s, 6 H) 0.84 (t, J=7.48 Hz, 3 H) carboxamide Example 336 N-[4-(1-benzoylpiperidin-4-yl)pheny1]-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-3-3/1)pyridine bis hydrochloride.
Example 336B
N-(4-(piperidin-4-yl)pheny1)-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-l-carboxylate.
Example 336C
N-[4-(1-benzoylpiperidin-4-yl)pheny1]-3-(pyridazin-3-yl)azetidine-1-carboxamide The title compound was prepared as described in Example 1E, substituting N-(4-(piperidin-4-yl)pheny1)-3-(pyridazin-3-yl)azetidine-1-carboxamide for N-(4-(azetidin-3-yloxy)pheny1)-3-(pyridin-3-yl)azetidine-1-carboxamide and benzoic acid for (S)-methylbutanoic acid. 11-I NMR (400 MHz, DMSO) 6 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-4-yl]pheny1}-3-(pyridazin-3-(ESI(+)) yl)azetidine-l-carboxamide m/e 460 (M+H) 338 N-{4-[1-(2-methylbenzoyl)piperidin-4-yl]pheny1}-3-(pyridazin-3-(ESI(+)) yl)azetidine-l-carboxamide m/e 456 (M+H) 339 N- {4-[1-(2,2-dimethylpropanoyl)piperidin-4-yl]phenyl} -3-(ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 422 (M+H) 340 N-{4-[1-(cyclopropylcarbonyl)piperidin-4-yl]pheny1}-3-(pyridazin- (ESI(+)) 3-yl)azetidine-1-carboxamide m/e 406 (M+H) 341 N-[4-(1-acetylpiperidin-4-yl)pheny1]-3-(pyridazin-3-yl)azetidine-1-(ESI(+)) carboxamide m/e 380 (M+H) 342 N-{4-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]pheny1}-3-(pyridazin-(ESI(+)) 3-yl)azetidine-1-carboxamide m/e 436 (M+H) 343 N-{4-[1-(cyclobutylcarbonyl)piperidin-4-yl]pheny1}-3-(pyridazin-3-(ESI(+)) yl)azetidine-l-carboxamide m/e 420 (M+H) 344 3-(pyridazin-3-y1)-N- {4-[1-(4,4,4-trifluorobutanoyl)piperidin-4-(ESI(+)) yl]phenyl}azetidine-l-carboxamide m/e 462 (M+H) 345 3-(pyridazin-3-y1)-N- {4-[1-(3,3,3-trifluoropropano yl)piperidin-4-(ESI(+)) yl]phenyl}azetidine-l-carboxamide m/e 448 (M+H) 346 N-(4- {1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}pheny1)-3-(ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 420 (M+H) 347 N-{4-[1-(cyclopropylacetyl)piperidin-4-yl]pheny1}-3-(pyridazin-3-(ESI(+)) yl)azetidine-l-carboxamide m/e (M+H) Example 348 N-{4-[(1-benzoylpiperidin-4-yOmethyl]pheny1}-3-(pyridazin-3-y1)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 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
20 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-(pip eridin-4-ylmethyl)pheny1)-3 -(pyridazin-3 -yl)azetidine- 1-carb oxamide The title compound was prepared as described in Example 1D, substituting tert-butyl 4-(4-(3 -(pyridazin-3 -yl)azetidine- 1-carb oxamido)b enzyl)pip eridine-l-carboxylate for tert-butyl 3- (4-(3-(pyridin-3 -yl)azetidine-l-c arboxamido)phenoxy) azetidine-l-carboxylate.
Example 348G
N- {4- [(1-b enzoylpip eridin-4-yOmethyl] phenyl } -3 -(pyridazin-3 -yl)azetidine-l-carboxamide The title compound was prepared as described in Example 1E, substituting N-(4-(pip eridin-4-ylmethyl)pheny1)-3 -(pyridazin-3 -yl)azetidine- 1-carb oxamide for N-(4- (azetidin-3 -yloxy)pheny1)-3 -(pyridin-3 -yl)azetidine-l-carb oxamide and benzoic acid for (S)-2-methylbutanoic acid. 11-I NMR (400 MHz, DMSO) 6 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 lA and using an appropriate amine as described in Example 1C.
Ex Name MS
349 N-(4- { [1-(2- fluorobenzoyl)piperidin-4-yl]methyl}pheny1)-3-(ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 474 (M+H) 350 N-(4- { [142,2- dimethylpropanoyl)piperidin-4-yl]methyl} phenyl)-3 - (ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 474 (M+H) 351 N-(4- { [1-(3,3-dimethylbutanoyl)piperidin-4-yl]methyl} phenyl)-3 - (ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 450 (M+H) 352 N-(4- { [1-(2- ethylbutanoyl)pip eridin-4-yl] methyl } phenyl)-3 -(ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 450 (M+H) 353 3 -(pyridazin-3 -y1)-N- (4- { [1- (4,4,4-trifluorobutanoyl)pip eridin-4- (ESI(+)) yl]methyl} phenyl)azetidine-l-carboxamide m/e 476 (M+H) 354 N-(4- { [1-(2-methylpropanoyl)piperidin-4-yl]methyl} phenyl)-3 -(ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 422 (M+H) 355 N- {4- [(1-acetylpiperidin-4-yl)methyl]phenyl} -3 -(pyridazin-3-(ESI(+)) yl)azetidine-l-carboxamide m/e 394 (M+H) 356 N-[4-({1-[(2S)-2-methylbutanoyl]piperidin-4-yl}methyl)pheny1]-3- (ESI(+)) (pyridazin-3-yl)azetidine-1-carboxamide m/e 436 (M+H) 357 N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4- (ESI(+)) yl}methyl)pheny1]-3-(pyridazin-3-yl)azetidine-1-carboxamide m/e 434 (M+H)

Claims (11)

WHAT IS CLAIMED IS:

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, 5R4, 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, CI, Br and I;
R3, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; wherein each R3 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, 5R5, 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, 5R6, 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, CI, Br and I;
R4, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R4 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R7, OR7, 5R7, 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, CI, Br and I;
R5, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R5 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R8, OR8, SR8, S(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, CI, Br and I;
R6, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R6 alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R9, OR9, SR9, S(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 R19, OR19, 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)NHO2R10, 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, CI, Br and I;
R19, at each occurrence, is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein each R19 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.

