BIZYCLINICALLY SUBSTITUTED PIPERIDINE DERIVATIVES AS T-CELL ACTIVATORS

Description

[0001] The present invention generally relates to substituted bicyclic compounds that activate T cells, promote T cell proliferation, and / or exhibit antitumor activity. Provided herein are substituted bicyclic compounds, compositions comprising such compounds, and compounds and compositions for use in methods. The invention further pertains to pharmaceutical compositions comprising at least one compound according to the invention that are useful in methods for the treatment of proliferative disorders, such as cancer, and viral infections.BACKGROUND OF THE INVENTION

[0002] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. However, although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as "self' and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively subvert anti-tumor immunity. These mechanisms include dysfunctional T-cell signaling (Mizoguchi et al., (1992) Science 258:1795-98), suppressive regulatory cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and the co-opting of endogenous "immune checkpoints", which serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-489).

[0003] Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T cell functions propagated through the TCR signaling pathway. Thus, DGKs serve as intracellular checkpoints and inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation. Supporting evidence include knock-out mouse models of either DGKα or DGKζ which show a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese M.J. et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock B.A. et al., (2006) 11: 1174-81). Furthermore tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients were observed to overexpress DGKα which resulted in inhibited T cell function (Prinz, P.U. et al., J Immunology (2012) 12:5990-6000). Thus, DGKα and DGKζ are viewed as targets for cancer immunotherapy (Riese M.J. et al., Front Cell Dev Biol. (2016) 4: 108; Chen, S.S. et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686.

[0004] There remains a need for compounds useful as inhibitors of one or both of DGKα and DGKζ. Additionally, there remains a need for compounds useful as inhibitors of one or both of DGKα and DGKζ that have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases.

[0005] Accordingly, an agent that is safe and effective in restoring T cell activation, lowering antigen threshold, enhancing antitumor functionality, and / or overcoming the suppressive effects of one or more endogenous immune checkpoints, such as PD-1, LAG-3 and TGFβ, would be an important addition for the treatment of patients with proliferative disorders, such as cancer, as well as viral infections.

[0006] The US application US2005 / 266510 discloses a 2-thioxo-quinazoline having DGK inhibition activity.SUMMARY OF THE INVENTION

[0007] Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

[0008] Applicants have found compounds that have activity as inhibitors of one or both of DGKα and DGKζ. Further, applicants have found compounds that have activity as inhibitors of one or both of DGKα and DGKζ and have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

[0009] The present invention provides substituted bicyclic compounds of Formula (I), which are useful as inhibitors of DGKα, DGKζ, or both DGKα and DGKζ, including salts thereof.

[0010] The present invention also provides pharmaceutical compositions comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0011] The present invention also provides compounds for use in a method of treating a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ, the method comprising administering to a mammalian patient a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof.

[0012] Also described (but not claimed) are processes and intermediates for making the compounds of Formula (I) and / or salts thereof.

[0013] The present invention also provides a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, for use in therapy.

[0014] The present invention also provides the use of the compounds of Formula (I) and / or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of proliferative disorders, such as cancer and viral infections.

[0015] The compounds of Formula (I) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing viral infections and various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as viral infections and cancer.

[0016] These and other features of the invention will be set forth in expanded form as the disclosure continues.DETAILED DESCRIPTION

[0017] The first aspect of the present invention provides at least one compound of Formula (I): or a salt thereof, wherein: XisN; Y is CR 3 or N; L is -O-, -S-, -S(O) 2 -, -NR 4c -, or -NR 4d C(O)-; R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , C 3-4 cycloalkyl substituted with zero to 4 R 1a , C 1-3 alkoxy substituted with zero to 4 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e ; each R 1a is independently F, Cl, -CN, -OH, -OCH 3 , or -NR a R a ; each R a is independently H or C 1-3 alkyl; each R e is independently C 3-4 cycloalkyl or C 1-3 alkyl substituted with zero to 4 R 1a ; R 2 is H, C 1-3 alkyl substituted with zero to 4 R 2a , C 2-3 alkenyl substituted with zero to 4 R 2a , or C 3-4 cycloalkyl substituted with zero to 4 R 2a ; each R 2a is independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), C 3-4 cycloalkyl, C 3-4 alkenyl, or C 3-4 alkynyl; R 3 is H, F, Cl, Br, -CN, C 1-3 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 fluorocycloalkyl, -NO 2 , or pyridinyl substituted with zero to 2 R 3a ; each R 3a is halo, -CN, C 1-3 alkyl, or C 1-3 alkoxy; R 4 is R 4a , -CH 2 R 4a , or -CH 2 CH 2 R 4a ; R 4a is C 3-6 cycloalkyl, C 5-14 heterocyclyl, C 6-10 aryl, or C 5-14 heteroaryl, each substituted with zero to 4 R 4b ; each R 4b is independently F, Cl, Br, -CN, -OH, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 alkyl), C 1-4 alkoxy, -O(C 1-4 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-3 fluoroalkoxy, -O(CH) 1-3 NR c R c , -OCH 2 CH=CH 2 , -OCH 2 C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NR c R c , -NR a S(O) 2 (C 1-3 alkyl), -NR a C(O)(C 1-3 alkyl), -NR a C(O)O(C 1-4 alkyl), -P(O)(C 1-3 alkyl) 2 , -S(O) 2 (C 1-3 alkyl), -O(CH 2 ) 1-2 (C 3-6 cycloalkyl), -O(CH 2 ) 1-2 (morpholinyl), C 3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CR c R c (phenyl); each R c is independently H or C 1-2 alkyl; R 4c is H, C 1-6 alkyl, or R 4a ; R 4d is H or C 1-6 alkyl; each R 5 is independently F, Cl, -CN, -OH, C 1-6 alkyl substituted with zero to 4 R g , C 1-3 alkoxy substituted with zero to 4 R g , C 2-4 alkenyl substituted with zero to 4 R g , C 2-4 alkynyl substituted with zero to 4 R g , -(CH 2 ) 1-2 (C 3-4 cycloalkyl substituted with zero to 4 R g ), phenyl substituted with zero to 4 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 4 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -O(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl), or two R 5 attached to the same carbon atom form =O; each R g is independently F, Cl, -CN, -OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, -O(CH 2 ) 1-2 O(C 1-2 alkyl), C 3-5 cycloalkyl, or -NR c R c ; each R 6 is H, F, Cl, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -OCH 3 ; R 7 is H or -CH 3 ; m is zero, 1, 2, or 3; and n is zero, 1, or 2.

[0018] The second aspect of the present invention provides at least one compound of Formula (I): or a salt thereof, wherein: XisN; Y is CR 3 or N; L is -O-, -S-, -S(O) 2 -, -NR 4c -, or -NR 4d C(O)-; R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , C 3-4 cycloalkyl substituted with zero to 4 R 1a , C 1-3 alkoxy substituted with zero to 4 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e ; each R 1a is independently F, Cl, -CN, -OH, -OCH 3 , or -NR a R a ; each R a is independently H or C 1-3 alkyl; each R e is independently C 3-4 cycloalkyl or C 1-3 alkyl substituted with zero to 4 R 1a ; R 2 is H, C 1-3 alkyl substituted with zero to 4 R 2a , C 2-3 alkenyl substituted with zero to 4 R 2a , or C 3-4 cycloalkyl substituted with zero to 4 R 2a ; each R 2a is independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), C 3-4 cycloalkyl, C 3-4 alkenyl, or C 3-4 alkynyl; R 3 is H, F, Cl, Br, -CN, C 1-3 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 fluorocycloalkyl, -NO 2 , or pyridinyl substituted with zero to 2 R 3a ; each R 3a is halo, -CN, C 1-3 alkyl, or C 1-3 alkoxy; R 4 is R 4a , -CH 2 R 4a , or -CH 2 CH 2 R 4a ; R 4a is C 3-6 cycloalkyl, C 5-14 heterocyclyl, C 6-10 aryl, or C 5-14 heteroaryl, each substituted with zero to 4 R 4b ; each R 4b is independently F, Cl, Br, -CN, -OH, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 alkyl), C 1-4 alkoxy, -O(C 1-4 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-3 fluoroalkoxy, -O(CH) 1-3 NR c R c , -OCH 2 CH=CH 2 , -OCH 2 C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NR c R c , -NR a S(O) 2 (C 1-3 alkyl), -NR a C(O)(C 1-3 alkyl), -NR a C(O)O(C 1-4 alkyl), -P(O)(C 1-3 alkyl) 2 , -S(O) 2 (C 1-3 alkyl), -O(CH 2 ) 1-2 (C 3-6 cycloalkyl), -O(CH 2 ) 1-2 (morpholinyl), C 3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CR c R c (phenyl); each R c is independently H or C 1-2 alkyl; R 4c is H, C 1-6 alkyl, or R 4a ; R 4d is H or C 1-6 alkyl; each R 5 is independently F, Cl, -CN, -OH, C 1-6 alkyl substituted with zero to 4 R g , C 1-3 alkoxy substituted with zero to 4 R g , C 2-4 alkenyl substituted with zero to 4 R g , C 2-4 alkynyl substituted with zero to 4 R g , C 3-4 cycloalkyl substituted with zero to 4 R g , phenyl substituted with zero to 4 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 4 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl); each R g is independently F, Cl, -CN, -OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, -O(CH 2 ) 1-2 O(C 1-2 alkyl), C 3-5 cycloalkyl, or -NR c R c ; each R 6 is H, F, Cl, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -OCH 3 ; R 7 is H or -CH 3 ; m is zero, 1, 2, or 3; and n is zero, 1, or 2.

[0019] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N and Y is CR 3 . Compounds of this embodiment have the structure of Formula (V):

[0020] Included in this embodiment are compounds in which L is O. Also, included in this embodiment are compounds in which each R 6 is H.

[0021] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N and Y is N. Compounds of this embodiment have the structure of Formula (VII):

[0022] Included in this embodiment are compounds in which L is O. Also, included in this embodiment are compounds in which each R 6 is H.

[0023] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , cyclopropyl substituted with zero to 3 R 1a , C 1-3 alkoxy substituted with zero to 3 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n CH 3 , or -P(O)(CH 3 ) 2 ; each R 1a is independently F, Cl, or -CN; each R a is independently H or C 1-3 alkyl; R 2 is H, C 1-2 alkyl substituted with zero to 2 R 2a , or C 2-3 alkenyl substituted with zero to 2 R 2a ; each R 2a is independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 alkenyl, or C 3-4 alkynyl; R 3 is H, F, Cl, Br, -CN, C 1-2 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, -NO 2 , or pyridinyl substituted with zero to 1 R 3a ; R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; each R 4b is independently F, Cl, Br, -CN, -OH, C 1-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 alkyl), C 1-4 alkoxy, -O(C 1-3 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-2 fluoroalkoxy, -O(CH) 1-2 NR c R c , -C(O)(C 1-3 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -NR c R c , -S(O) 2 (C 1-2 alkyl), C 3-6 cycloalkyl, or -CR c R c (phenyl); R 4c is H, C 1-4 alkyl, or R 4a ; R 4d is H or C 1-4 alkyl; each R 5 is independently F, -CN, -OH, C 1-5 alkyl substituted with zero to 4 R g , C 1-3 alkoxy substituted with zero to 3 R g , C 2-3 alkenyl substituted with zero to 4 R g , C 2-3 alkynyl substituted with zero to 4 R g , -(CH 2 ) 1-2 (C 3-4 cycloalkyl substituted with zero to 4 R g ), phenyl substituted with zero to 3 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 3 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -O(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl); each R 6 is H, F, or -CH 3 ; and R 7 is H or -CH 3 . Included in this embodiment are compounds in which R 7 is H, D, -CH 3 , or -CD 3 .

[0024] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , cyclopropyl substituted with zero to 3 R 1a , C 1-3 alkoxy substituted with zero to 3 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n CH 3 , or -P(O)(CH 3 ) 2 ; each R 1a is independently F, Cl, or -CN; each R a is independently H or C 1-3 alkyl; R 2 is H, C 1-2 alkyl substituted with zero to 2 R 2a , or C 2-3 alkenyl substituted with zero to 2 R 2a ; each R 2a is independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 alkenyl, or C 3-4 alkynyl; R 3 is H, F, Cl, Br, -CN, C 1-2 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; each R 4b is independently F, Cl, Br, -CN, -OH, C 1-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 alkyl), C 1-4 alkoxy, -O(C 1-3 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-2 fluoroalkoxy, -O(CH) 1-2 NR c R c , -C(O)(C 1-3 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -NR c R c , -S(O) 2 (C 1-2 alkyl), C 3-6 cycloalkyl, or -CR c R c (phenyl); R 4c is H, C 1-4 alkyl, or R 4a ; R 4d is H or C 1-4 alkyl; each R 5 is independently F, -CN, -OH, C 1-5 alkyl substituted with zero to 4 R g , C 1-2 alkoxy substituted with zero to 3 R g , C 2-3 alkenyl substituted with zero to 4 R g , C 2-3 alkynyl substituted with zero to 4 R g , C 3-4 cycloalkyl substituted with zero to 4 R g , phenyl substituted with zero to 3 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 3 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl); and each R 6 is H, F, or -CH 3 . Included in this embodiment are compounds in which R 7 is H, D, -CH 3 , or -CD 3 .

[0025] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR 3 ; or X is N and Y is N; L is -O-, -NH-, -N(CH 3 )-, or -N(CH 3 )C(O)-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 is R 4a or -CH 2 R 4a ; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH- 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl); and each R 6 is H.

[0026] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR 3 ; or X is N and Y is N; L is -O- or -NH-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, C 1-2 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, -NO 2 , or pyridinyl substituted with zero to 1 R 3a ; R 4 is R 4a or -CH 2 R 4a ; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 )- 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy; each R 6 is H; and R 7 is H. Included in this embodiment are compounds in which R 7 is D.

[0027] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR 3 ; or X is N and Y is N; L is -O-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 is R 4a or -CH 2 R 4a ; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH- 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl); and each R 6 is H; and R 7 is H or -CH 3 . Included in this embodiment are compounds in which R 7 is H, D, -CH 3 , or -CD 3 .

[0028] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR 3 ; or X is N and Y is N; L is -O-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 is R 4a or -CH 2 R 4a ; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 )- 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy; each R 6 is H; and R 7 is H. Included in this embodiment are compounds in which R 7 is D.

[0029] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR 3 ; L is -O-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 is R 4a or -CH 2 R 4a ; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy; each R 6 is H; and R 7 is H. Included in this embodiment are compounds in which R 7 is D.

[0030] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is N; L is -O-; R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 ; R 2 is -CH 3 ; R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 is R 4a or -CH 2 R 4a ; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each Rs is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy; each R 6 is H; and R 7 is H. Included in this embodiment are compounds in which R 7 is D.

[0031] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -O-.

[0032] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -S- or -S(O) 2 -.

[0033] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -S-.

[0034] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -S(O) 2 -.

[0035] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -NR 4C - or -NR 4d C(O)-.

[0036] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -NR 4c . Included in this embodiment are compounds in which R 4c is H or C 1-4 alkyl. Also, included in this embodiment are compounds in which R 4c is R 4a .

[0037] One embodiment provides a compound of Formula (I) or a salt thereof, wherein L is -NR 4d C(O)-. Included in this embodiment are compounds in which R 4d is H or C 1-2 alkyl.

[0038] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , C 3-4 cycloalkyl substituted with zero to 4 R 1a , C 1-3 alkoxy substituted with zero to 4 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e . Included in this embodiment are compounds in which R 1 is H, F, Cl, Br, -CN, C 1-3 alkyl substituted with zero to 4 R 1a , cyclopropyl substituted with zero to 3 R 1a , C 1-3 alkoxy substituted with zero to 3 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n CH 3 , or -P(O)(CH 3 ) 2 . Also, included in this embodiment are compounds in which R 1 is H, F, Cl, Br, -CN, C 1-2 alkyl substituted with zero to 4 R 1a , cyclopropyl substituted with zero to 1 R 1a , C 1-3 alkoxy substituted with zero to 3 R 1a , -C(O)NR a R a , -NR a R a , -S(O) n CH 3 , or -P(O)(CH 3 ) 2 . Additionally, included in this embodiment are compounds in which R 1 is F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 .

[0039] One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R 1a is independently F, Cl, -CN, -OH, or -OCH 3 . Included in this embodiment are compounds in which each R 1a is independently F, Cl, -CN, or -OCH 3 . Also, included in this embodiment are compounds in which each R 1a is independently F, Cl, or -CN.

[0040] One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R a is independently H or C 1-2 alkyl. Included in this embodiment are compounds in which each R a is independently H or -CH 3 .

[0041] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 2 is H, C 1-3 alkyl substituted with zero to 3 R 2a , or C 3-4 cycloalkyl substituted with zero to 2 R 2a . Included in this embodiment are compounds in which R 2 is H or C 1-2 alkyl substituted with zero to 2 R 2a . Also, included in this embodiment are compounds in which R 2 is H or -CH 3 . Additionally, included in this embodiment are compounds in which R 2 is -CH 3 .

[0042] One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R 2a is independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 alkenyl, or C 3-4 alkynyl. Included in this embodiment are compounds in which each R 2a is independently F, Cl, -CN, -OH, -OCH 3 , or cyclopropyl.

[0043] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 3 is H, F, Cl, Br, -CN, C 1-3 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, -NO 2 , or pyridinyl substituted with zero to 2 R 3a . Included in this embodiment are compounds in which R 3 is H, F, Cl, Br, -CN, C 1-2 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, -NO 2 , or pyridinyl substituted with zero to 1 R 3a . Also, included in this embodiment are compounds in which R 3 is H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl. Additionally, included in this embodiment are compounds in which R 3 is H, F, Cl, Br, -CN, -CH 3 , or -NO 2 .

[0044] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is Cl; and R 3 is -CN.

[0045] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is Br; and R 3 is -CN.

[0046] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is H.

[0047] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is F; and R 3 is -NO 2 .

[0048] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -OCH 3 ; and R 3 is -CN.

[0049] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is -CN.

[0050] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is -NO 2 .

[0051] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -C(O)NH 2 ; and R 3 is H.

[0052] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is -CH 3 .

[0053] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is F.

[0054] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is Cl.

[0055] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is -CN; and R 3 is Br.

[0056] One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is N; Y is CR 3 ; R 1 is Cl; and R 3 is H.

[0057] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a or -CH 2 R 4a . Included in this embodiment are compounds in which R 4 is R 4a . Also included in this embodiment are compounds in which R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b .

[0058] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a or -CH 2 R 4a . Included in this embodiment are compounds in which R 4 is R 4a . Also, included in this embodiment are compounds in which R 4 is -CH 2 R 4a . Further, included in this embodiment are compounds in which R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b .

[0059] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a ; and R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b . Included in this embodiment are compounds in which R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0060] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a ; and R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b . Included in this embodiment are compounds in which R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0061] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a , -CH 2 R 4a , or -CH 2 CH 2 R 4a ; and R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b . Included in this embodiment are compounds in which R 4a is R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0062] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4 is R 4a , -CH 2 R 4a , or -CH 2 CH 2 R 4a ; and R 4a is C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b . Included in this embodiment are compounds in which R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0063] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0064] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 2 R 4b ; and each R 4b is independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl.

[0065] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1, 2 or 3. Included in this embodiment are compounds in which m is zero, 1 or 2. Also, included in this embodiment are compounds in which m is 1 or 2.

[0066] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1, 2 or 3; and each R 5 is independently F, -CN, -OH, C 1-5 alkyl substituted with zero to 4 R g , C 1-3 alkoxy substituted with zero to 3 R g , C 2-3 alkenyl substituted with zero to 4 R g , C 2-3 alkynyl substituted with zero to 4 R g , -(CH 2 ) 1-2 (C 3-4 cycloalkyl substituted with zero to 4 R g ), phenyl substituted with zero to 3 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 3 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -O(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl). Included in this embodiment are compounds in which each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl).

[0067] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1, 2 or 3; and each R 5 is independently F, -CN, -OH, C 1-5 alkyl substituted with zero to 4 R g , C 1-2 alkoxy substituted with zero to 3 R g , C 2-3 alkenyl substituted with zero to 4 R g , C 2-3 alkynyl substituted with zero to 4 R g , C 3-4 cycloalkyl substituted with zero to 4 R g , phenyl substituted with zero to 3 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 3 R g , -(CH 2 ) 1-2 (heterocyclyl substituted with zero to 4 R g ), -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl). Included in this embodiment are compounds in which each R 5 is independently hydrogen, F, -CN, -OH, C 1-2 alkyl substituted with zero to 4 R g , or C 1-2 alkoxy. Also, included in this embodiment are compounds in which each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy.

[0068] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1 or 2; and each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl). Included in this embodiment are compounds in which each R 5 is independently F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl).

[0069] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1; and R 5 is hydrogen, F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl). Included in this embodiment are compounds in which each R 5 is independently F, -OH, C 1-2 alkyl, C 1-3 alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl).

[0070] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1 or 2; and each R 5 is independently hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy. Included in this embodiment are compounds in which each R 5 is independently F, -OH, C 1-2 alkyl, or C 1-2 alkoxy.

[0071] One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1; and R 5 hydrogen, F, -OH, C 1-2 alkyl, or C 1-2 alkoxy. Included in this embodiment are compounds in which R 5 is F, -OH, C 1-2 alkyl, or C 1-2 alkoxy.