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 Y1 is ; wherein indicates the point of attachment to the carbonyl and indicates the point of attachment to the nitrogen containing heteroaryl.

5. The compound of claim 4, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with OR4.

6. The compound of claim 4, or a therapeutically acceptable salt thereof, wherein R2 is phenyl; wherein each R2 phenyl is substituted with R4.

7. The compound of claim 5 or 6, or a therapeutically acceptable salt thereof, wherein R4 is independently heterocyclyl.

8. The compound of claim 1, selected from the group consisting of N-[4-({1-[(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}

(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)-(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)-tetrahydro furan-2-ylcarbonyl] azetidin-yl} oxy)phenyl]azetidine-1-carboxamide;
3 -(pyridin-3 -yl)-N- [4-( { 1- [(2 S)-tetrahydro furan-2-ylcarbonyl] azetidin-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-carboxamide;
N-(4- { [1 -(2,2- dimethylpropanoyl)piperidin-4-yl] oxy} phenyl)-3 - (pyridin-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-l-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-l-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-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-carboxamide;
3-(pyridin-3-yl)-N-(4- {1-[(2S)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-l-carboxamide;
3-(pyridin-3-yl)-N-(4- {1-[(2R)-tetrahydrofuran-2-ylcarbonyl]pyrrolidin-3-yl}phenyl)azetidine-l-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-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-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-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-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 - [(1 S,4R)-bicyclo [2.2. 1 ]hept-2-ylacetyl] azetidin-3 -yl}
oxy)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
N-(4- { [1 -(2,3 -dimethylbutanoyl)azetidin-3 -yl]oxy} phenyl)-3 - (pyridin-3 -yl)azetidine-1 -carboxamide;
N-(4- { [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-carboxamide;
N- {4- [( 1 -prop anoylazetidin-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-ylc arb onyl)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)carb onyl] 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-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-yl]phenyl} azetidine- 1 -carboxamide;
N- {4- [1 -(2-methylpropyl)- 1 H-pyrazol-4-yl]phenyl} -3 - (pyridin-3 -yl)azetidine- 1 -carboxamide;
N- [4- (1 -propyl- 1 H-pyrazol-4-yl)phenyl] -3 -(pyridin-3 -yl)azetidine- 1 -carboxamide;
3 -(pyridin-3 -yl)-N-(4- { 1- [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4-yl} phenyl)azetidine- 1 -carboxamide;
3 -(4-chloropyridin-3 -yl)-N-(4- { 1 - [(3 S)-tetrahydrofuran-3 -ylcarbonyl]piperidin-4-yl} phenyl)azetidine- 1 -carboxamide;
3 -(2-chloropyridin-3 -yl)-N- {4- [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- [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- (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-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- 1 H-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-yl)azetidine- 1 -carboxamide;
N-(4- { 1 - [( 1 S,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-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-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-carboxamide;
N-(4- {1- [(1-methyl-1H-pyrrol-2-yl)carbonyl]azetidin-3-yl} phenyl)-3-(pyridin-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-carboxamide;
N- {4- [1-(cyclohexylmethyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [143,3- dimethylbutyl)piperidin-4-yl]phenyl} -3-(pyridin-3-yl)azetidine-carboxamide;
N- {4- [1- (2-methylpentyl)piperidin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-carboxamide ;
N- {4- [1- (2-methylpropyl)piperidin-4-yl]phenyl } -3- (pyridin-3-yl)azetidine-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-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- (tetrahydro furan-2-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide ;
N- {4- [1- (2-methylpropyl)azetidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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- (tetrahydro furan-3-ylmethyl)azetidin-3-yl]phenyl } azetidine-1-carboxamide ;
N- {4- [142,2- dimethylbutyl)azetidin-3-yl]phenyl} -3-(pyridin-3-yl)azetidine-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-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-1-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-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-carboxamide;
N- {4- [1- (methoxyacetyl)pyrrolidin-3-yl]phenyl } -3- (pyridin-3-yl)azetidine-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] -(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(morpholin-4-ylacetyl)pyrrolidin-3-yl]oxy} phenyl)-3- (pyridin-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] -(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]

(pyridin-3-yl)azetidine-1-carboxamide;
N-(4- { [(3R)-1-(5-oxo-1-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] -(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-1-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-carb oxamide ;
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-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-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-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-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-l-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-l-carboxamide;
N-[4-({1-[(1-methylcyclopropyl)carbonyl]piperidin-4-yl}methyl)phenyl]-3-(pyridazin-3-yl)azetidine- 1 -carboxamide; and pharmaceutically acceptable salts thereof.

9. A composition for treating inflammatory and tissue repair disorders;
particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD
(chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage;
autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia, said composition comprising an excipient and a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof.

10. A method of treating inflammatory and tissue repair disorders;
particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases;
dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof.

11. A method of treating inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases;
dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, and ataxia telengiectasia or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of claim 1, or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.