[0072] One embodiment provides a compound of Formula (I) or a salt thereof, having a structure selected from:

[0073] One embodiment provides a compound of Formula (I) or a salt thereof, having a structure selected from:

[0074] One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is: 4-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (243 and 246); 4-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (251 and 253); 4-((2S,SR)-2,5-dimethyl-4-(3-(trifluoromethyl) phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 4-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (255 and 258); (±)-trans-6-chloro-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (271-272); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (273-274); 6-chloro-4-((3R,4R)-3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (275); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy) piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (276-277); 4-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (278-279); 6-chloro-4-((2 S,4R, SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one (300); 4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one(302);4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1 -yl)-1 -methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (303); 6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (304); 4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (305); 6-chloro-4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d] pyrimidin-2(1H)-one (306); 4-((2S,4S,SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (307); 1-methyl-2-oxo-4-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (339-340); (±)-trans-6-chloro-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (399); trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (400-401); trans-4-(3-ethoxy-4-phenoxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (402-403); or 4-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (404-405).

[0075] One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is: 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (10); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (11); 6-chloro-4-(4-(3,4-difluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (12); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethoxy) phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (13); 6-chloro-4-(4-(4-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (14); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15); 6-chloro-4-(4-(4-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (16); 6-chloro-4-(4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (17); 6-chloro-4-(4-(2-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (18); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (19); 6-chloro-4-(4-(4-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20); 6-chloro-1-methyl-2-oxo-4-(4-(p-tolyloxy)piperidin-1-yl)-11,2-dihydro-1,5-naphthyridine-3-carbonitrile (21); 6-chloro-1-methyl-2-oxo-4-(4-(m-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (22); 6-chloro-4-(4-(2-chloro-5 -fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-11o-1, 2-dihydro-1,5-naphthyridine-3-carbonitrile (23); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (24); 4-((1-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide (25); 4-(4-(4-bromo-2-methylphenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (26); 6-chloro-4-(4-(3-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (27); 6-chloro-4-(4-(3-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (28); -chloro-1-methyl-4-(4-(2-methyl-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1, 5-naphthyridine-3-carbonitrile (29); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (30); 4-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (31); 6-chloro-4-(4-(4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (32); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (33); 6-chloro-4-(4-(3-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-11,2-dihydro-1,5-naphthyridine-3-carbonitrile (34); 6-chloro-4-(4-(2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (35); 6-chloro-4-(4-(4-fluoro-2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (36); 6-chloro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (37); 6-chloro-4-(4-(3-chloro-4-cyanophenoxy) piperidin-1-yl)-1-methyl-2-oxo-11,2-dihydro-1,5-naphthyridine-3 -carbonitrile (38); 6-chloro-4-(4-(4-chloro-3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (39); 6-chloro-4-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (40); 6-chloro-4-(4-(2-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (41); 6-chloro-4-(4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (42); 6-chloro-4-(4-(2-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (43); 6-chloro-4-(4-(2-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (44); 6-chloro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (45); 6-chloro-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (46); 6-bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (47); 6-methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy) phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (48); 1-methyl-2,6-dioxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperi din-1-yl)-1,2, 5, 6-tetrahydro-1, 5-naphthyridine-3-carbonitrile (49); 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (50); 5-methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (51); 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (52); 5-methyl-6-oxo-8-(4-(4-(tert-pentyl)phenoxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (54); 8-(4-(4-benzylphenoxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (55); 8-(4-(4-butylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (56); 5-methyl-6-oxo-8-(4-(4-propylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (57); 8-(4-(4-cyclopentylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (58); 8-(4-(4-cyclopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (59); 8-(4-(4-isopropyl-3-methylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (60); 5-methyl-6-oxo-8-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (61); 5-methyl-6-oxo-8-(4-(4-pentylphenoxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (62); 8-(4-(4-cyclohexylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (63); 8-(4-(4-(2-cyclohexylpropan-2-yl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (64); 8-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (65); 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (66); 8-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-(4-((6-(tert-butyl)pyridazin-3-yl)oxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (68); 5-methyl-6-oxo-8-(4-(quinoxalin-2-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (69); 8-(4-((2,6-dimethylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70); 5-methyl-6-oxo-8-(4-(quinazolin-4-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71); 5-methyl-8-(4-((2-methylpyrimidin-4-yl) oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (72); 8-(4-((7-chloro-4-methoxyquinolin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (73); 8-(4-((1, 7-naphthyridin-8-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (74); 5-methyl-6-oxo-8-(4-(phthalazin-1-yloxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (75); 5-methyl-6-oxo-8-(4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (76); 5-methyl-6-oxo-8-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (77); 8-(4-((2-isopropyl-6-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (78); (+ / -)6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (79); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (80); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (81); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy) piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (82-84); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (85-87); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (88-90); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (91-93); 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (94-96); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (97-99); 8-((3R,4R)-4-(4-cyclopentylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (100-102); 8-((3R,4R)-4-(3,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (103-105); 8-((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (106); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107-109); 8-((3R,4R)-4-(4-ethylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110); 8-((3R,4R)-4-(4-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (111); 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((3R,4R)-4-(2,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (113-115); 8-((3R,4R)-4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (116-118); 5-methyl-8-((3R,4R)-3-methyl-4-(p-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (119-121); 8-((3R,4R)-4-(3-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (122); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (123); 8-((3R,4R)-4-(2-fluoro-6-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (125-127); 8-((3R,4R)-4-(4-fluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (128-130); 5-methyl-8-((3R,4R)-3-methyl-4-(2,4,6-trifluorophenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (131); 8-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (132); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (133-135); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (136); 8-((3R,4R)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (137-139); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (140-142); 8-((3R,4R)-3-ethyl-4-(4-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (143-145); 8-((3R,4R)-3-ethyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (146-148); 8-((3R,4R)-3-ethyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (149-151); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (152-154); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (155-157); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (158-160); 8-((3R,4R)-3-ethyl-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (161); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (162-163); 8-((3R,4S)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (164); 8-((3R,4S)-4-(3-(tert-butyl) phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (165-167); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (169-171); 8-((3R,4S)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (172-174); 8-((3R,4S)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (175); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (176-178); 8-((3R,4S)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (179-181); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (182-184); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy) piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (185);(+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (186); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl) phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (187); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (188); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (189-191); 8-((3R,4R)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (192-194); 8-((3R,4R)-3-ethyl-4-(4-fluoro-3-propylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (195); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (196-198); 8-((3R,4R)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (199-201); 8-((3R,4S)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (202-204); 8-((3R,4S)-4-((5-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (205-207); 8-((3R,4S)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (208-210); 8-((3R,4S)-4-((4-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (211-213); 8-((3R,4S)-4-((6-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (214-216); 5-methyl-8-((3R,4S)-3-methyl-4-(pyrimidin-2-yloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (217); 8-((3R,4S)-4-((4-methoxypyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (218); 5-methyl-8-((3R,4S)-3-methyl-4-((5-propylpyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (219); 5-methyl-8-((3R,4S)-3-methyl-4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (220); 8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (221); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (222); 8-((3R,4S)-4-((5-cyclopropylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (223); 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (224); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (225-227); (+ / ) 8-((3R,4S)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (228); (+ / -) 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (229); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (230); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (231); (+ / -)8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (232); 8-(4-((5-isopropoxypyridin-2-yl) oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (233); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (234); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (235); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (236); 7-fluoro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (237); 7-chloro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (238); 7-bromo-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (239); 7-(6-methoxypyridin-3-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (240); 7-(2-methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy) phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (241); (+ / -) 6-bromo-1-methyl-4-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (242); 8-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (243 and 246); 8-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (251 and 253); 4-((2S,SR)-2,5-dimethyl-4-(3-(trifluoromethyl) phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 8-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (255 and 258); (±)-trans-8-(3-hydroxy-4-(3-(trifluoromethyl) phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (259-260); (±)-trans-8-(3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (261-262); 8-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (263-264); (±)-cis-8-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (265-266); (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (267-268); (±)-trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-methoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (269-270); 8-((2S,5R)-4-((5-methoxypyridin-2-yl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (280-281); N-((2S,SR)-1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (282-283); N-(1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (284-287); N-(1-(3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-N-methyl-4-(trifluoromethyl)benzamide (288-293). 8-((2S,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl) oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (294); 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (295); 8-((2S,4R,SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (296); 8-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl) oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (297); 8-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (298); 8-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (299); 8-((2S,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl) phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (308); 8-((2R, 4S, 5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (309); 8-((2R,4R,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (310); 8-((2R,4S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (311); 8-((2S,4R,SS)-2,5-dimethyl-4-(p-tolyloxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (312); 8-((2S,4R,5S)-4-(3-chlorophenoxy)-2, 5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (313); 8-((2S,4R,5S)-4-(3-cyanophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (314); 8-((2S,4R,5S)-4-(4-fluorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (315); 8-((2S,5S)-2,5-dimethyl-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316A); 8-(2,5)-dimethyl-4-(methyl(4-(trifluoromethyl)phenyl) amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316-319); 8-((2S,5S)-2,5-dimethyl-4-(methyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (320-321); 8-(4-((4-fluorobenzyl) (methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (322-325); -(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (326-328); 8-(4-((4,4-difluorocyclohexyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (329-330); 8-((2S,5R)-4-((4-fluorobenzyl)(methyl) amino)-2, 5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (331-332); 8-((2S,SS)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (333-334); 8-((2S,5S)-4-((5-Isopropoxypyridin-2-yl)oxy)-2,4,5-trimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (335-336); 5-methyl-6-oxo-8-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (337-338); trans-8-(3-ethoxy-4-phenoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (341-342); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (343-344); 8-((3S,4S)-3-ethoxy-4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (345-346); 8-((3S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (347-348); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (349-350); 8-((3S,4S)-3-ethoxy-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (351-352); 8-((3S,4S)-3-ethoxy-4-(4-(methylsulfonyl)phenoxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (353-354); 8-((3S,4S)-3-ethoxy-4-((2-methylbenzo[d]oxazol-5-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (355-356); 8-((3S,4S)-4-(4-chloro-3-fluorophenoxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (357-358); 8-((3S,4S)-3-ethoxy-4-((2-(trifluoromethyl)pyridin-4-yl)oxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (359-362); trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (363-364); 8-((3S,4S)-3-ethoxy-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (365-366); trans-8-(3-ethoxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (367-368); cis- 8-(3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (369-370); cis-8-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (371-372); trans-8-4-(benzo[d]thiazol-2-yloxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (373-374); 8-((3S,4S)-3-ethoxy-4-((6-isopropoxypyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (375-376); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrazin-2-yl) oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (377-378); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrimidin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (379-380); 8-((3S,4S)-3-ethoxy-4-((3-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (381-382); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyridin-2-yl)methoxy) piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (383-384); 8-((3R,4R)-3-(2-(dimethylamino)ethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (385-386); 8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (387-388); 8-((3R,4R)-3-(2-methoxyethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (389-390); 5-methyl-8-((3R,4R)-3-(2-morpholinoethoxy)-4-(3-(trifluoromethyl) phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyri dine-2-carbonitrile (391-392); 5-methyl-6-oxo-8-((3R,4R)-3-(2,2,2-trifluoroethoxy)-4-(3-(trifluoromethyl)phenoxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (393-394); trans-8-(3-isopropoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (395-396); or trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (397-398).

[0076] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.DEFINITIONS

[0077] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0078] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one, or one or more.

[0079] As used herein, the phrase "compounds and / or salts thereof' refers to at least one compound, at least one salt of the compounds, or a combination thereof. For example, compounds of Formula (I) and / or salts thereof includes a compound of Formula (I); two compounds of Formula (I); a salt of a compound of Formula (I); a compound of Formula (I) and one or more salts of the compound of Formula (I); and two or more salts of a compound of Formula (I).

[0080] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0081] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication.

[0082] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0083] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

[0084] In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0085] The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, and I.

[0086] The term "cyano" refers to the group -CN.

[0087] The term "amino" refers to the group -NH 2 .

[0088] The term "oxo" refers to the group =O.

[0089] The term "alkyl" as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, "C 1-4 alkyl" denotes straight and branched chain alkyl groups with one to four carbon atoms.

[0090] The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 fluoroalkyl" is intended to include C 1 , C 2 , C 3 , and C 4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF 3 and -CH 2 CF 3 .

[0091] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH 2 OH, -CH 2 CH 2 OH, and C 1-4 hydroxyalkyl.

[0092] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. For example, "C 2-6 alkenyl" denotes straight and branched chain alkenyl groups with two to six carbon atoms.

[0093] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. For example, "C 2-6 alkynyl" denotes straight and branched chain alkynyl groups with two to six carbon atoms.

[0094] The term "cycloalkyl," as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 cycloalkyl" denotes cycloalkyl groups with three to six carbon atoms.

[0095] The term "fluorocycloalkyl" as used herein is intended to include a cycloalkyl group substituted with one or more fluorine atoms.

[0096] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH 3 ). For example, "C 1-3 alkoxy" denotes alkoxy groups with one to three carbon atoms.

[0097] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" represent a fluoroalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C 1-4 fluoroalkoxy" is intended to include C 1 , C 2 , C 3 , and C 4 fluoroalkoxy groups.

[0098] The terms "carbocyclo", "carbocyclic" or "carbocyclyl" may be used interchangeably and refer to cyclic groups having at least one saturated or partially saturated non-aromatic ring wherein all atoms of all rings are carbon. The carbocyclyl ring may be unsubstituted or may contain one or more substituents as valence allows. Thus, the term includes nonaromatic rings such as for example, cycloalkyl, cycloalkenyl, and cycloalkynyl rings. Exemplary bicyclic carbocyclyl groups include, indanyl, indenyl, dihydronaphthalenyl, tetrahydronaphthenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, bicycloheptanyl, bicyclooctanyl, and bicyclononanyl.

[0099] The term "aryl" as used herein, refers to a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen that is bonded to the aromatic ring(s). Representative examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. The aryl ring may be unsubstituted or may contain one or more substituents as valence allows.

[0100] The term "benzyl," as used herein, refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group. The phenyl ring may be unsubstituted or may contain one or more substituents as valence allows.

[0101] The term "heteroatom" refers to oxygen (O), sulfur (S), and nitrogen (N).

[0102] The terms "heterocyclo", "heterocyclic", or "heterocyclyl" may be used interchangeably and refer to cyclic groups having at least one saturated or partially saturated non-aromatic ring and wherein one or more of the rings have at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1 to 3 heteroatoms independently selected from O, S, and / or N. The ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may be unsubstituted or may contain one or more substituents as valence allows.

[0103] Exemplary monocyclic heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dihydroisoindolyl, and tetrahydroquinolinyl

[0104] The term "heteroaryl" refers to unsubstituted and substituted aromatic groups that have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms independently selected from O, S, and / or N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The 5- to 14-membered heteroaryl groups include 5- or 6-membered monocyclic heteroaryl groups, 9- or 10-membered bicyclic heteroaryl groups, and 11 to 14-membered tricyclic heteroaryl groups. The fused rings completing the bicyclic group and the tricyclic heteroaryl group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic and tricyclic heteroaryl groups must include only aromatic rings. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.

[0105] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0106] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

[0107] Exemplary tricyclic heteroaryl groups include acridinyl, benzoquinolinyl, benzoisoquinolinyl, and benzonaphthyridinyl.

[0108] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0109] The compounds of Formula (I) can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to one or more salts thereof. The term "salt(s)" denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt(s) may include zwitterions (inner salts), e.g., when a compound of Formula (I) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0110] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0111] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.

[0112] The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as a solid.

[0113] It should further be understood that solvates (e.g., hydrates) of the Compounds of Formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0114] In addition, compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of Formula (I) are also contemplated herein as part of the present invention.

[0115] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0116] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor of DGKα and / or DGKζ, or effective to treat or prevent viral infections and proliferative disorders, such as cancer.

[0117] As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and / or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0118] The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13< C and 14< C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0119] Compounds in accordance with Formula (I) and / or pharmaceutically acceptable salts thereof can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered.

[0120] Also embraced within this invention is a class of pharmaceutical compositions comprising a compound of Formula (I) and / or pharmaceutically acceptable salts thereof; and one or more non-toxic, pharmaceutically-acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.

[0121] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.

[0122] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.

[0123] A tablet can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropylcellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0124] Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) and / or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0125] Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0126] An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0127] Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and / or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.

[0128] Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[0129] An emulsion of at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and / or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

[0130] The compounds of Formula (I) and / or at least one pharmaceutically acceptable salt thereof can, for example, also be delivered intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0131] Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).

[0132] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.

[0133] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0134] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[0135] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0136] The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0137] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.

[0138] For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

[0139] Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternate compositions of this invention comprise a compound of the Formula (I) described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.UTILITY

[0140] The compounds of Formula (I) are useful for the treatment of cancer.

[0141] In another embodiment, the present invention provides a combined preparation of a compound of Formula (I), and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and / or prophylaxis of multiple diseases or disorders associated with DGK target inhibition in T cells.

[0142] In another aspect, the invention provides compounds for use in a method of treating a patient suffering from or susceptible to a medical condition that is associated with DGK target inhibition in T cells. A number of medical conditions may be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof. For example, the compounds described herein may be used to treat or prevent viral infections and proliferative diseases such as cancer.

[0143] The compounds for Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful in treating or preventing any disease or conditions that are associated with DGK target inhibition in T cells. These include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), and proliferative diseases (e.g., cancer). The compounds of Formula (I) and pharmaceutical compositions comprising in at least one compound of Formula (I) may be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. The compound of Formula (I) or pharmaceutical composition comprising at least compound of Formula (I) may be administered orally. The Formula (I) or pharmaceutical composition comprising at least compound of Formula (I) may be administered parenterally.

[0144] The compounds of Formula (I) can inhibit activity of the diacylglycerol kinase alpha and zeta (DGKα / ζ). For example, the compounds of Formula (I) can be used to inhibit activity of DGKα and DGKζ in a cell or in an individual in need of modulation of DGKα and DGKζ by administering an inhibiting amount of a compound of Formula (I) or a salt thereof.

[0145] The present invention further provides compounds for use in methods of treating diseases associated with activity or expression, including abnormal activity and / or overexpression, of DGKα and DGKζ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of DGKα and DGKζ enzyme, such as over expression or abnormal activity. A DGKα and DGKζ -associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGKα and DGKζ enzyme activity. Examples of DGKα and DGKζ associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.

[0146] Compound(s) of Formula (I) may be sequentially administered prior to administration of the immuno-oncology agent. Compound(s) of Formula (I) may be administered concurrently with the immuno-oncology agent. Compound(s) of Formula (I) may be sequentially administered after administration of the immuno-oncology agent.

[0147] Compounds of Formula (I) may be co-formulated with an immuno-oncology agent.

[0148] Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. The antibody may be a monoclonal antibody. The monoclonal antibody may be humanized or human.

[0149] The immuno-oncology agent may be (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0150] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-HS (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DRS, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α / TNEβ, TNFR2, TNFα, LTβR, Lymphotoxin α 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0151] T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0152] Other agents that can be combined with compounds of Formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of Formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0153] Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0154] Compounds of Formula (I) can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites.

[0155] The immuno-oncology agent may be a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0156] The immuno-oncology agent may be a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224

[0157] The immuno-oncology agent may be a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0158] The immuno-oncology agent may be a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0159] The immuno-oncology agent may be a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0160] The immuno-oncology agent may be a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0161] The immuno-oncology agent may be an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0162] The immuno-oncology agent may be an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0163] The immuno-oncology agent may be an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0164] The immuno-oncology agent may be a CD40 agonist, such as an agonistic CD40 antibody. The immuno-oncology agent may be a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0165] The immuno-oncology agent may be a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0166] The immuno-oncology agent may be MGA271 (to B7H3) (WO11 / 109400).

[0167] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0168] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. An ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. An in vitro cell can be a cell in a cell culture. An in vivo cell is a cell living in an organism such as a mammal.

[0169] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the DGKα and DGKζ enzyme with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having DGKα and DGKÇ, as well as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing DGKα and DGKζ enzyme.

[0170] The term " DGKα and DGKζ inhibitor" refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and / or diacylglycerol kinase zeta (DGKα and DGKζ) in T cells resulting in T cell stimulation. The DGKα and DGKζ inhibitor may be a reversible or irreversible DGKα and DGKζ inhibitor. "A reversible DGKα and DGKζ inhibitor" is a compound that reversibly inhibits DGKα and DGKζ enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible DGKα and DGKζ inhibitor" is a compound that irreversibly destroys DGKα and DGKζ enzyme activity by forming a covalent bond with the enzyme.

[0171] Types of cancers that may be treated with the compound of Formula (I) include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

[0172] One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors can be optionally used in combination with the compounds of Formula (I) for treatment of DGKα and DGKζ associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0173] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN ®< ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0174] In the treatment of melanoma, suitable agents for use in combination with the compounds of Formula (I) include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY ™< . Compounds of Formula (I) may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma.

[0175] Compounds of Formula (I) may also be used in combination with vaccine therapy in the treatment of melanoma. Antimelanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.

[0176] Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds of Formula (I), using a hyperthermic isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects. Usually the fluid is warmed to 38.9 °C to 40 °C. Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).

[0177] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

[0178] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.

[0179] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine.

[0180] Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.

[0181] Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (HERCEPTIN ®< ), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF-β).

[0182] Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0183] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.

[0184] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0185] The pharmaceutical composition of the invention may optionally include at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors such as, for example, STI 571 (GLEEVEC ®< ); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA ®< , SSI-774) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of Formula (I) may be in separate pharmaceutical compositions. In a specific embodiment of the present invention, at least one compound of Formula (I) and at least one STI may be administered to the patient concurrently or sequentially. In other words, at least one compound of Formula (I) may be administered first, at least one STI may be administered first, or at least one compound of Formula (I) and at least one STI may be administered at the same time. Additionally, when more than one compound of Formula (I) and / or STI is used, the compounds may be administered in any order.

[0186] The present invention further provides a pharmaceutical composition for use in the treatment of a chronic viral infection in a patient comprising at least one compound of Formula (I), optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier.

[0187] Also provided is compounds for use in a method for treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

[0188] At least one compound of Formula (I) and at least one chemotherapeutic agent may be administered to the patient concurrently or sequentially. In other words, at least one compound of Formula (I) may be administered first, at least one chemotherapeutic agent may be administered first, or at least one compound of Formula (I) and the at least one STI may be administered at the same time. Additionally, when more than one compound of Formula (I) and / or chemotherapeutic agent is used, the compounds may be administered in any order. Similarly, any antiviral agent or STI may also be administered at any point in comparison to the administration of the compound of Formula (I).

[0189] Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Notably, parasitic infections (e.g., malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents.

[0190] Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.

[0191] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir; BCH-I0652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dideoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.

[0192] Pharmaceutical kits may be useful, for example, in methods of treatment or prevention of DGKα and DGKζ -associated diseases or disorders, and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0193] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0194] The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compounds of Formula (I), formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally, one or more additional therapeutic agents described above.

[0195] The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0196] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms; and not injurious to the patient.

[0197] The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.

[0198] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0199] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

[0200] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0201] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

[0202] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0203] A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. L gelatin capsule.

[0204] A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0205] The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an anticancer agent or other pharmaceutically active material.

[0206] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[0207] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0208] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0209] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the therapeutic effect and gradually increase the dosage until the effect is achieved.

[0210] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.

[0211] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.

[0212] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0213] The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.METHODS OF PREPARATION

[0214] The compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Examples of compounds of the present invention prepared by methods described in the general schemes are given in the Examples section set out hereinafter. Preparation of homochiral examples may be carried out by techniques known to one skilled in the art. For example, homochiral compounds may be prepared by separation of racemic products or diastereomers by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically or diastereomerically enriched products.

[0215] The reactions and techniques described in this section are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods given below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art, with alternatives required when incompatible substituents are present. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of a protecting group used for protection of reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007).

[0216] In a further enablement, intermediates and examples of the current invention may be prepared using stereoselective methodologies know in the art, examples of which are shown in the following schemes.

[0217] Both antipodes of chiral oxazolidinones of the type depicted can be reacted with acyl chlorides at low temperature to yield N-acyl derivatives. These can be converted into the related boron enolates and condensed with 2-(2-alkyl-1,3-dioxolan-2-yl)acetaldehydes to yield 4-benzyl-3-(2-alkyl-3-hydroxy-4-(2-alkyl-1,3-dioxolan-2-yl)butanoyl)oxazolidinones of known stereochemistry. Deprotection of the product dioxolanes using for example, ferric chloride in acetone can yield 1-(4-benzyl-2-oxooxazolidin-3-yl)-2-alkyl-3-hydroxyalkyl-1,5-diones. Subsequent reductive amination using benzylamine with for example, sodium triacetoxyborohydride can provide diastereomeric mixutures of 4-benzyl-3-(5-(benzylamino)-2-alkyl-3-hydroxyalkanoyl)oxazolidinones. The resultant amines may be intramolecularly cyclized by heating in MeOH under microwave conditions to provide chromatographically separable 1-benzyl-3-alkyl-4-hydroxy-6-alkylpiperidin-2-ones. Succeeding reduction of the product piperidinones with for example, borane or LAH can yield N-benyl-2-alkyl-4-hydoxy-5-alkylpiperidines. Removal of the benzyl moiety under hydrogenolysis conditions in the presence of di-tert-butyl dicarbonate can allow access to tert-butyl 4-hydroxy-2,5-dialkylpiperidine-1-carboxylates that are useful intermediates in the syntheses of examples of the current invention. In a further step, the stereochemistry of the 4-hydroxy moeity in these and related intermediates may be inverted using standard Mitsunobu conditions employing p-nitrobenzoic acid to yield esters from which the desired alcohols can be liberated by base catalyzed hydrolysis. Employing these methodologies with approprately functionalized oxazolidinones and aldehydes can yield intermediates of known stereochemistry. An example of the utilization of such compounds to access additional embodiments of the current invention is shown in the methodologies outlined in the following scheme.

[0218] In these instances, N-boc protected 2,5-dialkyl-4 hydroxypiperidines can first be deprotected under standard conditions and then reacted with suitably derivitized 1-alkylpyrido[3,2-d]pyrimidin-2(1H)-ones or 1-alkyl-1,5-naphthyridin-2(1H)-ones to give product alcohols that can subsequently be reacted under either Mitsunobu conditions, or with selected heterocycles under SNAr conditions to give examples of the current invention. Alternatively, the N-boc protected 2,5-dialkyl-4 hydroxypiperidines may first be reacted under Mitsunobu conditions with appropriately functionalized phenols, or with selected heterocycles under SNAr conditions to give additional intermediates of the type depicted above. Subseqent reaction with suitably functionalized pyrido[3,2-d]pyrimidin-2(1H)-ones or naphthyridin-2(1H)-ones can provide access to additional examples. In some cases, the 2,5-dialkyl-4-hydroxypiperidines or their related ethers can be reacted with 4,6-dichloro-1-alkyllpyrido[3,2-d]pyrimidin-2(1H)-ones or 4,6-dichloro-1-alkyl-1,5-naphthyridin-2(1H)-ones to access the related 4-N-piperidinyl derivatives, thus facilitating the introduction of additional functionality at the 6-position of the bicyclic heterocyle, for example a nitrile group, which are further embodiments of the current invention.EXAMPLES

[0219] The following examples illustrate the particular and preferred embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols as well as scientific abbreviations and symbols have their usual and customary meanings unless otherwise specified. Additional abbreviations employed in the Examples and elsewhere in this application are defined above. Common intermediates are generally useful for the preparation of more than one Example and are identified sequentially (e.g., Intermediate 1, Intermediate 2, etc.) and are abbreviated as Int. 1 or I1, Int. 2 or I2, etc. Compounds of the Examples are identified by the example and step in which they were prepared (e.g., "1-A" denotes the Example 1, step A), or by the example only where the compound is the title compound of the example (for example, "1" denotes the title compound of Example 1). In some instances alternate preparations of intermediates or examples are described. Frequently chemists skilled in the art of synthesis may devise alternative preparations which may be desirable based on one or more considerations such as shorter reaction time, less expensive starting materials, ease of operation or isolation, improved yield, amenable to catalysis, avoidance of toxic reagents, accessibility of specialized instrumentation, and decreased number of linear steps, etc. The intent of describing alternative preparations is to further enable the preparation of the examples of this invention. In some instances some functional groups in the outlined examples and claims may be replaced by well-known bioisosteric replacements known in the art, for example, replacement of a carboxylic acid group with a tetrazole or a phosphate moiety. 1< H NMR data collected in deuterated dimethyl sulfoxide used water suppression in the data processing. The reported spectra are uncorrected for the effects of water suppression. Protons adjacent to the water suppression frequency of 3.35 ppm exhibit diminished signal intensity.

[0220] In the examples, the use of hashed wedge bonds imply relative stereochemistry. The "(+ / -)" designation preceding the name of a compound indicates a racemic mixture. The "(rel)" designation indicates that all stereochemical designations for the compound are relative and not absolute. The use of a non-hashed bond at a chiral center implies unknown relative stereochemistry. In the tables below, the stereochemistry of the example is shown in the column labeled "Stereo. Chem." wherein the designation "A" represents "achiral", the designation "R" represents a racemic mixture, and the designation "H" represents a homochiral material.ABBREVIATIONS

[0221] Acacetyl anhyd.anhydrous aq.aqueous BOPbenzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate Bubutyl DCMdichloromethane DEAdiethylamine DIEA or DIPEAdiisopropylethylamine DMFdimethylformamide DMSOdimethyl sulfoxide dppf1,1'-bis(diphenylphosphino)ferrocene Etethyl EtOAcethyl acetate EtOHethanol h, hours or hrshour(s) HClhydrochloric acid HPLChigh pressure liquid chromatography LCliquid chromatography LCMSliquid chromatography- mass spectrometry Mmolar mMmillimolar Memethyl MeOHmethanol Mesyl-Clmethanesulfonyl chloride MHzmegahertz minsminute(s) M +1< (M+H) +< MSmass spectrometry n or Nnormal NH 4 OAcammonium acetate nMnanomolar NMPN-methylpyrrolidinone Pd 2 (dba) 3 tris-(dibenzylideneacetone)dipalladium pet etherpetroleum ether Phphenyl POCl 3 phosphorous oxychloride rt or Ret timeretention time sat.saturated TEAtriethylamine TFAtrifluoroacetic acid THFtetrahydrofuran

[0222] Methodologies that can be employed in the syntheses of intermediates useful in the preparation of examples of the current invention are shown in the scheme below.

[0223] Benzooxazine-2,4(1H)-diones of the type shown can be treated with strong base and a methylating reagent such as methyl iodide to afford 1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-diones. These can be treated with, for example, nitro acetates to generate 1-methyl-3-nitroquinoline-2,4(1H,3H)-diones. Such compounds can in turn be converted to the related 4-chloro derivatives that can be reacted with a diversity of functionalized piperidines to afford examples of the current invention.

[0224] In other methodologies, picolinic acids may be esterified under standard conditions and then treated with, for example, acetic anhydride to give ethyl 3-acetamidopicolinates. These may be alkylated under standard conditions and subsequently treated with a mixture of hydrogen peroxide and trifluoroacetic anhydride to access the related N-oxides, for example, 2-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide. Under conditions known in the art, these intermediates can be converted to 6-cyano-3-(N-methylacetamido)picolinates that on treatment with base can cyclize to give 1,5-naphthyridine-2,4(1H,3H)-diones. Compounds of this type can be derivatized in a plurality of ways to access a number of useful intermediates. For example, treatment under standard nitration conditions can generate the related 1-methyl-3-nitro-1,5-naphthyridine-2,4(1H,3H)-diones that can be converted under standard conditions to the 4-chloro- or 4-trifluoromethanesulfonate intermediates that can be reacted with a variety of functionalized piperidines to afford additional examples of the current invention. Alternatively, treatment under bromination conditions, for example, N-bromosuccinimide in DMF, can give the related 3-bromo derivatives, which when derivatized as described above allow both the introduction of a diversity of piperidines at the 4-position of the heterocycle, as well as further derivatization at the 3-position of the naphthyridine. For example, aromatic and heteroaromatic moieties may be introduced at this vector through coupling chemistries that are known in the art.

[0225] In additional methodology, ethyl 3-amino-6-bromopicolinates generated from the related ethyl 3-amino-picolinates can be treated as described above to give 6-bromo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-diones that allow the introduction of a diversity of moieties at the 6-position of the naphthyridine heterocycle, one instance being the introduction of the cyano function at this position as shown in Scheme 1.

[0226] Additional methodologies that can be useful in the synthesis of intermediates of the current invention are shown in the following scheme.

[0227] Ethyl 3-amino-6-bromopicolinates on treatment with 2-cyanoacetyl chloride can be made to cyclize to generate 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitriles. These may be alkylated at N1 under standard conditions and subsequently converted to the related 6-bromo-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethane sulfonates that are useful in the preparation of other examples. Alternatively, sequential treatments with POCl 3 and HCl in dioxane gives access to 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitriles that are also useful intermediates.

[0228] Other synthetic methods that may be useful for the introduction of a cyano motif at the 6-position of examples of the current invention can involve treatment of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate intermediates with zinc and zinc cyanide under palladium catalyzed conditions to generate ethyl 3-(2-cyanoacetamido)-6-cyanopicolinates. These can be derivatized using methodologies as previously described to access 4-chloro-6-isocyano-1-methyl-2-oxo-1, 2-dihydro-1,5-naphthyridine-3-carbonitriles that can be reacted with diversely functionalized piperidines to generate a number of examples of the current invention.

[0229] Additional useful intermediates can be prepared by condensing suitably functionalized naphthyridinone and quinolone heterocycles with variously functionalized piperidines as indicated in the scheme below. Such intermediates may be converted to examples of the current invention by further elaboration using, for example, Mitsunobu or SN Ar reactions with appropriately functionalized aromatic or heteroaromatic coupling partners.

[0230] Methodology for the preparation of useful piperidine intermediates and additional examples is shown in the scheme below.

[0231] In these instances N-protected cis-4-hydroxy-3-alkylpiperidines can be treated with carboxylic acids, for example under Mitsunobu conditions, to provide trans-4-benzoyloxy-3-alkylpiperidines. These may be subsequently hydrolyzed to access the related trans-4-hydroxy-3-alkylpiperidines that can be utilized in methodology analogous to that discussed previously, whereby subsequent deprotection and condensation of the intermediate trans 4-hydroxy-3-alkylpiperidines with suitably functionalized naphthyridinones or quinolones generates trans-4-hydroxy-3-alkylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine or related quinolone intermediates that can again be reacted under Mitsunobu or SN Ar conditions to provide further examples of the current invention.

[0232] In other instances, it may be preferable to prepare intermediate piperidine ethers that can subsequently be reacted with appropriately functionalized naphthyridinones and quinolones to provide additional examples. Some illustrative examples are shown in the following schemes. In this methodology N-protected alkylpiperidin-4-ones of the type shown can be reduced by methods known in the art to provide access to N-protected 3-alklpiperidin-4-ols.

[0233] The relative stereochemistry of the alkyl and hydroxy substituents can be controlled by numerous methods, some examples being concurrent treatment with phosphoric acid and sodium borohydride to give predominantly the trans-product, or the use of L-selectride in THF to give predominantly the cis-product as shown. Further treatment of these intermediates with strong base and appropriately functionalized heterocycles under SN AR conditions can result in the syntheses of N-protected cis-or trans-3-alkyl-4-(heteroaryloxy)piperidines. These intermediates on deprotection, can be reacted with suitably functionalized naphthyridinones or quinolones to provide a diversity of examples of the current invention.INTERMEDIATE 1(+ / -) trans-1-benzyl-3-methylpiperidin-4-ol

[0234]

[0235] Phosphoric acid (85%, 4.25 g, 36.9 mmol) was added dropwise to a solution of 1-benzyl-3-methylpiperidin-4-one (7.5 g, 36.9 mmol) in water (50 mL) and methanol (25 mL) at -10 °C. Sodium borohydride (2.79 g, 73.8 mmol) was then added in portions, and on addition the resulting mixture was allowed to warm to room temperature and stirring was continued overnight. The pH of the solution was adjusted to ~ 9 by the addition of 5 M sodium hydroxide solution. The resultant mixture was extracted with ethyl acetate (3 x 15 mL), and the combined extracts were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo to give the product as a viscous yellow oil, (4.65 g, 22.65 mmol, 61.4 % yield). LCMS (m / z): (M+H) +< = 206.3, 1< H NMR (500 MHz, CHLOROFORM-d) δ 7.52-7.12 (m, 5H), 3.71-3.40 (m, 2H), 3.22-3.10 (m, 1H), 2.93-2.86 (m, 1H), 2.85-2.79 (m, 1H), 2.11-1.99 (m, 1H), 1.97-1.87 (m, 1H), 1.76-1.56 (m, 3H), 1.54-1.39 (m, 1H), 1.05-0.86 (m, 3H).INTERMEDIATE 2(+ / -) tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate

[0236]

[0237] A solution of (+ / -) (trans)-1-benzyl-3-methylpiperidin-4-ol (2.5 g, 12.18 mmol) and Boc-anhydride (3.11 mL, 13.39 mmol) in methanol (50 mL) was degassed and flushed with nitrogen (2 x). Next, 10% Pd-C (1.2 g, 1.128 mmol) was added and the mixture again evacuated and flushed with nitrogen (2 x) before being evacuated and filled with hydrogen at 1 atmosphere (balloon). The reaction mixture was stirred vigorously under the hydrogen atmosphere for 2 days. It was then filtered through celite, and the filtrate was washed with methanol and the washings combined with the original filtrate. The combined solutions were concentrated under vacuum to give the product as a viscous, yellow-colored oil, (1.71 g, 7.94 mmol, 65.2 % yield). LCMS:(m / z) (M-tBu+ACN+H) +< = 201.2. 1< H NMR (500 MHz, CHLOROFORM-d) δ 4.10-3.85 (m, 2H), 3.40-3.24 (m, 1H), 2.93-2.71 (m, 1H), 2.62-2.34 (m, 1H), 1.99-1.87 (m, 1H), 1.50-1.46 (m, 11H), 1.57-1.40 (m, 12H), 1.06-0.99 (m, 3H).INTERMEDIATE 3(+ / -) 5-isopropoxy-2-((trans-3-methylpiperidin-4-yl)oxy)pyridine, TFA

[0238]

[0239] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF was added dropwise to a solution of (+ / -) tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate (120 mg, 0.557 mmol) in THF (4 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-fluoro-5-isopropoxypyridine (0.100 mL, 0.836 mmol) was added. The reaction mixture was then heated at 60 °C overnight. The reaction was then quenched by the addition of water and the resultant mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a yellow-colored oil. This material was purified by preparative reverse phase HPLC using a CH 3 CN-H 2 O-TFA system as eluent. Homogeneous fractions were combined and concentrated under reduced pressure. The residual material was then treated a mixture of TFA (0.5 mL) in DCM (2 mL) for 3 h at room temperature. The resultant mixture was then concentrated in vacuo to give the product as a brown oil, (40 mg, 0.110 mmol, 19.70 % yield).INTERMEDIATE 4(+ / -) 2-((trans-3-ethylpiperidin-4-yl)oxy)-5-isopropoxypyridine

[0240]

[0241] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.090 mL, 1.090 mmol) in THF was added dropwise to a solution of (+ / -) tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (100 mg, 0.436 mmol) in THF (2 mL). The mixture was stirred at room temperature for 30 min, then 2-fluoro-5-isopropoxypyridine (0.078 mL, 0.654 mmol) in THF (1mL) and the reaction mixture was heated at 60 °C for 5 hr under nitrogen. The reaction mixture was cooled to room temperature, water was added and the resultant mixture was extracted with ethyl acetate (3 x). The organic layers were combined, washed with brine and then dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a yellow, viscous oil. This material was purified by flash chromatography on silica get using 20% ethyl acetate in hexanes as eluent. Homogeneous fractions were combined and evaporated in vacuo to give the product as a viscous, colorless oil. This was treated directly with TFA (1 mL) in DCM (3 mL) at room temperature overnight. The resultant mixture was then concentrated in vacuo to give the TFA salt of the title compound as a brown colored oil, (153 mg, 0.311 mmol, 71.3 % yield). LCMS: (m / z) 265:(M+H) +< = 265.25.INTERMEDIATE 5(+ / -) 5-isopropyl-2-((cis-3 -methylpiperi din-4-yl)oxy)pyridine

[0242]

[0243] Sodium hydride (60% in mineral oil) (69.7 mg, 1.742 mmol) was added in portions to a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 10 min, then 2-chloro-5-isopropylpyridine (163 mg, 1.045 mmol) in THF (1mL) was added. The reaction mixture was then heated at 60 °C overnight. The reaction was then quenched by the addition of water and the resultant mixture was extracted with ethyl acetate (3 x). The organic layers were collected, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give a brown, viscous oil. The crude product was purified by preparative reverse phase HPLC using CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and evaporated in vacuo and the residue treated with TFA (1 mL) in DCM (2 mL) for 3 h at room temperature. The resultant solution was reduced in vacuo to give the bis-TFA salt of the title compound as a yellow-colored oil, (58.3 mg, 0.126 mmol, 18.10 % yield). LCMS: (m / z): 235.1:(M+H) +< .INTERMEDIATE 6(+ / -) 5-isopropoxy-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine

[0244]

[0245] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF was added dropwise to a solution of a 9:1 mixture of cis- and trans-tert-butyl-4-hydroxy-3-methylpiperidine-1-carboxylate (120 mg, 0.557 mmol) in THF (4 mL). The mixture was stirred at room temperature for 30 min, then 2-fluoro-5-isopropoxypyridine (0.100 mL, 0.836 mmol) was added and the reaction mixture was heated at 60 °C overnight. The reaction was then quenched by the addition of water and the resultant mixture extracted with ethyl acetate (3 x). The extracts were combined, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by reverse phase preparative HPLC using CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated under reduced pressure overnight. The residue was then dissolved in dichloromethane (2 mL) and TFA 0.5 mL was added. The solution was stirred at room temperature for 3 hr. The mixture was then evaporated in vacuo to give the TFA salt of the title compound as a brown, viscous oil, (40 mg, 0.110 mmol, 19.70 % yield). LCMS: (m / z):(M+H) +< = 251.3.INTERMEDIATE 7(+ / -)2-((3,3-dimethylpiperidin-4-yl)oxy)-5-isopropoxypyridine

[0246]

[0247] A 1.0 M solution of potassium bis(trimethylsilyl)amide (0.872 mL, 0.872 mmol) in THF was added dropwise to a solution of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (80 mg, 0.349 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-fluoro-5-isopropoxypyridine (0.062 mL, 0.523 mmol) was added. The reaction mixture was stirred at room temperature overnight, and was then quenched by the addition of water. The resultant mixture was extracted with ethyl acetate (3 x) and the combined extracts were washed with brine, dried over MgSO 4 , filtered and evaporated in vacuo to give the crude product as a brown oil. The product was purified by reverse phase preparative HPLC using CH 3 CN-H 2 O-TFA system. Homogeneous fractions were collected and concentrated under reduced pressure. The residue was then dissolved in DCM (3 mL) and treated with TFA (1 mL) at room temperature for 4 hr. The solution was then concentrated in vacuo to give the TFA salt of the title compound as a viscous, brown-colored oil, (24 mg, 0.063 mmol, 18.18 % yield). (m / z):(M+H) +< = 251.3.INTERMEDIATE 8(+ / -) 5-(difluoromethyl)-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine

[0248]

[0249] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF was added dropwise to a solution of tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (120 mg, 0.557 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-chloro-5-(trifluoromethyl)pyridine (137 mg, 0.836 mmol) in THF (1mL) was added and the mixture heated at 60 °C overnight. The reaction was quenched by the addition of water, and the resultant mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was then purified by reverse phase preparative HPLC using CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated under reduced pressure. The residue was then dissolved in dichloromethane (1 mL) and treated with TFA (0.5 mL) for 3 h at room temperature. The mixture was then evaporated in vacuo to give the TFA salt of the title compound as a brown, viscous oil, (160 mg, 0.340 mmol, 61.0 % yield). LCMS: (m / z):(M+H) +< = 243.3.INTERMEDIATE 9(+ / -) 2-isopropyl-6-((cis-3-methylpiperidin-4-yl)oxy)pyridine

[0250]

[0251] Sodium hydride (69.7 mg, 1.742 mmol) (60% in mineral oil) was added in portions to a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in anhydrous THF (2 mL). On addition, the reaction mixture was stirred at room temperature for 10 min., then 2-chloro-6-isopropylpyridine (163 mg, 1.045 mmol) in THF (1mL) was added and the mixture heated at 60 °C under nitrogen overnight. The reaction was then quenched by the addition of water and the resultant mixture was extracted with ethyl acetate (3 x). The extracts were combined, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a brown, viscous oil. The product was purified by preparative reverse phase. HPLC using CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and TFA (1 mL) was added and the ensuing mixture was stirred at room temperature for 3 hr before being concentrated in vacuo to give the TFA salt of the title compound as a yellow-colored viscous oil, (53 mg, 0.115 mmol, 16.45 % yield). LCMS: (m / z):(M+H) +< = 235.1.INTERMEDIATE 10(+ / -) 2-((cis-3-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridine

[0252]

[0253] Sodium hydride (69.7 mg, 1.742 mmol) (60% in mineral oil) was added to a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in anhydrous THF (2 mL). The mixture was stirred at room temperature for 10 min, then 2-chloro-5-(trifluoromethyl)pyridine (190 mg, 1.045 mmol) in THF (1mL) was added and the reaction mixture was heated at 60 °C for 3 h, before being quenched by the addition of water. The mixture was then extracted using ethyl acetate (3 x), the extracts combined and washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using reverse phase preparative HPLC using a CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated in vacuo. The residue was then dissolved in dichloromethane (2 mL) TFA (1 mL) was added, and the resultant mixture was stirred at room temperature for 3 h before being concentrated under vacuum to give the TFA salt of the title compound as a white solid, (157 mg, 0.419 mmol, 60.2 % yield). LCMS: (m / z):(M+H) +< = 260.9.INTERMEDIATE 11(+ / -) 4-isopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine

[0254]

[0255] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.742 mL, 1.742 mmol) in THF was added dropwise to a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-chloro-4-isopropylpyridine (163 mg, 1.045 mmol) in THF (1mL) was added and the ensuing mixture was heated at 60 °C, under nitrogen overnight. The reaction was then quenched by the addition of water. The mixture was then extracted using ethyl acetate (3 x), the extracts combined and washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using reverse phase preparative HPLC using a CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated in vacuo. The residue was then dissolved in dichloromethane (1 mL) TFA (0.5 mL) was added, and the resultant mixture was stirred at room temperature for 3 h before being concentrated under vacuum to give the TFA salt of the title compound as a viscous, yellow-colored oil, (42 mg, 0.091 mmol, 13.04 % yield). LCMS: (m / z):(M+H) +< = 235.0.INTERMEDIATE 12(+ / -) 5-cyclopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine

[0256]

[0257] A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.161 mL, 1.161 mmol) in THF was added dropwise to a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (100 mg, 0.464 mmol) in anhydrous THF (2 mL). The mixture was stirred at room temperature for 30 min. Next, 2-chloro-5-cyclopropylpyridine (107 mg, 0.697 mmol) in THF (1 mL) was then added and the reaction mixture was heated at 60 °C overnight. The reaction was quenched by the addition of water. The resultant mixture was extracted with ethyl acetate (3 x), and the extracts were combined, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as a viscous yellow oil. The product was purified using reverse phase preparative HPLC using a CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined and concentrated in vacuo. The residue was then dissolved in dichloromethane (1 mL) TFA (0.5 mL) was added, and the resultant mixture was stirred at room temperature for 3 h before being concentrated under vacuum to give the TFA salt of the title compound as a viscous yellow oil, (10 mg, 0.043 mmol, 9.27 % yield). LCMS: (m / z):(M+H) +< = 232.55.

[0258] Other related intermediates could be prepared by the methodology shown in the scheme below, which involved the reaction of a potassium alkoxide salt of an unprotected hydroxypiperidine with a chloro-pyrimidine.INTERMEDIATE 13(+ / -) 2-((cis-3-methylpiperidin-4-yl)oxy)pyrimidine

[0259]

[0260] Potassium bis(trimethylsilyl)amide (0.901 mL, 0.901 mmol) was added to a solution of (+ / -) cis-3-methylpiperidin-4-ol (104 mg, 0.901 mmol) in THF (2 mL) and the mixture was stirred at room temperature for 30 min. The amino alcohol did not completely dissolve in THF, and a suspension was always observed, even on addition of the base. A solution of 2-chloropyrimidine (86 mg, 0.751 mmol) in THF (1 mL) was then added and the mixture was left to stir at 60 °C overnight. The reaction mixture was then evaporated to dryness and the crude residue was used in subsequent experiments. LCMS: Start % B: 0, Final % B: 100. Gradient Time: 3.00 min. Stop Time: 3.50 min. Flow Rate: 1.0 mL / min. Wavelength 1: 220 nm. Solvent Pair: AA S174 / S175. Solvent A: A1=10 mM NH 4 OAc in CH 3 CN:Water (5:95) S174. Solvent B: B1=10 mMNH 4 OAc in CH 3 CN:water (95:5) S175. Column, Id: 3, Name: 3 (AA SCP 3 min) Acquity BEH C18 1.7 µm 2.1 x 50 mm. Retention Time = 1.213 min. (m / z): (M+H) +< = 194.2.

[0261] In a similar fashion, the following intermediates were prepared. TABLE 1Intermediate No.HeterocycleIntermediateLCMS R T (min.)(m / z): (M+H) +< I-14 1.63236.3I-15 0.92224.0I-16 1.02234.0I-17 1.08302.9 [+ACN]I-18 0.98222.0I-19 0.88208.0 INTERMEDIATE 206-fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0262]

[0263] A 60% dispersion of sodium hydride (0.530 g, 13.25 mmol) in mineral oil was added in portions to a solution of 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2 g, 11.04 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 30 min, then methyl iodide (0.829 mL, 13.25 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water and a yellow solid separated that was collected by filtration. The solid was suspended in ethyl acetate, and the resultant mixture was filtered and the filtrate concentrated in vacuo to give the product as a yellow colored solid, (395 mg, 2.024 mmol, 18.33 % yield). LCMS: (m / z):(M+H) +< = 196. 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.83-7.74 (m, 2H), 7.55-7.46 (m, 1H).INTERMEDIATE 216-fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione

[0264]

[0265] To a solution of ethyl 2-nitroacetate (293 mg, 2.198 mmol) in NMP (5 ml) in a round-bottomed flask at 0 °C, a 60% dispersion of sodium hydride (96 mg, 2.398 mmol) in mineral oil was added in portions. The reaction mixture was stirred 5 minutes at 0 °C, then 15 minutes at room temperature. Then 6-fluoro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (390 mg, 1.998 mmol) was added and the reaction mixture was heated at 120 °C for 2 hr. LC / MS shown completion of reaction. The reaction was quenched with the addition of ice-water. The mixture was acidified with 1 N HCl solution. Ethyl ether was added and 6-fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione (140 mg, 0.588 mmol, 29.4 % yield) as a yellow solid. LCMS: (m / z):(M+H) +< = 239.INTERMEDIATE 224-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one

[0266]

[0267] In a sealed tube, 6-fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione (140 mg, 0.588 mmol) and phosphorus oxychloride (3 mL, 32.2 mmol) were added. The reaction mixture was heated at 95 °C for 4 hr. The mixture was poured into ice-water, neutralized with saturated NaHCO 3 solution, and extracted with dichloromethane (2 X 20 mL). The organic layers were combined, dried (MgSO 4 ) and concentrated to give 4-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (140 mg, 0.546 mmol, 93 % yield) as an orange solid. LCMS:(m / z) 257 (MH +< ).INTERMEDIATE 23Ethyl 3-aminopicolinate

[0268]

[0269] To a stirred suspension of 3-aminopicolinic acid (150 g, 1086 mmol) in ethanol (1500 mL) at 0-5 °C was added H 2 SO 4 (463 mL, 8688 mmol) through a 1 L addition funnel over 60 min. After completion of the addition, the clear brown solution was refluxed at 90 °C for 24 h. The reaction mixture was then cooled to room temperature before being poured onto ice pellets in a 10 L beaker with overhead stirring. The mixture was basified using NH 4 OH solution (~2 L required) to pH ~9, and stirred at room temperature for a further 60 min. Solid material was observed in the beaker which was filtered through Buchner funnel, washed with water (1 L) and dried under line vacuum to yield 60 g of product as an off-yellow solid. The filtrate was extracted using DCM (3 x 1000 mL), and the combined extracts were washed with brine (1 x 1.5 L), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield ethyl 3-aminopicolinate (116 g, 691 mmol, 63.6 % yield). LCMS: m / z = 167.2 (m / z):(M+H); RT 0.78 min; Method: Column-KINETEX-XB-C18 (75 X 3mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 24Ethyl 3-acetamidopicolinate

[0270]

[0271] To a stirred solution of ethyl 3-aminopicolinate (115 g, 692 mmol) in THF (1000 mL) was added Ac 2 O (588 mL, 6228 mmol) at room temperature. The reaction mixture was heated to 60 °C under a nitrogen atmosphere for ~7-8 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated at water bath temperature (~ 50 °C) under line vacuum, followed by acetic acid removal under high vacuum at 50 °C to yield an off-white solid. The solid was triturated with petroleum ether (500 mL), stirred for 30 min at room temperature, then filtered through a Buchner funnel and washed with petroleum ether (500 mL). The filtrate was dried under vacuum at room temperature for 3 h to yield ethyl 3-acetamidopicolinate (139 g, 641 mmol, 93 % yield) as an off-white solid; LCMS: m / z = 209.3 (m / z): (M+H); rt 0.76 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3 mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 25Ethyl 3-(N-methylacetamido)picolinate

[0272]

[0273] To a stirred light brown suspension of ethyl 3-acetamidopicolinate (75 g, 360 mmol) and cesium carbonate (176 g, 540 mmol) in DMF (750 mL) was added methyl iodide (36.0 mL, 576 mmol) at room temperature (slight exotherm observed). The resulting partial brown mixture was stirred at room temperature for ~8 h. The reaction was quenched with water (1500 mL) [slight exotherm observed] and extracted with DCM (3 x 1000 mL). The combined extracts were washed with water (2 x 1000 mL) and the aqueous layer re-extracted with DCM (2 x 500 mL). The combined organic solutions were washed with brine (2 x 1000 mL), dried over Na 2 SO 4 , filtered and concentrated at ~50 °C, and then dried under vacuum at ~60 °C to yield a brown colored solution (contains some DMF). The material was dried under high vacuum to remove DMF at 58 °C for 25 min to yield a brown solid, which was dissolved in petroleum ether (1000 mL), stirred for 30 min at room temperature, filtered through a Buchner funnel, washed with petroleum ether (500 mL) upon filtration, dried under line vacuum for 8 h to yield ethyl 3-(N-methylacetamido)picolinate (70 g, 302 mmol, 84 % yield) as a brown solid; LCMS: m / z = 223.2 (m / z): (M+H); rt 0.64 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 262-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide

[0274]

[0275] To a stirred brown clear solution of ethyl 3-(N-methylacetamido)picolinate (70 g, 315 mmol) in DCM (700 mL) at 0-5 °C was added urea hydrogen peroxide (44.4 g, 472 mmol), followed by trifluoroacetic anhydride (66.7 mL, 472 mmol) slowly over 40 min through a 100 mL addition funnel. The reaction mixture solidified during the trifluoroacetic anhydride addition. After completion of the addition, the reaction mixture was stirred at room temperature for ~2 h. The reaction was quenched with 10 % NaHCO 3 solution (700 mL). The reaction mixture was extracted with DCM (3 x 500 mL). The combined organic layer was washed with brine solution (2 x 500 mL), dried over Na 2 SO 4 and concentrated to yield 2-(ethoxycarbonyl)-3-(N-methylacetamido) pyridine 1-oxide (70 g, 285 mmol, 90 % yield) as a light yellow solid; LCMS: m / z = 239.0 (m / z): (M+H); rt 0.48 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 27Ethyl 6-cyano-3-(N-methylacetamido)picolinate

[0276]

[0277] To a stirred pale yellow solution of 2-(ethoxycarbonyl)-3-(N-methylacetamido) pyridine 1-oxide (50 g, 210 mmol) in DCM (500 mL) at room temperature was added trimethylsilyl cyanide (39.4 mL, 294 mmol). The reaction mixture was stirred for 10 min and then cooled to -10 °C. Benzoyl chloride (34.1 mL, 294 mmol) was added through a 50 mL addition funnel over 15 min followed by TEA (41.0 mL, 294 mmol) through a 50 mL addition funnel slowly over 20 min. An exothermic reaction was observed during TEA addition. The reaction mixture turned turbid (TEA salt) and stirring was continued for 2.5 h at the same temperature. The reaction was quenched with the addition of 10 % NaHCO 3 solution (500 mL). The mixture was extracted with DCM (3 x 300 mL). The combined organic solution was washed with brine (2 x 250 mL), then dried over Na 2 SO 4 and concentrated to yield a light yellow crude material. The crude material was purified through normal phase RediSep silica column on ISCO ®< using EA / petroleum ether as eluent. The product was isolated by 65-70 % EA / petroleum ether, fractions were concentrated to afford ethyl 6-cyano-3-(N-methylacetamido)picolinate (43 g, 83 % yield) as a light brown liquid; LCMS: m / z = 248.0 (m / z):(M+H); rt 1.26 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 288-Hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0278]

[0279] To a stirred solution of ethyl 6-cyano-3-(N-methylacetamido)picolinate (0.9 g, 3.64 mmol) in tetrahydrofuran (10 mL) was added KHMDS (4.80 mL, 4.37 mmol) at -78 °C over 10 min. The reaction mixture was stirred for 15 min. The reaction mixture was slowly warmed to room temperature over 30 min and then stirred for another 90 min. The reaction mixture was cooled to 0 °C. The reaction was quenched with the addition of saturated sodium bicarbonate solution (70 mL). The mixture was diluted with ethyl acetate (2 x100 mL). The aqueous layer was collected and acidified with 1.5 N HCL to adjust the pH to ~3.0. The mixture was stirred for 15 min to form a solid mass, which was filtered through a Buchner funnel to yield 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile 550 mg, 75 % yield) as a brown solid. LCMS: m / z = 202.0 (m / z):(M+H); rt 0.36 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3 mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 298-Chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0280]

[0281] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.55 g, 2.73 mmol) in acetonitrile (10 mL) was added POCl 3 (1.53 mL, 16.4 mmol). The reaction mixture was heated to 85 °C over 5 min and then stirred for 16 h. The reaction mixture was concentrated under reduced pressure to yield the crude product. The reaction mixture was cooled to 0 °C. The reaction was quenched by the addition of saturated sodium bicarbonate solution (50 mL). The resultant mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to yield 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.25 g, 29.1 % yield) as a brown solid. LCMS: m / z = 220.2 (m / z):(M+H); rt 1.53 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3 mm- 2.6µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 306-Cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate

[0282]

[0283] To a mixture of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.3 g, 1.49 mmol), DMAP (0.018 g, 0.15 mmol) and TEA (0.312 mL, 2.24 mmol) in DCM (30 mL) was added dropwise trifluoromethanesulfonic anhydride (0.269 mL, 1.640 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred for 3 h. The reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure to yield 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (0.45 g, 81 % yield) as a pale yellow solid; LCMS: m / z = 334.2 (m / z):(M+H); rt 1.40 min. LC-MS Method: Column-AQUITY UPLC BEH C18 (3.0 x 50 mm)1.7 µm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100 % B over 2.0 minutes, then a 0.2 minute hold at 100 % B, flow rate 0.7 mL / min.INTERMEDIATE 318-Hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0284]

[0285] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (1 g, 4.97 mmol) in acetic acid (10 mL) was added nitric acid (0.666 mL, 14.91 mmol). The mixture was heated to 80 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water, stirred for 10 min and the resulting solid was filtered to yield 8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.805 g, 65.1 % yield) as pale yellow solid; LCMS: m / z = 247.2:(M+H); rt 1.19 min.LC-MS Method: Column-KINETEX-XB-C18 (75 x 3 mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile(2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then Gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 328-chloro-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0286]

[0287] 8-Hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (192 mg, 0.780 mmol) was dissolved in a mixture of acetonitrile (3.1 mL) and DIEA (0.272 ml, 1.560 mmol) to give a yellow colored solution. POCl 3 (0.131 ml, 1.404 mmol) was then added and the mixture stirred under nitrogen at room temperature for 1 h. Benzyltriethylammonium chloride (200 mg, 0.878 mmol) was added and the mixture was heated at 65 °C for 1 h. The mixture was concentrated in vacuo, and the residue dissolved in ethyl acetate and the resultant solution poured onto ice. This was left for approximately 1 h, before being transferred to a separatory funnel. The organic layer was collected and the aqueous solution was extracted with additional ethyl acetate. The combined organic layers were washed sequentially with 1.5M K 2 HPO 4 solution, saturated NaHCO 3 solution and then brine. The mixture was then dried over MgSO 4 , filtered and then evaporated in vacuo to give a brown crystalline solid (204 mg, 90% yield). LCMS: (m / z): (M+H) +< = 264.9. 1< H NMR (CHLOROFORM-d) δ 8.03 (d, J=8.8 Hz, 1H), 7.89-7.97 (m, 1H), 3.82 (s, 3H).INTERMEDIATE 336-Cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate

[0288]

[0289] To a suspension of 8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.25 g, 1.016 mmol) in dry DCM (10 mL) was added TEA (0.212 mL, 1.523 mmol) followed by trifluoromethanesulfonic anhydride (0.183 mL, 1.117 mmol) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 3 h. The reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure to yield 6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (0.25 g, 48.8 % yield) as a light brown solid; LCMS: m / z = 379.2 (m / z):(M+H); rt 1.66 min. LC-MS Method: Column- AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 µm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100 % B over 2.0 minutes, then a 0.2 minute hold at 100 % B, flow rate 0.7 mL / min.INTERMEDIATE 347-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0290]

[0291] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (1000 mg, 4.97 mmol) in dry DMF (10 mL) was added NBS (973 mg, 5.47 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to yield residue. The residue was dissolved in water and stirred for 10 min. The solid material was filtered and washed with petroleum ether to yield 7-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.8 g, 56.9 % yield) as an off-white solid; LCMS: m / z = 282:(M+H); rt 1.60 min. Method: Column-KINETEX-XB-C18 (75 x 3 mm- 2.6 µm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100 % B over 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100 % B flow rate 1.5 mL / min; then gradient: 100-20 % B over 0.1 minutes, flow rate 1.5 mL / min.INTERMEDIATE 353-bromo-6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate

[0292]

[0293] To a stirred solution of 7-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.175 g, 0.625 mmol) and TEA (0.131 mL, 0.937 mmol) in dry DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.137 mL, 0.812 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with water, followed by brine wash, the organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to yield 3-bromo-6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (190 mg, 53.9 % yield) as a pale yellow solid; LCMS: m / z = 414 (m / z):(M+H); rt 1.61 min. Method: Column- AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 µm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100 % B over 2.0 minutes, then a 0.3 minute hold at 100 % B, flow rate 0.7 mL / min.INTERMEDIATE 36Ethyl 3-amino-6-bromopicolinate

[0294]

[0295] Ethyl 3-aminopicolinate (8.0 g, 48.1 mmol) was suspended in water (66 mL) in a 250 mL three neck round bottom flask equipped with a mechanical stirrer, addition funnel and thermocouple temperature probe. Sulfuric acid (1.7 mL, 31.9 mmol) and acetic acid (3.31 mL, 57.8 mmol) were added slowly while the flask was immersed in a room temperature water bath to control temperature. To the reaction mixture, a solution of bromine (2.5 mL, 48.5 mmol) in acetic acid (17.5 mL, 306 mmol) was added over 15 minutes at ambient temperature with vigorous stirring while maintaining the internal temperature of the reaction mixture below 23 °C. The water bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction suspension was filtered and rinsed with a small amount of water, and then dried in vacuo at room temperature to yield ethyl 3-amino-6-bromopicolinate (9.305 g) as a yellow solid. LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 µm particles; Mobile Phase A: 100 % water with 0.05% trifluoroacetic acid; Mobile Phase B: 100 % acetonitrile with 0.05% trifluoroacetic acid; Temperature: 40 °C; Gradient: 2-98 % B over 1.5 minutes, then a 0.5 minute hold at 98% B; Flow: 0.8 mL / min; Detection: UV at 220 nm. Retention Time 0.94 min.; Obs. Adducts: [M+H]; Obs. Masses: 245.0. 1< H NMR (DMSO-d 6 ) δ 7.44 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.88 (br. s., 2H), 4.29 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).INTERMEDIATE 37Ethyl 3-acetamido-6-bromopicolinate

[0296]

[0297] Ethyl 3-amino-6-bromopicolinate (1.31 g, 5.35 mmol) was dissolved in THF (6 mL) followed by the addition of acetic anhydride (1.6 mL, 16.96 mmol). The reaction mixture was a suspension / partial solution. The reaction mixture was placed under a nitrogen atmosphere and heated to reflux. The reaction mixture became homogeneous within 15 minutes. The reaction mixture was refluxed for 4 hrs. The reaction volatiles were removed in vacuo using a rotary evaporator. A small amount of ethyl acetate was added to the reaction residue and a nearly colorless solid was filtered off and dried in vacuo to yield ethyl 3-acetamido-6-bromopicolinate (787 mg). LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 µm particles; Mobile Phase A: 100 % water with 0.05% trifluoroacetic acid; Mobile Phase B: 100 % acetonitrile with 0.05% trifluoroacetic acid; Temperature: 40 °C; Gradient: 2-98 % B over 1.5 minutes, then a 0.5 minute hold at 98% B; Flow: 0.8 mL / min; Detection: UV at 220 nm. Retention Time 0.98 min.; Obs. Adducts: [M+H]; Obs. Masses: 287.0. 1< H NMR (DMSO-d 6 ) δ 10.40 (s, 1H), 8.32 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J=7.2 Hz, 3H). Removal of solvent from the filtrate provided an additional 695 mg of product (87% pure).INTERMEDIATE 38Ethyl 6-bromo-3-(N-methylacetamido)picolinate

[0298]

[0299] A solution was prepared by dissolving ethyl 3-acetamido-6-bromopicolinate (5 g, 17.41 mmol) into DMF (100 mL). Next, cesium carbonate (8.15 g, 25.01 mmol) and methyl iodide (1.75 mL, 28.0 mmol) were added. The reaction mixture was placed under a nitrogen atmosphere and stirred at room temperature for 2 hours and 40 minutes. Solvent was removed in vacuo using a rotary evaporator / vacuum pump combination. Ethyl acetate and DCM were added to the reaction residue along with chloroform and toluene. The mixture was filtered through a celite pad to remove salts. Solvents were again removed in vacuo using a rotary evaporator. The reaction residue was again dissolved in chloroform and toluene and filtered through a celite bed to remove trace insolubles still present. Removal of solvents in vacuo yielded 5.35 g of the product as an orange oil. LCMS; Column: Waters Acquity BEH 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 10:90 acetonitrile:water with 0.1% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.1% TFA; Temperature: 40 °C; Gradient 0 %B to 100 %B over 2 minutes, then 1 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection volume: 1 µL. Retention Time 1.07 min.; Obs. Adducts: [M+H]; Obs. Masses: 301.1. Proton NMR shows characteristics of restricted rotation (rotamers); 1< H NMR (500 MHz, CHLOROFORM-d) δ 7.72 (d, J=8.4 Hz, 0.8H), 7.66 (d, J=8.4 Hz, 0.2H), 7.51 (d, J=8.4 Hz, 0.8H), 7.45 (d, J=8.4 Hz, 0.2H), 4.50-4.36 (m, 2.0H), 3.37 (s, 0.6H), 3.19 (s, 2.4H), 2.24 (s, 0.6H), 1.82 (s, 2.5H), 1.43-1.36 (m, 3.1H).INTERMEDIATE 396-Bromo-4-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one

[0300]

[0301] A 25 mL round bottom flask was charged with KHMDS (4.3 mL, 2.150 mmol) (0.5 M in toluene), placed under nitrogen and cooled to -78 °C. To the solution of KHMDS was slowly added a solution of ethyl 6-bromo-3-(N-methylacetamido)picolinate (215mg, 0.714 mmol) in THF (2.5 mL) over approximately 3 minutes. The reaction mixture was warmed to room temperature and a 1:1 mixture of ethyl acetate and water were added to fill the 60 mL separatory funnel. The phases were allowed to separate. The aqueous phase was acidified with 2.5 mL of 1 N hydrochloric acid and concentrated on the rotary evaporator using a vacuum pump. The crude residue was swirled in an Erlenmeyer flask with 7 mL of water. A yellow solid collected and dried under vacuum to give the title compound (130.2 mg, 72%). LCMS; Column: Waters Acquity UPLC BEH C18 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 100 water with 0.05% TFA; Mobile Phase B: 100 acetonitrile 0.05% TFA; Temperature: 40 °C; Gradient 2 %B to 98 %B over 1.5 minutes, then 1 min hold at 100 %B; Flow: 0.8 mL / min; Detection: MS and UV (220 nm). Injection volume: 3 µL. Retention Time 0.8 min.; Obs. Adducts: [M+H]; Obs. Masses: 254.9, 256.9.INTERMEDIATE 406-Bromo-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate

[0302]

[0303] In a round bottom flask, 6-bromo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione (200 mg, 0.784 mmol) was combined with DMAP (9.58 mg, 0.078 mmol), DIPEA (0.205 mL, 1.176 mmol) and DCM (20 mL). To the resulting suspension, a solution of trifluoromethanesulfonic anhydride (0.141 mL, 0.863 mmol) in dichloromethane (2 mL) was added dropwise at 0 °C. The solution was stirred for 3 hours. LC / MS analysis indicated the reaction was complete. The solvent was removed under reduced pressure and the crude was purified by chromatography with 1:1 hexane:ethyl acetate on a 24 g silica gel column to afford the product as white solid (260 mg, 86 %). Analytical LC\MS conditions: Injection Vol= 1 µL, Start %B 0, Final %B 100, Gradient Time 2 Minutes, Flow Rate 1 mL / min, Wavelength 220 nm, Solvent Pair acetonitrile / water / TFA, Solvent A 10% Acetonitrile / 90 % Water / 0.1% TFA, Solvent B 90 % Acetonitrile / 10 % Water / 0.1% TFA, Column Acquity BEH C18 21. X 50 mm 1.7 µm, Oven Temp= 40 °C. LC\MS results; retention time 1.5 minutes, observed mass 386.7,388.7 (M +< ).INTERMEDIATE 412-cyanoacetyl chloride

[0304]

[0305] A few drops of DMF were added to a solution of 2-cyanoacetic acid (500 mg, 5.88 mmol) in CH 2 Cl 2 (5 mL). Then a solution of 2 M oxalyl chloride (3.23 mL, 6.47 mmol) in methylene chloride was added dropwise. The reaction mixture was stirred at room temperature for 2 hr. and concentrated.INTERMEDIATE 426-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile

[0306]

[0307] To a solution of ethyl 3-amino-6-bromopicolinate (1.3 g, 5.30 mmol) in DCM (10 mL), DIPEA (2.78 mL, 15.91 mmol) was added. Then 2-cyanoacetyl chloride (0.609 g, 5.88 mmol) in DCM (10 mL) was added slowly. The reaction mixture was stirred at room temperature for 10 min. LC / MS shown formation of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate (MS at 312). The reaction was quenched with water and the resultant mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried (MgSO 4 ) and concentrated to give a brownish thick oil as crude product. The crude product was triturated with ethyl acetate / hexanes to give a yellow solid. 1< HNMR confirms its structure as the cyclized product with DIPEA. The product was washed with 1 N HCl solution and 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (650 mg, 2.443 mmol, 46.1 % yield) as an off-white solid. 1< H NMR(DMSO-d 6 ). LCMS:(m / z) >90% pure, 266, 268 (MH +< ).INTERMEDIATE 436-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile

[0308]

[0309] To a solution of 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (250 mg, 0.940 mmol) in DMF (5 mL), 60% sodium hydride (113 mg, 2.82 mmol) in mineral oil was added in portions. The reaction mixture was stirred at room temperature for 30 min., and iodomethane (0.176 mL, 2.82 mmol) was added. The reaction mixture was stirred at room temperature for overnight.INTERMEDIATE 446-Bromo-3 -cyano-1 -methyl -2-oxo-1-2-oxo-1,2-dihydro-1, 5 -naphthyri din-4-yl trifluoromethanesulfonate

[0310]

[0311] To a stirred solution of 6-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (0.6 g, 2.14 mmol) in DCM (8 mL) were added TEA (0.896 mL, 6.43 mmol) and DMAP (0.026 g, 0.214 mmol) at 0 °C, followed by the addition of trifluoromethanesulfonic anhydride (0.724 mL, 4.28 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 3 h. The reaction was quenched with the addition of water (50 mL). The reaction mixture was diluted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield a brown solid. The crude compound was triturated with DCM and hexane (1:4) to yield 6-bromo-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (700 mg, 79 % yield) as a brown solid; LCMS: m / z = 414.1 (m / z):(M+H); rt 0.65 min. LC-MS Method: Column-AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 µm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100 % B over 2.0 minutes, then a 0.3 minute hold at 100 % B, flow rate 0.7 mL / min.INTERMEDIATE 456-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0312]

[0313] To a 500 mL round-bottom flask charged with 6-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (2.50 g, 8.93 mmol) in acetonitrile (89 ml), DIEA (9.4 ml, 53.8 mmol) was added and the mixture was stirred for 2 min during which time it became homogeneous. POCl 3 (3.3 ml, 35.4 mmol) was then added, followed by benzyltriethylammonium chloride (2.68 g, 11.77 mmol) and the reaction mixture was stirred under nitrogen at room temperature overnight. The mixture was then concentrated under line vacuum initially, then under high vacuum. The residue was then poured onto a mixture of ice and 1.5 M K 2 HPO 4 solution. After 30 min the mixture was extracted using chloroform (3 x). The combined extracts were washed sequentially with K 2 HPO 4 solution, 1 N HCl solution and then brine. The organic solution was then dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product as a brown solid (3.1g). The product was purified by flash chromatography on silica gel using 2% ethyl acetate in DCM as eluent. Homogeneous fractions were combined and evaporated under reduced pressure to give the product as a yellow colored solid, 1.922 g (yield 72%). LCMS:(m / z):(M+H) +< = 298.05. 1< H NMR (500 MHz, CHLOROFORM-d) δ 7.83 (d, J=8.8 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H).INTERMEDIATE 464,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0314]

[0315] A 4 M solution of HCl in dioxane (20 mL, 80 mmol) was added to 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (1 g, 3.35 mmol) in a dry glass pressure tube. The reaction mixture was sealed and heated at 85 °C for 4 days. The mixture was then cooled and concentrated under vacuum. The residue was triturated with methanol and a solid was collected by filtration and dried in vacuo to give the hydrochloride salt of the title compound as a brown colored solid, (0.78 g, 2.68 mmol, 80 % yield). (LCMS: (m / z):(M+H) +< = 254.15, 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J=9.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 3.66 (s, 3H).INTERMEDIATE 47Ethyl 6-bromo-3-(2-cyanoacetamido)picolinate

[0316]

[0317] To a stirred solution of ethyl 3-amino-6-bromopicolinate (2.0 g, 8.16 mmol) in DMF (15 mL) were added 2-cyanoacetic acid (1.388 g, 16.32 mmol) and TEA (2.84 mL, 20.40 mmol) followed by 1-propanephosphonic anhydride (10.78 mL, 17.95 mmol). The reaction mixture was stirred at room temperature for 16 hours and was then quenched by the careful addition of water (100 mL). The resultant mixture was stirred for 15 min during which time a solid separated that was collected by filtration to give the proudct as a yellow colored solid, (2.45 g, 7.85 mmol, 96 % yield).INTERMEDIATE 48Ethyl 6-cyano-3-(2-cyanoacetamido)picolinate

[0318]

[0319] To a stirred solution of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate (200 mg, 0.641 mmol) in NMP (8 mL) were added zinc (8.38 mg, 0.128 mmol) and zinc cyanide (150 mg, 1.282 mmol) under nitrogen. The mixture was purged with nitrogen for 3 min, after which dppf (21.31 mg, 0.038 mmol) and Pd 2 (dba) 3 (58.7 mg, 0.064 mmol) were added and purging was continued for a further 3 min. The reaction mixture was then heated to 80 °C over 5 min and the mixture was stirred for an additional hour before being allowed to cool to room temperature. The reaction was then quenched by the addition of water, and the resultant mixture was filtered through a bed of celite. The filtrate was extracted using ethyl acetate (3 x 100 mL) and the combined extracts were washed with brine solution (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography on silica gel using 34 % -39 % ethyl acetate / pet.ether as eluant. Homogeneous fractions were combined and evaporated in vacuo to give the product as a as brown solid, (70 mg, 0.271 mmol, 42.3 % yield) LCMS Method; Buffer: 10 mM AmmoniumAcetate pH -5 adjusted with HCOOH Mobile phase A: Buffer: ACN (95:5) Mobile phase B:Buffer: ACN (5:95) Description: Method:%B: Omin-5%: 1.1min - 95%:1.7min-95% Column Name: Acquity BEH C18 (2.1 x 50 mm) 1.7 um Method:C:\MassLynx\BMS_2013. Flow: 0.8 ml / min LCMS RT =1.10 min (M-H) -< = 257.2).INTERMEDIATE 496,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile

[0320]

[0321] To a stirred solution of ethyl 6-cyano-3-(2-cyanoacetamido)picolinate (70 mg, 0.271 mmol) in DCM (5 mL) was added triethylamine (0.113 mL, 0.813 mmol). The reaction mixture was warmed to 45 °C and then stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue triturated with ethyl acetate for 15 min. The resultant suspension was filtered and the filtrand dried under reduced pressure to give the product as a brown colored solid, (54 mg, 0.255 mmol, 94 % yield). LCMS: (m / z):(M+H) +< = 213.2INTERMEDIATE 505-methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile

[0322]

[0323] NaH (28.3 mg, 0.707 mmol was added to a stirred solution of 6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile (50 mg, 0.236 mmol) in DMF (3 mL) at 0 °C. The stirred mixture was then allowed to warm to room temperature. Methyl iodide (0.044 mL, 0.707 mmol) was added and stirring was continued under a nitrogen atmosphere for 3 h. The reaction was quenched by the addition of water (10mL). The pH of the mixture was adjusted to ~ 6 using 1.5 N HCl. The resultant mixture was stirred for 15 min during which time a solid separated that was collected by filtration and then dried under reduced pressure to give the product as a brown colored solid, (20 mg, 0.088 mmol, 37.5 % yield). LC-MS: Method info: Column-Ascentis Express C8 (50 X 2.1 mm-2.7 µm), Mphase A: (2%ACN-98 %H 2 O-10 mM NH 4 COOH), Mphase B: (98% ACN-2 % H 2 O-10 mM NH 4 COOH), Flow = 1mL / min, Time %B (0.0 0.0), (1.5 100.0), (3.2 100.0). LC-MS RT = 1.301 min (m / z): (M+H) +< = 225.0.INTERMEDIATE 518-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile

[0324]

[0325] The starting material, the hydrochloride salt of 5-methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile, was dried overnight at 90 °C under vacuum before performing the reaction. To a stirred suspension of the hydrochloride salt of 5-methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile (10 g, 38.1 mmol) in acetonitrile (100 mL) was added DIPEA (19.95 mL, 114 mmol). The resulting turbid brown solution was cooled to 0-5 °C and POCl 3 (40.8 mL, 438 mmol) was added slowly over ~20 min, after which the mixture was heated to 90 °C for ~ 1 h. The reaction mixture was cooled to room temperature and then concentrated under high vacuum to afford a pale brown colored residue. Ice pellets were added and the slurry was stirred for ~15 min, during which time a free flowing solid formed. The mixture was neutralized by the addition of saturated NaHCO 3 solution, and the product extracted using DCM (4 x 500 mL). The combined extracts were washed with brine (1 x 500 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the crude product as a brown colored solid. This was triturated with acetone (50 mL), and the product was collected by filtration and dried in vacuo to give 6 g of a solid. The filtrate was concentrated and the residue again triturated with acetone to give an additional 2.4 g of a solid. The solids were combined to give the title compound as a brown colored solid, (8.4 g, 33.8 mmol, 89 % yield).INTERMEDIATE 526-chloro-4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0326]

[0327] Piperidin-4-ol (110 mg, 1.084 mmol) was added to a solution of 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile hydrochloride (300 mg, 1.033 mmol) and triethylamine (0.720 mL, 5.16 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature overnight before being quenched by the addition of water. On stirring, a yellow colored solid separated and was collected by filtration and then dried in vacuo to give the title compound as a yellow solid, (325 mg, 1.020 mmol, 99 % yield). LCMS: (m / z): (M+H) +< = 319.08, 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.04 (d, J=9.2 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 4.72 (d, J=4.4 Hz, 1H), 4.14-3.99 (m, 2H), 3.87 (br dd, J=8.1, 4.0 Hz, 1H), 3.59 (ddd, J=13.0, 9.4, 3.3 Hz, 2H), 3.53 (s, 3H), 1.98 (ddd, J=9.4, 5.7, 2.9 Hz, 2H), 1.70 (td, J=8.4, 4.4 Hz, 2H).INTERMEDIATE 53(+ / -) 6-bromo-4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0328]

[0329] To a solution of 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (1.0 g, 3.35 mmol) in DMF (8 mL), (+ / -) cis-3-methylpiperidin-4-ol (0.405 g, 3.52 mmol) and triethylamine (1.167 mL, 8.37 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Water was then added and an orange solid separated that was collected by filtration. The crude product was triturated with methanol / dichloromethane and the final product was obtained by filtration as a yellow-colored solid, (0.82 g, 2.174 mmol, 64.9 % yield). LCMS: (m / z): (M+H) +< = 376.9. 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.97-7.87 (m, 1H), 8.02-7.79 (m, 1H), 4.79-4.64 (m, 1H), 3.91-3.71 (m, 4H), 3.51 (s, 3H), 3.45 (br dd, J=12.3, 10.1 Hz, 1H), 2.06 (ddd, J=9.7, 6.5, 3.2 Hz, 1H), 1.87 (br d, J=3.9 Hz, 2H), 0.91 (d, J=6.8 Hz, 3H).EXAMPLE 49(+ / -) 6-bromo-1-methyl-4-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0330]

[0331] To a solution of 4-(tert-pentyl)phenol (65.3 mg, 0.398 mmol) in THF (8 mL), triphenylphosphine (194 mg, 0.583 mmol) on solid support was added. The reaction mixture was stirred at room temperature for 5 min. Then, di-tert-butyl (E)-diazene-1,2-dicarboxylate (98 mg, 0.424 mmol) and (+ / -) 6-bromo-4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (100 mg, 0.265 mmol) were added. The reaction mixture was stirred at room temperature for 6 days. The reaction mixture was then filtered and the filtrate concentrated under vacuum to give a yellow solid. The product was purified using reverse phase preparative HPLC column using a CH 3 CN-H 2 O-TFA solvent system as eluent. Homogeneous fractions were collected and concentrated in vacuo to give the TFA salt of the title compound as a light-yellow colored solid, (31 mg, 0.049 mmol, 18.34 % yield). LCMS: (m / z):(M+H) +< = 523.0. 1< H NMR (400 MHz, Acetone) δ 7.98 (d, J=9.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.40-4.32 (m, 2H), 4.31-4.23 (m, 1H), 3.77 (ddd, J=13.4, 10.9, 2.8 Hz, 1H), 3.63 (s, 3H), 3.35 (dd, J=13.2, 9.8 Hz, 1H), 2.54-2.42 (m, 1H), 2.37 (ddd, J=12.6, 6.2, 2.9 Hz, 1H), 1.97-1.78 (m, 1H), 1.15 (d, J=6.6 Hz, 3H), 0.69 (t, J=7.5 Hz, 3H). A full assignment was not made due to obfuscation of certain compound associated peaks by solvent impurities.INTERMEDIATE 558-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile

[0332]

[0333] To a stirred suspension of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile hydrochloride (10 g, 38.1 mmol) in acetonitrile (100 mL) was added DIPEA (19.95 mL, 114 mmol). The turbid brown colored solution was cooled to 0-5 °C. POCl 3 (40.8 mL, 438 mmol) was then added slowly over ~20 min through a dropping funnel. The resulting mixture was heated to 90 °C for 1 min and then allowed to cool to room temperature. The mixture was concentrated under high vacuum to give a pale brown colored residue. Ice pellets were added and the resulting mixture was stirred for ~15 min during which time a free flowing solid formed. The mixture was neutralized using saturated NaHCO 3 solution and then extracted with DCM (4 x 500 mL). The combined extracts were washed with brine solution (1 x 500 mL), dried over Na 2 SO 4 , filtered and then concentrated to provide a brown colored material. The product was triturated with acetone (50 mL), and a solid was collected by filtration which was dried in vacuo to give the title compound as a brown solid (6 g). The filtrates were evaporated and the residue again triturated with acetone and additional product was obtained. The combined filtrates were dried in vacuo to give a the title compound as a brown solid, (8.4 g, 33.8 mmol, 89 % yield). LCMS: (M+H+ H 2 O) +< = 262.0. 1< H NMR (300MHz, DMSO-d 6 ) δ 8.49-8.37 (m, 2H), 3.72-3.61 (m, 3H).INTERMEDIATE 568-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0334]

[0335] 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (0.600 g, 1.800 mmol) and 4-hydroxypiperidine (0.266 g, 2.63 mmol) were added to a mixture of acetonitrile (18.00 ml) and N-ethyl-N-isopropylpropan-2-amine (0.95 ml, 5.45 mmol) in a 50 mL round bottom flask. The mixture was heated at 80 °C for 1 h. The heterogeneous mixture was then cooled in an ice-bath at 0 °C, and the resultant yellow precipitate was collected by filtration and then dried under vacuum to give the product as a yellow solid (473 mg, 92%). 1< H NMR (500 MHz, CHLOROFORM-d) δ 7.80 (d, J=8.7 Hz, 0.9H), 7.70 (d, J=8.7 Hz, 0.9H), 6.23 (s, 0.9H), 4.02 (br s, 1.0H), 3.94-3.85 (m, 2.0H), 3.64 (s, 3.0H), 3.27 (ddd, J=12.5, 9.1, 3.3 Hz, 2.0H), 2.15-2.07 (m, 1.9H), 1.87-1.76 (m, 2.0H).INTERMEDIATE 57(+ / -) 4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-6-cyano-1-methyl-1,5-naphthyridin-2(1H)-one

[0336]

[0337] cis-3-methylpiperidin-4-ol (34.6 mg, 0.300 mmol) was added to a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (100 mg, 0.300 mmol) and Hunig's base (0.105 mL, 0.600 mmol) in DMF (4 mL). The mixture was heated at 85 °C overnight. The solvent was removed under high vacuum and residue dissolved in EtOAc. The resultant solution was washed with water (2 x) and once with brine. The mixture was then dried over MgSO 4 , filtered and concentrated in vacuo to give 89 mg of a yellow solid, (100%). LCMS: R T = 1.01 (m / z): (M+H) +< = 299.03. 1< H NMR (400 MHz,) δ 8.02 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 5.88 (s, 1H), 3.72 (dddd, J=4.5, 4.2, 3.5, 3.4 Hz, 1H), 3.65 (s, 3H), 3.36 (dd, J=3.1, -12.2 Hz, 1H), 3.35 (ddd, J=12.1, 3.1, -12.2 Hz, 1H), 2.88 (dd, J=12.2, 4.5 Hz, 1H), 2.88 (dd, J=12.2, 11.8 Hz, 1H), 2.12 (dqt, J=11.8, 6.6, 4.5 Hz, 1H), 1.78 (dddd, J=12.1, 3.4, 3.1, -13.5 Hz, 1H), 1.72 (ddd, J=3.5, 3.1, -13.5 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H).INTERMEDIATE 58(+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate

[0338]

[0339] To a suspension of (+ / -) cis-3-methylpiperidin-4-ol (1g, 8.68 mmol) and triethylamine (1.452 mL, 10.42 mmol) in DCM (15 mL), Boc-anhydride (2.419 mL, 10.42 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with DCM and acidified with 1 N HCl solution to pH~6. The organic layer was separated, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure of solvent gave a yellowish oil. The crude product was then purified by flash chromatography using ethyl acetate / hexanes to (10-40%) as eluent. Homogeneous fractions were collected and evaporated under reduced pressure to give the product as a colorless, viscous oil, (1.35 g, 6.27 mmol, 72.2 % yield). LCMS: 216 (m / z):(M+H) +< = 216. 1< H NMR (500 MHz, CHLOROFORM-d) δ 3.98-3.81 (m, 1H), 3.69-3.52 (m, 2H), 3.42-3.25 (m, 1H), 3.16-2.96 (m, 1H), 1.86-1.64 (m, 3H), 1.48 (s, 9H), 0.96 (d, J=7.0 Hz, 3H).INTERMEDIATE 59(+ / -) tert-butyl trans-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate

[0340]

[0341] To a solution of (+ / -) tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (0.982 g, 4.56 mmol) in THF (8 mL), triphenylphosphine (1.675 g, 6.39 mmol) and benzoic acid (0.780 g, 6.39 mmol) were added. Next, di-tert-butyl (E)-diazene-1,2-dicarboxylate (1.470 g, 6.39 mmol) in THF was added dropwise at 0 °C and the mixture was warmed and stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography using ethyl acetate in hexanes (10- 30%) as eluent. Homogeneous fractions were combined and evaporated under vacuum to give the product as a viscous, colorless oil, (0.77 g, 2.411 mmol, 52.9 % yield). 1< H NMR (500 MHz, CHLOROFORM-d) δ 8.07 (d, J=7.6 Hz, 2H), 7.66-7.53 (m, 1H), 7.51-7.40 (m, 2H), 4.94-4.73 (m, 1H), 4.10-3.94 (m, 2H), 3.21-2.99 (m, 1H), 2.89-2.58 (m, br, 1H), 2.22-2.03 (m, 1H), 1.99-1.86 (m, 1H), 1.69-1.60 (m, 1H), 1.50 (s, 9H), 1.01 (d, J=6.6 Hz, 3H).INTERMEDIATE 60(+ / -) tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate

[0342]

[0343] To a solution of (+ / -) tert-butyl trans-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate (0.761 g, 2.383 mmol) in MeOH (10 mL), sodium hydroxide (0.476 g, 11.91 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was then separated, washed sequentially with water and brine, then dried over MgSO 4 , filtered and evaporated under vacuum to give the product as a viscous, colorless oil, (446 mg, 2.072 mmol, 87 % yield). 1< H NMR (500 MHz, CHLOROFORM-d) δ 4.16-3.88 (m, 2H), 3.37-3.19 (m, 1H), 2.93-2.75 (m, 1H), 2.67-2.34 (m, br, 1H), 2.00-1.84 (m, 1H), 1.55-1.40 (m, 11H), 1.02 (d, J=6.6 Hz, 3H).INTERMEDIATE 61(+ / -) trans-3-methylpiperidin-4-ol

[0344]

[0345] To a solution of (+ / -) tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate (440 mg, 2.044 mmol) in DCM (3 mL), TFA (1 mL, 12.98 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the TFA salt of the title compound as a colorless, viscous oil.INTERMEDIATE 62(+ / -) 8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0346]

[0347] (+ / -) trans-3-methylpiperidin-4-ol, trifluoroacetate (468 mg, 2.044 mmol) was added to a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (487 mg, 1.460 mmol) and Hunig's base (1.275 mL, 7.30 mmol) in DMF (5 mL). The reaction mixture was heated at 85 °C overnight. The mixture was diluted with water and a yellow solid separated that was collected by filtration and dried under vacuum to give the product as a solid, (385 mg, 1.290 mmol, 88 % yield). LCMS: (m / z):(M+H) +< = 299. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.16 (d, J=8.9 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 6.07 (s, 1H), 4.72 (d, J=5.5 Hz, 1H),4.08-3.96 (m, 1H), 3.94-3.85 (m, 1H), 3.53 (s, 3H), 3.25-3.14 (m, 1H), 3.00-2.88 (m, 1H), 2.72-2.62 (m, 1H), 1.97-1.83 (m, 1H), 1.70-1.49 (m, 2H), 0.98 (d, J=6.6 Hz, 3H).INTERMEDIATE 636-cyano-1-methyl-4-(5-methyl-3,6-dihydropyridin-1(2H)-yl)-1,5-naphthyridin-2(1H)-one

[0348]

[0349] A dry 20 mL scintillation vial fitted with a septum was charged with triphenylphosphane (polymer supported) 3 mmol / g (2.212 mL, 0.664 mmol) and then evacuated and flushed with nitrogen. THF (2 mL) was then added, followed after ~ 1 min. by 4-(trifluoromethoxy)phenol (0.039 mL, 0.302 mmol). The resultant mixture was mixed briefly, after which a solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (111 mg, 0.483 mmol) in THF (1 mL) was added via syringe in a single portion. The mixture was agitated on an orbital shaker for 3 min., after which a solution of 8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90 mg, 0.302 mmol)) in THF (2 mL) was added in a single portion. The vial was then shaken at room temperature overnight. The reaction mixture was subsequently filtered and evaporated to dryness. The residue was dissolved in 2 mL of DMF and the resultant solution fractionated via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 31% B, 31-71% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 32.9 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 281.11; Retention Time: 1.86 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 281.11; Retention Time: 1.69 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.19-8.12 (m, 1H), 8.10-8.02 (m, 1H), 6.08-6.02 (m, 1H), 5.65-5.56 (m, 1H), 3.77-3.73 (m, 2H), 3.69-3.64 (m, 2H), 3.56-3.51 (m, 2H), 2.32-2.22 (m, 2H), 1.76-1.66 (m, 3H).INTERMEDIATE 64(+ / -) tert-butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate

[0350]

[0351] A 1 M solution of L-Selectride (16.50 mL, 16.50 mmol) in THF was added dropwise to a solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (2.5 g, 11.00 mmol) in THF (10 mL) at -78 °C. The reaction mixture was stirred under nitrogen for 2 h., followed by the sequential addition of EtOH (2 mL), water (5 mL) and 1 M NaOH solution (5 mL) at the same temperature. The reaction mixture was then warmed to 0 °C and 30% aq. H 2 O 2 (5 mL) was added dropwise. The cold bath was removed and the reaction mixture was stirred at room temperature for 2 h after which it was diluted with EtOAc. An insoluble white solid precipitated which was removed by filtration. The filtrate was collected, washed sequentially with saturated NaHCO 3 solution and brine, and then dried over MgSO 4 , filtered and evaporated under reduced pressure to give a colorless, viscous oil. This mixture was fractionated using flash chromatography on silica gel using 10-30% EtOAc in Hexanes as eluent. Homogeneous fractions were collected and evaporated in vacuo to give the product as a colorless oil, (1.6 g, 6.98 mmol, 63.4 % yield). LCMS: (M-(t-Bu)+ACN+H) +< = 215.35. 1< H NMR (500 MHz, CHLOROFORM-d). All signals were very broad.INTERMEDIATE 65(+ / -) cis-3-ethylpiperidin-4-ol, TFA Salt.

[0352]

[0353] TFA (2 mL, 26.0 mmol) was added to a solution of tert-butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate (1.6 g, 6.98 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature overnight, after which it was concentrated under reduced pressure to afford the product as a viscous, pale-yellow oil, TFA salt (1.65 g, 6.78 mmol, 97 % yield). 1< H NMR (500 MHz, CHLOROFORM-d) δ 9.03-8.82 (m, 1H), 8.82-8.60 (m, 1H), 4.19-4.02 (m, 1H), 3.38-3.20 (m, 2H), 3.17-2.99 (m, 2H), 2.08-1.97 (m, 2H), 1.90-1.80 (m, 1H), 1.52-1.40 (m, 1H), 1.40-1.29 (m, 1H), 1.02-0.94 (m, 3H).INTERMEDIATE 66(+ / -) tert-butyl trans-4-(benzoyloxy)-3-ethylpiperidine-1-carboxylate

[0354]

[0355] To a solution of (+ / -) tert-butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate (1.5 g, 6.54 mmol) in THF (10 mL), triphenylphosphine (2.402 g, 9.16 mmol) and benzoic acid (1.118 g, 9.16 mmol) were added. Di-tert-butyl (E)-diazene-1,2-dicarboxylate (2.109 g, 9.16 mmol) was added in portions at 0 °C. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography using ethyl acetate in hexanes (0-20%) as eluent. Homogeneous fractions were combined and evaporated under vacuum to give the product as a viscous, colorless oil, (1.70 g, 5.10 mmol, 78 % yield).INTERMEDIATE 67(+ / -) tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate

[0356]

[0357] To a solution of (+ / -) tert-butyl trans-4-(benzoyloxy)-3-ethylpiperidine-1-carboxylate (1.7 g, 5.10 mmol) in MeOH (15 mL), sodium hydroxide (1.020 g, 25.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was then separated, washed sequentially with water and brine, then dried over MgSO 4 , filtered and evaporated under vacuum to give the crude product as a viscous oil. The mixture was fractionated using flash chromatography on silica gel using 10-30% ethyl acetate in hexanes as eluent. Homogeneous fractions were combined and evaporated under reduced pressure to afford tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (0.68 g, 2.97 mmol, 58.2 % yield) as a viscous colorless oil. 1< H NMR (500 MHz, CHLOROFORM-d) δ 3.95 (br d, J=12.6 Hz, 1H), 3.46 (br d, J=0.9 Hz, 1H), 3.05-2.87 (m, 1H), 1.97-1.87 (m, 1H), 1.75 (br d, J=1.6 Hz, 1H), 1.51-1.40 (m, 11H), 1.40-1.30 (m, 1H), 1.25-1.15 (m, 1H), 0.99 (t, J=7.4 Hz, 3H). Spectrum was broad and could not be fully assigned.INTERMEDIATE 68(+ / -) trans-3-ethylpiperidin-4-ol, TFA

[0358]

[0359] To a solution of (+ / -) tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (0.3 g, 1.308 mmol) in dichloromethane (3 mL), 1 mL TFA was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo.INTERMEDIATE 69(+ / -) 8-(cis-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0360]

[0361] (+ / -) cis-3-ethylpiperidin-4-ol TFA salt (1.2 g, 4.93 mmol) was added to a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (1.370 g, 4.11 mmol) and Hunig's base (2.87 mL, 16.45 mmol) in DMF (8 mL). The reaction mixture was heated at 85 °C overnight under nitrogen. The resultant mixture was diluted with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over MgSO 4 , filtered and evaporated under reduced pressure to give the crude product as an orange-colored solid. The product was triturated with methanol and the residual solid was collected by filtration, and air dried to give the product as a light-yellow colored solid (520 mg, 1.665 mmol, 40.5 % yield). A portion of the filtrate was then purified under the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 10% B, 10-50% B over 22 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.5 %; Observed Mass: 313.15; Retention Time: 1.17 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 99.3 %; Observed Mass: 313.13; Retention Time: 1.22 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.17-8.10 (m, 1H), 8.10-8.02 (m, 1H), 6.11-6.01 (m, 1H), 4.70-4.62 (m, 1H), 3.91-3.84 (m, 1H), 3.75-3.66 (m, 1H), 3.31-3.22 (m, 1H), 3.14-3.05 (m, 1H), 1.87-1.71 (m, 2H), 1.71-1.60 (m, 1H), 1.49-1.36 (m, 1H), 1.34-1.21 (m, 1H), 1.00-0.86 (m, 3H). The complete spectrum was not fully assigned due to the water suppression technique used.INTERMEDIATE 704-(3-chlorophenoxy)piperidine.

[0362]

[0363] Triphenylphosphine (156 mg, 0.596 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (100 mg, 0.497 mmol) and 3-chlorophenol (63.9 mg, 0.497 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 15 min after which DIAD (0.116 mL, 0.596 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and stirred under nitrogen overnight. The reaction was quenched by the addition of water and the resultant mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried (MgSO 4 ), filtered and concentrated in vacuo to give the crude product as a yellow solid. This material was dissolved in DCM (5 mL) and 3 mL of TFA was added. The mixture was stirred at room temperature for 2 h and was then concentrated to give a yellow viscous oil. The mixture was purified using reverse phase preparative HPLC using a CH 3 OH-H 2 O-TFA buffer system. Homogeneous fractions were combined and evaporated under reduced pressure to give the TFA salt of the title compound as a white solid (101.5 mg, 0.312 mmol, 62.7 % yield). LCMS: (m / z):(M+H) +< = 212.0. 1< H NMR (400 MHz, METHANOL-d 4 ) δ 7.30 (t, J=8.2 Hz, 1H), 7.08-7.06 (m, 1H), 7.03-6.99 (m, 1H), 6.98-6.94 (m, 1H), 4.96-4.87 (m, 1H), 4.79-4.66 (m, 1H), 3.48-3.37 (m, 2H), 3.28-3.15 (m, 2H), 2.25-2.11 (m, 2H), 2.11-1.96 (m, 2H).INTERMEDIATE 714-(3-fluoro-5-methylphenoxy)piperidine

[0364]

[0365] Triphenylphosphine on solid support (3 mmol / g) (289 mg, 1.1 mmol) was added to a dried 20 mL scintillation vial that was then capped and flushed with nitrogen. The resin was suspended in DCM (3 mL) and the reaction vial was placed on an orbital shaker for 2 min. 3-Fluoro-5-methylphenol (0.081 mL, 0.745 mmol) was then added in a single portion and the mixture further agitated briefly, after which di-tert-butyl (E)-diazene-1,2-dicarboxylate (183 mg, 0.795 mmol) was added. The mixture was then shaken for a further 3 min, and tert-butyl 4-hydroxypiperidine-1-carboxylate (100 mg, 0.497 mmol) was then, and the resultant mixture was agitated at room temperature overnight. The suspension was filtered, and the resin was washed with DCM. The washings and the filtrates were combined and evaporated under reduced pressure. The residue was treated with 6 mL of a mixture of DCM and TFA, 1:1 for 30 min, and the ensuing mixture was evaporated to dryness. The residue was dissolved in DCM and 5 N NaOH solution was added. The mixture was extracted using DCM. The extracts were combined, dried over MgSO 4 , filtered and concentrated in vacuo to give the product as a colorless oil (63 mg, 61%). LCMS: (m / z):(M+H) +< = 210.10.INTERMEDIATE 72(+ / -) cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidine, TFA.

[0366]

[0367] To a solution of tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (100 mg, 0.464 mmol) in THF (2 mL), 1.0 M solution of potassium bis(trimethylsilyl)amide (1.161 mL, 1.161 mmol) in THF was added. The reaction mixture was stirred at room temperature for 30 min, then 1-fluoro-4-(trifluoromethyl)benzene (114 mg, 0.697 mmol) in THF (1 mL) was added. The reaction mixture was then heated at 60 °C for 4 h. The reaction was then quenched with water. The resultant mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO 4 , filtered and evaporated under reduced pressure to give an oil. The product was fractionated using preparative HPLC using a CH 3 CN-H 2 O-TFA system as eluent. Homogeneous fractions were combined and concentrated under reduced pressure for 24 h. The residue was dissolved in DCM (3 mL) and 1 mL TFA was added. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum to give the TFA salt of the title compound as a white solid (120 mg, 0.321 mmol, 69.2 % yield). LCMS: (m / z):(M+H) +< =260. 1< H NMR (CD 3 OD): 1< H NMR (500 MHz, METHANOL-d 4 ) δ 7.63 (br d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.77-4.73 (m, 1H), 3.28-3.12 (m, 4H), 2.33-2.18 (m, 2H), 2.08-1.93 (m, 1H), 1.11 (d, J=6.9 Hz, 3H).

[0368] The following method (Method A) was used to prepare a number of the following examples of the current invention.EXAMPLE 1 (REFERENCE)6-fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one

[0369]

[0370] 4-(3-Fluoro-5-methylphenoxy)piperidine (20 mg, 0.096 mmol) was added to a solution of 4-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (20.44 mg, 0.080 mmol) and Hunig's Base (0.028 mL, 0.159 mmol) in DMF and the resultant mixture was stirred at room temperature overnight. The crude reaction mixture was then filtered, subsequently purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 41-81% B over 25 minutes, then a 6-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 22.1 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine thefinal purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature:50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 429.94; Retention Time: 2.34 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 429.95; Retention Time: 2.33 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.76-7.57 (m, 3H), 6.75-6.62 (m, 2H), 6.64-6.55 (m, 1H), 4.68 (dt, J=7.7, 3.9 Hz, 1H), 3.66 (s, 3H), 3.45-3.31 (m, 2H), 2.30 (s, 3H), 2.22-2.10 (m, 2H), 1.97-1.81 (m, 2H). A full assignment of all peaks in the spectrum was not accomplished due to the water suppression technique employed in the NMR experiment.

[0371] The following examples were prepared according to Method B.EXAMPLE 2 (REFERENCE)6-fluoro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one

[0372]

[0373] Triphenylphosphane on solid support 3 mmol / g (82.0 mg, 0.313 mmol) was added to a dried 20 mL scintillation vial. The resin was suspended in anhydrous DCM (3 mL) for a period of 2 min under nitrogen. 4-Isopropylphenol (12.72 mg, 0.093 mmol) was the added, followed after 5 min by the addition of di-tert-butyl (E)-diazene-1,2-dicarboxylate (22.93 mg, 0.100 mmol). The resultant suspension was agitated on an orbital shaker for 3 min., and 6-fluoro-4-(4-hydroxypiperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (20 mg, 0.062 mmol) was added in a single portion. Shaking was continued at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue triturated with 2 mL of DMF. The suspension was then filtered and the crude product fractionated using preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 53-93% B over 20 minutes, then a 6-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 8.8 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 440.16; Retention Time: 2.56 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 440.18; Retention Time: 2.54 min. 1< H NMR (600 MHz, DMSO-d 6 ) δ 7.74-7.67 (m, 2H), 7.63 (dd, J=9.4, 2.0 Hz, 1H), 7.16 (br d, J=8.4 Hz, 2H), 6.93 (br d, J=8.8 Hz, 2H), 4.62 (br s, 1H), 3.64 (s, 3H), 3.14-3.07 (m, 1H), 2.87-2.77 (m, 1H), 2.19-2.07 (m, 2H), 1.93-1.83 (m, 2H), 1.17 (d, J=7.0 Hz, 6H). Some peaks associated with the piperazine ring were obscured by the water suppression techniques used in the acquisition of the spectrum.

[0374] In similar fashions, the following reference examples were prepared.Method A:

[0375] Method B:

[0376]

[0377] Method A was used to prepare a number of the following examples.EXAMPLE 106-chloro-4-(4-(3 -methoxyphenoxy)piperidin-1 -yl)-1 -methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0378]

[0379] To a solution of 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile hydrochloride (15 mg, 0.052 mmol) in DMF (1.5 mL), 4-(3-methoxyphenoxy)piperidine hydrochloride (13.84 mg, 0.057 mmol) and triethylamine (0.036 mL, 0.258 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. It was then diluted with methanol (2 mL), filtered and the crude mixture was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 38-78% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 16.5 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 425.06; Retention Time: 2.05 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 425.1; Retention Time: 2.09 min. 1< H NMR (600 MHz, DMSO-d 6 ) δ 8.07 (br d, J=8.8 Hz, 1H), 7.81 (br d, J=8.8 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 6.65-6.49 (m, 3H), 4.78 (dt, J=7.4, 3.8 Hz, 1H), 4.09-3.97 (m, 2H), 3.77-3.69 (m, 4H), 2.19 (td, J=6.1, 2.9 Hz, 2H), 1.99-1.79 (m, 2H). The full spectrum was not assigned due to the water suppression technique used in the acquisition of the spectrum.

[0380] The following method (Method B) was used to prepare a number of the following examples of the current invention.EXAMPLE 116-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0381]

[0382] To a solution of 2-(trifluoromethyl)phenol (30.5 mg, 0.188 mmol) in DCM (2 mL), triphenylphosphane (49.4 mg, 0.188 mmol) was added. The mixture was stirred at room temperature for 5 min, then 6-chloro-4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15 mg, 0.047 mmol) was added and the reaction mixture was stirred for 15 min before DIAD (0.037 mL, 0.188 mmol) was added in a single portion. The resultant mixture was stirred at room temperature under nitrogen overnight. It was then concentrated in vacuo, and the residue dissolve in a 1:1 mixture of CAN and DMF (1.8 mL). This crude mixture was then purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 41-81% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 8.0 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 463.02; Retention Time: 2.20 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 463.01; Retention Time: 2.24 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.08 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.65 (br d, J=7.0 Hz, 2H), 7.42 (br d, J=8.5 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 5.03 (br s, 1H), 4.01-3.94 (m, 2H), 3.86-3.79 (m, 2H), 3.54 (s, 3H), 2.24 (br d, J=12.2 Hz, 2H), 1.96 (br d, J=6.4 Hz, 2H).

[0383] In a similar fashion to the preceding two methods, the following examples can be prepared.Method C:

[0384] Method D:

[0385] TABLE 3Ex. No.Ar StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method12 A12.14431.1B13 A12.31479.0B14 A12.00425.1B15 A12.53451.0A16 A24.22428.9A17 A12.38497.1B18 A12.16429.1A19 A12.30478.9A20 A12.10413.1B21 A24.11408.9A22 A12.21409.1B23 A24.12446.9A24 A12.30463.1B25 A11.65466.1B26 A12.43487.0A27 A12.26428.9A28 A24.17426.9A29 A12.47493.1B30 A12.32463.1B31 A12.31467.1B32 A11.93420.1B33 A12.27479.1B34 A11.97420.1B35 A11.98425.1B36 A11.95443.0B37 A12.47437.1B38 A12.16454.0B39 A12.27459.1B40 A12.49443.1B41 A12.46513.1B42 A12.49513.0B43 A11.86420.0B44 A12.07413.1B45 A12.08413.1B46 A12.07395.1B EXAMPLE 476-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0386]

[0387] To a solution of 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.167 mmol) in DMF (4 mL), 4-(4-(trifluoromethoxy)phenoxy)piperidine (48.1 mg, 0.184 mmol) and triethylamine (0.093 mL, 0.670 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and was then quenched by the addition of water. A white colored solid separated and was collected by filtration, 85 mg. 20 mg of this material was dissolved in a 1:1 mixture of DMF and methanol, and this solution was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 41-81% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg, and its estimated purity by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.7 %; Observed Mass: 523.02; Retention Time: 2.34 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.8 %; Observed Mass: 523.03; Retention Time: 2.36 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 7.97-7.92 (m, 1H), 7.91-7.87 (m, 1H), 7.30 (br d, J=8.5 Hz, 2H), 7.14 (br d, J=8.9 Hz, 2H), 4.80 (br d, J=3.4 Hz, 1H), 4.12-3.99 (m, 2H), 3.72 (br t, J=10.1 Hz, 1H), 2.19 (br s, 2H), 1.95-1.80 (m, 2H). The full spectrum was not assigned due to the water suppression technique used in the acquisition of the spectrum.EXAMPLE 486-methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile

[0388]

[0389] 6-Bromo-1 -methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1 -yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (30 mg, 0.057 mmol), 5-[di(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'h-[1,4']bipyrazole (3.80 mg, 5.73 µmol), cesium carbonate (18.68 mg, 0.057 mmol) and Pd(OAc) 2 (0.644 mg, 2.87 µmol) were loaded into a dry vial that was subsequently sealed, evacuated and flushed with nitrogen. Acetonitrile (2 mL) and methanol (0.1 mL) were then added and the reaction mixture was heated at 80 °C overnight. The crude material was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 41% B, 41-81% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 14.4 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 475.04; Retention Time: 2.24 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 475.05; Retention Time: 2.18 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.02 (br d, J=9.2 Hz, 1H), 7.31 (br d, J=8.5 Hz, 2H), 7.25 (d, J=9.2 Hz, 1H), 7.15 (br d, J=8.9 Hz, 2H), 4.78 (br s, 1H), 4.14 (br d, J=12.5 Hz, 2H), 3.92 (s, 3H), 3.79 (br t, J=9.6 Hz, 2H), 2.22 (br s, 2H), 1.91 (br d, J=8.2 Hz, 2H).EXAMPLE 505-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile

[0390]

[0391] 6-Bromo-1 -methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1 -yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.096 mmol), zinc (1.249 mg, 0.019 mmol), zinc cyanide (6.73 mg, 0.057 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (7.80 mg, 9.55 µmol) were loaded into a dry microwave vial that was sealed, evacuated and then flushed with nitrogen. NMP (4 mL) was added and the resultant mixture was irradiated in the microwave at 75 °C for 4.5 hr. The reaction mixture was then cooled to room temperature, diluted with acetonitrile and filtered. The filtrate was fractionated using reverse phase preparative HPLC using a CH 3 CN-H 2 O-TFA system. Homogeneous fractions were combined, neutralized with saturated NaHCOs solution and then concentrated in vacuo. The product was obtained as a yellow solid, (22.5 mg, 0.048 mmol, 50.2 % yield). LCMS:(m / z) (method 2) RT = 4.39 min. (m / z):(M+H) +< = 470.1. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J=8.8 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.31 (br d, J=8.8 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 4.83 (dt, J=7.4, 4.0 Hz, 1H), 4.18-4.02 (m, 2H), 3.78 (br t, J=9.5 Hz, 2H), 3.55 (s, 3H), 2.29-2.16 (m, 2H), 2.02-1.84 (m, 2H).EXAMPLE 515-methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0392]

[0393] To a solution of 8-chloro-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (15 mg, 0.057 mmol) in DMF (1.5 mL), 4-(4-(trifluoromethoxy)phenoxy) piperidine (16.29 mg, 0.062 mmol) and triethylamine (0.024 mL, 0.170 mmol) were added. The reaction mixture was stirred at room temperature for over the weekend. The resultant solution was purified via preparative HPLC with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 38-78% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 19.1 mg, and its estimated purity by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 490.09; Retention Time: 2.3 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 99.1 %; Observed Mass: 490.1; Retention Time: 2.25 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.43-8.12 (m, 1H), 7.43-7.03 (m, 2H), 4.90-4.59 (m, 1H), 3.70-3.48 (m, 2H), 2.25-2.12 (m, 1H), 1.97-1.85 (m, 1H). The full spectrum was not assigned due to the water suppression technique used in the acquisition of the spectrum.

[0394] The following method (Method A) was used to prepare a number of the following examples of the current invention.EXAMPLE 525-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0395]

[0396] 8-Chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (22 mg, 0.100 mmol) was dissolved in DMF (1 mL) contained in a one dram pressure vial. 4-[4-Trifluoromethoxy)phenoxy]piperidine (32 mg, 0.122 mmol) was added together with potassium carbonate (40 mg, 0.289 mmol) and the reaction vessel was evacuated, flushed with nitrogen, sealed and then heated in an oil bath at 90 °C for 5 h. The reaction mixture was allowed to cool before being diluted to a volume of 2 mL by the addition of acetonitrile and two drops of water. This mixture was filtered, and the crude solution was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 33% B, 33-73% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 26.1 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 445.12; Retention Time: 2.19 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 445.14; Retention Time: 2.12 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.10-7.96 (m, 1.9H), 7.25 (br d, J=8.2 Hz, 1.9H), 7.08 (br d, J=8.9 Hz, 2.0H), 6.12 (s, 0.9H), 4.65 (br s, 0.9H), 3.75 (br d, J=7.6 Hz, 1.2H), 3.51 (s, 2.6H), 3.33 (br t, J=9.2 Hz, 1.9H), 2.09 (br s, 2.1H), 1.83-1.68 (m, 2.0H). Reported chemical shifts are uncorrected for the effects of water suppression

[0397] The following method (Method B) was used to prepare a number of the following examples of the current invention.EXAMPLE 53 (REFERENCE)4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile

[0398]

[0399] Triphenylphosphine resin (56.6 mg, 0.217 mmol) (70 mg @ ~3 mmol / g) was placed in an oven dried, vacuum cooled one dram vial, charge) and suspended in NMP (0.5 mL) under nitrogen, and the mixture was left to stand for 2 min. 4-Tert-butylphenol (23.0 mg, 0.153 mmol) and di-tert-butyl azodicarboxylate (43 mg, 0.187 mmol) were then added and the mixture was shaken for a further 5 min. A solution of 8-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile in N-Methyl-2-pyrrolidinone (1.0 mL, 28mg, 0.098 mmol) was added and the resultant suspension was maintained under nitrogen and agitated at room temperature overnight. The mixture was then filtered and the volume of filtrate was adjusted to 2 mL by the addition of more NMP. The crude material was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 42% B, 42-82% B over 20 minutes, then a 7-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 0.6 mg and its estimated purity by LCMS analysis was 96%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 417.18; Retention Time: 2.31 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 96.4 %; Observed Mass: 417.06; Retention Time: 2.27 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.16 (d, J=8.9 Hz, 1.0H), 8.08 (d, J=8.9 Hz, 1.0H), 7.29 (br d, J=8.5 Hz, 1.9H), 6.92 (br d, J=8.5 Hz, 1.9H), 6.14 (s, 1.0H), 4.66-4.55 (m, 1.0H), 3.82-3.71 (m, 2.0H), 3.54 (s, 1.8H), 2.16-2.02 (m, 2.0H), 1.88-1.73 (m, 1.9H), 1.25 (s, 9.0H).

[0400] In a similar fashion, the following examples can be prepared.Method A:

[0401] Method B:

[0402] TABLE 4Ex. No.Ar StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method54 A12.51431.1B55 A12.26451.2B56 A12.40417.1B57 A12.33403.3B58 A12.54429.1B59 A12.10401.0B60 A12.38417.0B61 A12.27415.0B62 A12.57431.1B63 A12.55443.1B64 A12.48479.1B65 A12.18433.3B

[0403] The following method (Method A) was used to prepare a number of the following examples of the current invention.EXAMPLE 668-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0404]

[0405] In a dried one dram vial, 8-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (29 mg, 0.102 mmol) was dissolved in NMP (1.0 ml) under nitrogen. Sodium hydride (10.6 mg, 0.265 mmol) was then added and the mixture was stirred for 3 min, after which 2-fluoro-5-isopropoxypyridine (17 µL, 0.142 mmol) was added. Stirring was continued at room temperature overnight. The reaction was then quenched by the addition of acetic acid, and the volume was adjusted to 1.8 mL by the addition of NMP. This mixture was filtered and then purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 30% B, 30-70% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 9.3 mg, and its estimated purity by LCMS analysis was 97%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 97.3 %; Observed Mass: 420.07; Retention Time: 1.95 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.8 %; Observed Mass: 420.32; Retention Time: 1.85 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.11 (s, 1.0H), 8.07-8.00 (m, 1.0H), 7.79 (d, J=3.1 Hz, 1.0H), 7.36 (dd, J=8.9, 3.1 Hz, 1.0H), 6.74 (d, J=9.2 Hz, 1.0H), 6.13 (s, 1.0H), 5.18-5.04 (m, 1.0H), 4.49 (dt, J=12.1, 6.0 Hz, 1.0H), 3.85-3.71 (m, 1.7H), 3.30 (br t, J=9.6 Hz, 1.8H), 2.18-2.04 (m, 2.0H), 1.87-1.71 (m, 2.0H), 1.23 (d, J=5.8 Hz, 6.0H). Water suppression at 3.57 ppm diminishes the intensity of adj acent signals.

[0406] In a similar fashion the following examples can be prepared. TABLE 5Ex. No.Heteroaryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method67 A11.97396.0A68 A11.64419.3A69 A11.92413.3A70 A11.14391.1A71 A11.46413.0A72 A11.10377.1A73 A12.30476.1A74 A11.46413.0A75 A11.28412.9A76 A11.80431.3A77 A12.11430.2A78 A11.34419.3A EXAMPLE 79(+ / -) 6-cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one

[0407]

[0408] A dry 20 mL scintillation vial fitted with a septum was charged with triphenylphosphane (polymer supported) 3 mmol / g (2.212 mL, 0.664 mmol) and then evacuated and flushed with nitrogen. THF (2 mL) was then added, followed after ~ 1 min. by 4-(trifluoromethoxy)phenol (0.039 mL, 0.302 mmol). The resultant mixture was mixed briefly, after which a solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (111 mg, 0.483 mmol) in THF (1 mL) was added via syringe in a single portion. The mixture was agitated on an orbital shaker for 3 min., after which a solution of 8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90 mg, 0.302 mmol)) in THF (2 mL) was added in a single portion. The vail was then shaken at room temperature overnight. The reaction mixture was subsequently filtered and evaporated to dryness. The residue was dissolved in 2 mL of DMF and the resultant solution fractionated via preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 31% B, 31-71% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 13.3 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100.0 %; Observed Mass: 459.09; Retention Time: 2.44 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 % B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 459.08; Retention Time: 2.28 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.21-8.13 (m, 1H), 8.18-8.04 (m, 2H), 8.12-8.04 (m, 1H), 7.33-7.24 (m, 2H), 7.15-7.08 (m, 2H), 6.17-6.11 (m, 1H), 4.27 (br d, J=3.7 Hz, 1H), 4.04-3.87 (m, 2H), 3.59-3.51 (m, 3H), 3.39 (br d, J=4.9 Hz, 1H), 3.23-3.12 (m, 1H), 3.00 (br t, J=11.3 Hz, 1H), 2.24-1.99 (m, 2H), 1.73-1.58 (m, 1H), 1.07 (br d, J=6.4 Hz, 3H).

[0409] The above racemic mixture was resolved by a chiral SFC separation method. Approximately 10.1 mg of racemate were resolved into two peaks collected in IPA w / 0.1%DEA. The chiral purity for the isolates were estimated based on the prep chromatogram below. IsolateChiral Purity1st Eluting Peak>95 %2nd Eluting Peak>95 % Preparative Chromatographic Conditions:

[0410] Instrument:Waters 100 Prep SFCColumn:Chiral AD, 30 x 250 mm. 5 micronMobile Phase:75% CO 2 / 25% IPA w / 0.1%DEAFlow Conditions:100 mL / minDetector Wavelength:220 nmInjection Details:1500 µL 10.1 mg dissolved in 4 mL MeOH Analytical Chromatographic Conditions(Before Prep):

[0411] Instrument:Shimadzu Nexera UC SFCColumn:Chiralpak AD, 4.6 x 100 mm, 5 micronMobile Phase:75% CO 2 / 25% IPA w / 0.1%DEAFlow Conditions:2 mL / minDetector Wavelength:220 nmExample 80: Isolate 1:First eluting peak Example 81: Isolate 2: Second eluting peakEXAMPLE 806-cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (rel)

[0412]

[0413] Analytical LC / MS was used to determine purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 % B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.7 %; Observed Mass: 458.95; Retention Time: 2.2 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 96.3 %; Observed Mass: 459.1; Retention Time: 2.26 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.32-7.90 (m, 2H), 7.33-7.02 (m, 4H), 6.13 (s, 1H), 4.31-4.18 (m, 1H), 4.03-3.88 (m, 2H), 3.57-3.51 (m, 3H), 3.21-3.12 (m, 1H), 3.04-2.93 (m, 1H), 2.24-2.15 (m, 1H), 2.11-2.00 (m, 1H), 1.74-1.55 (m, 1H), 1.10-1.02 (m, 3H).EXAMPLE 816-cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (rel)

[0414]

[0415] Analytical LC / MS was used to determine purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 % B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.3 %; Observed Mass: 459.08; Retention Time: 2.2 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 97.8 %; Observed Mass: 459.24; Retention Time: 2.26 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.19-8.00 (m, 2H), 7.32-7.05 (m, 4H), 6.13 (s, 1H), 4.32-4.20 (m, 1H), 4.02-3.88 (m, 2H), 3.57-3.52 (m, 3H), 3.21-3.10 (m, 1H), 3.05-2.90 (m, 1H), 2.24-2.14 (m, 1H), 2.11-2.00 (m, 1H), 1.72-1.57 (m, 1H), 1.09-1.02 (m, 3H).

[0416] Using similar methodology and purification techniques, the following examples were prepared. TABLE 6Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method82 R12.60445.2A83 H12.60445.3A84 H12.60445.3A85 R12.27447.1A86 H32.23447.1A87 H32.23447.1A88 R12.46431.0A89 H32.40431.1A90 H32.40431.1A91 R32.25415.2A92 H32.22415.3A93 H32.22415.3A94 R12.53417.2A95 H12.405417.3A96 H12.40417.3A97 R12.44443.1A98 H12.26443.2A99 H12.25443.2A100 R12.60443.3A101 H32.57443.4A102 H32.57443.3A103 R12.11411.1A104 H12.10411.1A105 H12.10411.1A106 R32.69457.1A107 R32.14389.2A108 H42.13389.1A109 H42.107389.3A110 R12.26403.2A111 R12.24415.2A112 R12.27461.1A113 R12.06411.1A114 H12.05411.1A115 H12.05411.1A116 R12.24461.1A117 H32.20461.2A118 H32.20461.2A119 R32.12389.2A120 H32.08389.4A121 H32.07389.3A122 R12.35417.2A123 R12.42431.2A124 R12.22461.1A125 R12.06411.1A126 H32.01411.1A127 H32.01411.2A128 R12.00393.3A129 H31.96393.0A130 H31.96393.4A131 R12.12429.1A132 R11.91447.2A

[0417] Using methodology related to that presented in the preceeding scheme and table and employing (+ / -) 8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile as a coupling partner with appropiately functionalized phenols in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE 7Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method136 R12.12414.2A

[0418] Using related methodology and and employing (+ / -) 8-(cis-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as a coupling partner with appropiately functionalized phenols in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE8Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< Method137 R32.44431.2A138 H52.48431.1A139 H52.48431.1A140 R32.41457.1A141 H32.31457.3A142 H32.30457.2A143 R12.53431.1A144 H32.48431.0A145 H32.48431.4A146 R12.38457.0A147 H32.39457.3A148 H32.39457.3A149 R12.73459.1A150 H32.73459.1A151 H32.74459.1A152 R32.54445.1A153 H32.61445.1A154 H32.62445.1A155 R32.32429.2A156 H12.35429.2A157 H12.35428.9A158 R12.36460.9A159 H32.40461.1A160 H32.39461.2A161 R32.38447.1A162 H32.35472.9A163 H32.35473.3A

[0419] Using methodology related to that presented in the preceeding table and employing (+ / -) 8-(trans-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as a coupling partner with appropiately functionalized phenols in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers was achieved using preparative HPLC techniques as described above. TABLE 9Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 164 R32.58431.1165 R32.54445.3166 H32.54445.0167 H32.66445.1168 R12.37457.1

[0420] Using methodology related to that presented in the preceeding table and employing (+ / -) 8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as a coupling partner with appropiately functionalized phenols in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers was achieved using preparative HPLC techniques as described above. TABLE 10Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 169 R12.64444.9170 H32.62445.0171 H32.62445.2172 R12.28446.9173 H32.31447.1174 H32.32447.1175 R12.52431.0176 R12.40417.3177 H32.43417.0178 H32.43417.3179 R32.24415.0180 H12.26415.3181 H12.26415.3182 R12.43417.3183 H32.46417.1184 H32.46417.3 EXAMPLE 185(+ / -) 5-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide

[0421]

[0422] A suspension of sodium hydride (3.54 mg, 0.074 mmol) and (+ / -) 8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (20 mg, 0.067 mmol) in DMF (2 mL) was heated at 80 °C under nitrogen for 15 mins. 1-fluoro-4-(trifluoromethyl)benzene (9.36 µL, 0.074 mmol) was then added in a single portion and heating was continued overnight, and the reaction mixture was left at room temperature for 48 h. The crude material was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 0-minute hold at 24% B, 24-64% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its estimated purity by LCMS analysis was 92%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.2 %; Observed Mass: 317.13; Retention Time: 1.29 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 91.8 %; Observed Mass: 317.14; Retention Time: 1.12 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.21-8.14 (m, 1H), 8.08-8.01 (m, 1H), 7.82-7.74 (m, 1H), 7.51-7.46 (m, 1H), 6.07-6.02 (m, 1H), 3.84-3.75 (m, 1H), 3.57-3.50 (m, 1H), 3.19-3.07 (m, 1H), 2.06-1.95 (m, 1H), 1.90-1.71 (m, 2H), 0.97-0.85 (m, 3H). Not all signals were assigned due to water suppression. Racemic.EXAMPLE 186(+ / -) 5-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0423]

[0424] The TFA salt of (+ / -) cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidine, (40.3 mg, 0.108 mmol) was added to a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (30 mg, 0.090 mmol) and Hunig's base (0.047 mL, 0.270 mmol) in DMF (1.5 mL) and the reaction mixture was heated at 85 °C overnight. The crude material was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 40% B, 40-80% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS signals. Fractions containing the product were combined and dried via centrifugal evaporation. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 99.3 %; Observed Mass: 442.98; Retention Time: 2.3 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100.0 %; Observed Mass: 443.21; Retention Time: 2.33 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.20-8.11 (m, 1H), 8.11-8.02 (m, 1H), 7.72-7.57 (m, 2H), 7.32-7.12 (m, 2H), 6.21-6.06 (m, 1H), 4.84-4.63 (m, 1H), 2.36-2.21 (m, 1H), 2.10-1.90 (m, 2H), 1.12-0.91 (m, 3H). The full spectrum was not assigned due to the water suppression technique employed.

[0425] The racemic product was further fractionated using SFC-chiral chromatography. The following two enantiomers were obtained and characterized.EXAMPLE 1875-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (rel)

[0426]

[0427] Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 % B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 97.5 %; Observed Mass: 442.84; Retention Time: 2.25 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 99.4 %; Observed Mass: 443.07; Retention Time: 2.25 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.22-8.12 (m, 1H), 8.12-8.01 (m, 1H), 7.69-7.58 (m, 2H), 7.28-7.17 (m, 2H), 6.23-6.09 (m, 1H), 4.84-4.66 (m, 1H), 2.39-2.19 (m, 1H), 2.13-1.92 (m, 2H), 1.12-0.88 (m, 3H). The full spectrum was not assigned due to the water suppression technique employed.EXAMPLE 1885-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (rel)

[0428]

[0429] Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 % B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 96.4 %; Observed Mass: 443.09; Retention Time: 2.26 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.6 %; Observed Mass: 443.07; Retention Time: 2.25 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.23-8.11 (m, 1H), 8.11-8.02 (m, 1H), 7.78-7.55 (m, 2H), 7.31-7.15 (m, 2H), 6.21-6.05 (m, 1H), 4.82-4.62 (m, 1H), 2.37-2.12 (m, 1H), 2.06-1.92 (m, 2H), 1.06-0.92 (m, 3H). The full spectrum was not assigned due to the water suppression technique employed.

[0430] Using methodology related to that presented in the preceeding table and employing 3,6-dicyano-1 -methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate as a coupling partner with appropiately functionalized (+ / -) cis-3-methyl-4-aryloxypiperidine intermediates, the following examples were be prepared. Isolation of specific enantiomers was achieved using preparative HPLC techniques as described above. TABLE 11Ex. No.ArylStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 189 R32.31468.0190 H12.25468.1191 H12.25468.1

[0431] Using methodology related to that presented in the preceeding table and employing 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate as a coupling partner with appropiately functionalized (+ / -) trans-3-ethyl-4-aryloxypiperidine intermediates, the following examples were prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE 12Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 192 R12.17447.9193 H12.13448.3194 H12.13448.1195 R12.50449.2196 R32.62445.3197 H32.62445.2198 H32.62445.2

[0432] Using methodology related to that presented in the preceeding table and employing 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate as a coupling partner with appropiately functionalized (+ / -) trans-3-methyl-4-aryloxypiperidine intermediates, the following examples were prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE 13Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 199 Diastereomeric mixture32.00434.1200 H12.12434.3201 H12.12434.3

[0433] Using methodology related to that presented in the preceeding table and 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate as a coupling partner with appropiately functionalized (+ / -) cis-3-ethyl-4-aryloxypiperidine intermediates in an SN Ar reaction, the following examples can be prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE 14Ex. No.ArylStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 202 R32.18448.1203 H32.04448.2204 H32.04448.4

[0434] Using methodology related to that presented in the preceeding table and 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate as a coupling partner with appropiately functionalized (+ / -) cis-3-methyl-4-aryloxypiperidine intermediates, the following examples were prepared. Isolation of specific enantiomers can be achieved using preparative HPLC techniques as described above. TABLE 15Ex. No.Aryl StructureStereo. Chem.LCMS MethodLCMS RT(m / z): (M+H) +< 205 R31.88418.1206 H31.78418.2207 H31.79418.2208 R32.01426.3209 H11.99426.1210 H11.99426.0211 R11.74418.3212 H31.73418.1213 H31.73418.1214 R32.12418.1215 H31.92418.1216 H31.92418.1217 R11.46377.1218 R31.39407.1219 R11.86419.1220 R11.18391.1221 R11.71405.1222 R11.88445.1223 R11.81417.0224 R31.84416.1225 R32.23444.0226 H32.17443.9227 H32.17444.2 EXAMPLE 228(+ / -) 8-(cis-4-((5-isopropoxypyridin-2-yl)oxy)-3-rnethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

[0435]

[0436] Sodium hydride (60% in mineral oil, 10.05 mg, 0.251 mmol) was added to a solution of (+ / -) 8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2- carbonitrile (30 mg, 0.101 mmol) in anhydrous N-methyl-2-pyrrolidinone (1.0 ml). The reaction mixture was stirred at room temperature for 5 minutes and then 2-fluoro-5-isopropoxypyridine (0.018 ml, 0.151 mmol) was added and stirring was continued at room temperature overnight. The reaction was quenched by the addition of acetic acid (0.014 ml, 0.251 mmol), diluted with acetonitrile and then filtered. The filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with ammonium acetate; Gradient: a 0-minute hold at 26% B, 26-66% B over 30 minutes, then a 0-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 6.8 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 100 %; Observed Mass: 434.20; Retention Time: 2.08 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 100 %; Observed Mass: 434.13; Retention Time: 2.04 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.23-8.15 (m, 1H), 8.14-8.03 (m, 1H), 7.88-7.78 (m, 1H), 7.46-7.35 (m, 1H), 6.88-6.70 (m, 1H), 6.19-6.08 (m, 1H), 5.28-5.18 (m, 1H), 4.60-4.47 (m, 1H), 3.64-3.45 (m, 3H), 2.40-2.28 (m, 1H), 2.11-2.01 (m, 1H), 2.01-1.89 (m, 1H), 1.35-1.23 (m, 6H), 1.10-0.94 (m, 3H). Racemic. The spectrum was not fully assigned due to the water suppression technique employed.EXAMPLE 229(+ / -) 5-methyl-8-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile

[0437]

[0438] In a microwave tube, the TFA salt of (+ / -) 6-bromo-1-methyl-4-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (31 mg, 0.049 mmol), zinc (0.636 mg, 9.73 µmol), zinc cyanide (3.43 mg, 0.029 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.97 mg, 4.86 µmοl) were added. The tube was sealed, evacuated and then flushed with nitrogen. NMP (1.5 mL) was then added and the reaction mixture was heated at 80 °C for 4 h. The mixture was then allowed to cool before being diluted to a volume of 2 mL by the addition of acetonitrile. The resultant mixture was filtered, and the crude solution was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-Mm ammonium acetate; Gradient: a 0-minute hold at 52% B, 52-92% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 10.2 mg, and its estimated purity by LCMS analysis was 98%. Analytical LC / MS was used to determine the final purity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: Purity: 98.5 %; Observed Mass: 469.88; Retention Time: 2.62 min. Injection 2 conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 results: Purity: 98.8 %; Observed Mass: 470.17; Retention Time: 2.61 min. 1< H NMR (500 MHz, DMSO-d 6 ) δ 8.26 (d, J=8.9 Hz, 1H), 8.15 (d, J=9.2 Hz, 1H), 7.24 (br d, J=8.5 Hz, 2H), 6.96 (br d, J=8.5 Hz, 2H), 4.32 (br dd, J=7.5, 4.4 Hz, 1H), 4.26-4.14 (m, 1H), 4.26-4.11 (m...

Claims

1. A compound of Formula (I): or a salt thereof, wherein: XisN; Y i s CR3 or N; L is -O-, -S-, -S(O)2-, -NR4c-, or -NR4dC(O)-; R1 is H, F, Cl, Br, -CN, C1-3 alkyl substituted with zero to 4 R1a, C3-4 cycloalkyl substituted with zero to 4 R1a, C1-3 alkoxy substituted with zero to 4 R1a, -C(O)NRaRa, -NRaRa, -S(O)nRe, or -P(O)ReRe; each R1a is independently F, Cl, -CN, -OH, -OCH3, or -NRaRa; each Ra is independently H or C1-3 alkyl; each Re is independently C3-4 cycloalkyl or C1-3 alkyl substituted with zero to 4 R1a; R2 is H, C1-3 alkyl substituted with zero to 4 R2a, C2-3 alkenyl substituted with zero to 4 R2a, or C3-4 cycloalkyl substituted with zero to 4 R2a; each R2a is independently F, Cl, -CN, -OH, -O(C1-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl; R3 is H, F, Cl, Br, -CN, C1-3 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, -NO2, or pyridinyl substituted with zero to 2 R3a; each R3a is halo, -CN, C1-3 alkyl, or C1-3 alkoxy; R4 is R4a, -CH2R4a, or -CH2CH2R4a; R4a is C3-6 cycloalkyl, C5-14 heterocyclyl, C6-10 aryl, or C5-14 heteroaryl, each substituted with zero to 4 R4b; each R4b is independently F, Cl, Br, -CN, -OH, C1-6 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, -(CH2)1-2O(C1-3 alkyl), C1-4 alkoxy, -O(C1-4 hydroxyalkyl), -O(CH)1-3O(C1-3 alkyl), C1-3 fluoroalkoxy, -O(CH)1-3NRcRc, -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), -C(O)NH2, -C(O)NH(C1-4 alkyl), -C(O)N(C1-4 alkyl)2, -NRcRc, -NRaS(O)2(C1-3 alkyl), -NRaC(O)(C1-3 alkyl), -NRaC(O)O(C1-4 alkyl), -P(O)(C1-3 alkyl)2, -S(O)2(C1-3 alkyl), -O(CH2)1-2(C3-6 cycloalkyl), -O(CH2)1-2(morpholinyl), C3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CRcRc(phenyl); each Rc is independently H or C1-2 alkyl; R4c is H, C1-6 alkyl, or R4a; R4d is H or C1-6 alkyl; each R5 is independently F, Cl, -CN, -OH, C1-6 alkyl substituted with zero to 4 Rg, C1-3 alkoxy substituted with zero to 4 Rg, C2-4 alkenyl substituted with zero to 4 Rg, C2-4 alkynyl substituted with zero to 4 Rg, -(CH2)1-2(C3-4 cycloalkyl substituted with zero to 4 Rg), phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcC(O)(C1-4 alkyl), -(CH2)1-2NRcC(O)O(C1-4 alkyl), -O(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NRcS(O)2(C1-4 alkyl), -C(O)(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), -C(O)O(C3-4 cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4 cycloalkyl), or two R5 attached to the same carbon atom form =O; each Rg is independently F, Cl, -CN, -OH, C1-3 alkoxy, C1-3 fluoroalkoxy, -O(CH2)1-2O(C1-2 alkyl), C3-5 cycloalkyl, or -NRcRc; each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; R7 is H or -CH3; m is zero, 1, 2, or 3; and n is zero, 1, or 2.

2. The compound according to Claim 1 or a salt thereof, wherein: R1 is H, F, Cl, Br, -CN, C1-3 alkyl substituted with zero to 4 R1a, cyclopropyl substituted with zero to 3 R1a, C1-3 alkoxy substituted with zero to 3 R1a, -C(O)NRaRa, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; each R1a is independently F, Cl, or -CN; each Ra is independently H or C1-3 alkyl; R2 is H, C1-2 alkyl substituted with zero to 2 R2a, or C2-3 alkenyl substituted with zero to 2 R2a; each R2a is independently F, Cl, -CN, -OH, -O(C1-2 alkyl), cyclopropyl, C3-4 alkenyl, or C3-4 alkynyl; R3 is H, F, Cl, Br, -CN, C1-2 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, -NO2, or pyridinyl substituted with zero to 1 R3a; R4a is C3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R4b; each R4b is independently F, Cl, Br, -CN, -OH, C1-6 alkyl, C1-2 fluoroalkyl, C1-3 hydroxyalkyl, -(CH2)1-2O(C1-3 alkyl), C1-4 alkoxy, -O(C1-3 hydroxyalkyl), -O(CH)1-3O(C1-3 alkyl), C1-2 fluoroalkoxy, -O(CH)1-2NRcRc, -C(O)(C1-3 alkyl), -C(O)OH, -C(O)O(C1-3 alkyl), -C(O)NH2, -C(O)NH(C1-3 alkyl), -C(O)N(C1-3 alkyl)2, -NRcRc, -S(O)2(C1-2 alkyl), C3-6 cycloalkyl, or -CRcRc(phenyl); R4c is H, C1-4 alkyl, or R4a; R4d is H or C1-4 alkyl; each R5 is independently F, -CN, -OH, C1-5 alkyl substituted with zero to 4 Rg, C1-3 alkoxy substituted with zero to 3 Rg, C2-3 alkenyl substituted with zero to 4 Rg, C2-3 alkynyl substituted with zero to 4 Rg, -(CH2)1-2(C3-4 cycloalkyl substituted with zero to 4 Rg), phenyl substituted with zero to 3 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 3 Rg, -(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -O(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), -(CH2)1-2NR,C(O)(C1-4 alkyl), -(CH2)1-2NRcC(O)O(C1-4 alkyl), -(CH2)1-2NRcS(O)2(C1-4 alkyl), -C(O)(C1-4 alkyl), -C(O)OH, -C(O)O(C1-4 alkyl), -C(O)O(C3-4 cycloalkyl), -C(O)NRaRa, or -C(O)NRa(C3-4 cycloalkyl); and each R6 is H, F, or -CH3.

3. The compound according to any one of claims 1-2 or a salt thereof, wherein: L is -O-, -NH-, -N(CH3)-, or -N(CH3)C(O)-; R1 is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2 is -CH3; R3 is H, F, Cl, Br, -CN, -CH3, -NO2, methylpyridinyl, or methoxypyridinyl; R4 is R4a or -CH2R4a; R4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzooxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted with zero to 3 R4b; each R4b is independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -C(CH3)2CH2CH3, -CHF2, -CF3, -OCH3, -OCH(CH3)2, -OC(CH3)3, -OCF3, -C(O)N(CH3)2, -S(O)2CH3, -CH-2(phenyl), -C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R5 is independently hydrogen, F, -OH, C1-2 alkyl, C1-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and each R6 is H.

4. The compound according to any one of claims 1-3 or a salt thereof, wherein Y is CR3.

5. The compound according to any one of claims 1-3 or a salt thereof, wherein Y is N.

6. The compound according to any one of claims 1-5 or a salt thereof, wherein L is -O-.

7. The compound according to any one of claims 1-5 or a salt thereof, wherein L is -NR4c-.

8. The compound according to any one of claims 1-5 or a salt thereof, wherein L is -NR4dC(O)-.

9. The compound according to claims 1-5 or a salt thereof, having a structure selected from:

10. The compound according to claim 1 or a salt thereof, wherein said compound is: 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (10); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (11); 6-chloro-4-(4-(3,4-difluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (12); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (13); 6-chloro-4-(4-(4-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (14); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15); 6-chloro-4-(4-(4-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1, 5-naphthyridine-3-carbonitrile (16); 6-chloro-4-(4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (17); 6-chloro-4-(4-(2-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1, 5-naphthyridine-3-carbonitrile (18); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (19); 6-chloro-4-(4-(4-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20); 6-chloro-1 -methyl-2-oxo-4-(4-(p-tolyloxy)piperi din-1-yl)-11,2-dihydro-1,5-naphthyridine-3-carbonitrile (21); 6-chloro-1-methyl-2-oxo-4-(4-(m-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (22); 6-chloro-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (23); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (24); 4-((1-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide (25); 4-(4-(4-bromo-2-methylphenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (26); 6-chloro-4-(4-(3-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (27); 6-chloro-4-(4-(3-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (28); 6-chloro-1-methyl-4-(4-(2-methyl-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (29); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (30); 4-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (31); 6-chloro-4-(4-(4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (32); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (33); 6-chloro-4-(4-(3-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (34); 6-chloro-4-(4-(2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (35); 6-chloro-4-(4-(4-fluoro-2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (36); 6-chloro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (37); 6-chloro-4-(4-(3-chloro-4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (38); 6-chloro-4-(4-(4-chloro-3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (39); 6-chloro-4-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (40); 6-chloro-4-(4-(2-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (41); 6-chloro-4-(4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (42); 6-chloro-4-(4-(2-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (43); 6-chloro-4-(4-(2-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (44); 6-chloro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (45); 6-chloro-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (46); 6-bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (47); 6-methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (48); 1-methyl-2,6-dioxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2,5,6-tetrahydro-1,5-naphthyridine-3-carbonitrile (49); 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (50); 5-methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (51); 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (52); 5-methyl-6-oxo-8-(4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (54); 8-(4-(4-benzylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (55); 8-(4-(4-butylphenoxy)piperi din-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (56); 5-methyl-6-oxo-8-(4-(4-propylphenoxy)piperidin-1-yl)-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (57); 8-(4-(4-cyclopentylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (58); 8-(4-(4-cyclopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (59); 8-(4-(4-isopropyl-3-methylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (60); 5-methyl-6-oxo-8-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (61); 5-methyl-6-oxo-8-(4-(4-pentylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (62); 8-(4-(4-cyclohexylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (63); 8-(4-(4-(2-cyclohexylpropan-2-yl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (64); 8-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1, 5-naphthyridine-2-carbonitrile (65); 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (66); 8-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-(4-((6-(tert-butyl)pyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (68); 5 -m ethyl-6-oxo-8-(4-(qui noxali n-2-yl oxy)pip eri di n-1-yl)-5, 6-dihydro-1, 5 -naphthyri dine-2-carbonitrile (69); 8-(4-((2,6-dimethylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70); 5-methyl-6-oxo-8-(4-(quinazolin-4-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71); 5-methyl-8-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (72); 8-(4-((7-chloro-4-methoxyquinolin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (73); 8-(4-((1,7-naphthyridin-8-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (74); 5-methyl-6-oxo-8-(4-(phthalazin-1-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (75); 5-methyl-6-oxo-8-(4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (76); 5-methyl-6-oxo-8-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (77); 8-(4-((2-isopropyl-6-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (78); (+ / -)6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (79); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (80); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (81); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (82-84); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (85-87); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (88-90); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (91-93); 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (94-96); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (97-99); 8-((3R,4R)-4-(4-cyclopentylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (100-102); 8-((3R,4R)-4-(3,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (103-105); 8-((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (106); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107-109); 8-((3R,4R)-4-(4-ethylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110); 8-((3R,4R)-4-(4-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (111); 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((3R,4R)-4-(2,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (113-115); 8-((3R,4R)-4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (116-118); 5-methyl-8-((3R,4R)-3-methyl-4-(p-tolyloxy)piperidin-1-yl)-6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile (119-121); 8-((3R,4R)-4-(3-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (122); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (123); 8-((3R,4R)-4-(2-fluoro-6-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (125-127); 8-((3R,4R)-4-(4-fluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (128-130); 5-methyl-8-((3R,4R)-3-methyl-4-(2,4,6-trifluorophenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (131); 8-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (132); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7-dicarbonitrile (136); 8-((3R,4R)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (137-139); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (140-142); 8-((3R,4R)-3-ethyl-4-(4-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (143-145); 8-((3R,4R)-3-ethyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (146-148); 8-((3R,4R)-3-ethyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (149-151); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (152-154); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (155-157); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (158-160); 8-((3R,4R)-3-ethyl-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (161); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (162-163); 8-((3R,4S)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (164); 8-((3R,4S)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (165-167); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (169-171); 8-((3R,4S)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (172-174); 8-((3R,4S)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (175); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (176-178); 8-((3R,4S)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (179-181); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (182-184); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (185); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (186); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (187); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (188); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (189-191); 8-((3R,4R)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (192-194); 8-((3R,4R)-3-ethyl-4-(4-fluoro-3-propylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (195); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (196-198); 8-((3R,4R)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (199-201); 8-((3R,4S)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (202-204); 8-((3R,4S)-4-((5-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (205-207); 8-((3R,4S)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (208-210); 8-((3R,4S)-4-((4-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (211-213); 8-((3R,4S)-4-((6-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (214-216); 5-methyl-8-((3R,4S)-3-methyl-4-(pyrimidin-2-yloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (217); 8-((3R,4S)-4-((4-methoxypyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (218); 5-methyl-8-((3R,4S)-3-methyl-4-((5-propylpyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (219); 5-methyl-8-((3R,4S)-3-methyl-4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (220); 8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (221); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (222); 8-((3R,4S)-4-((5-cyclopropylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (223); 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (224); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (225-227); (+ / -) 8-((3R,4S)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (228); (+ / -) 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (229); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (230); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (231); (+ / -)8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (232); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (233); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (234); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (235); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (236); 7-fluoro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (237); 7-chloro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (238); 7-bromo-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (239); 7-(6-methoxypyridin-3-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (240); 7-(2-methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (241); (+ / -) 6-bromo-1-methyl-4-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (242); 8-((2 S, 5 S)-4-((5-isopropoxypyridin-2-yl)oxy)-2, 5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (243 and 246); 8-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (251 and 253); 4-((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 8-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (255 and 258); (±)-trans-8-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (259-260); (±)-trans-8-(3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (261-262); 8-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (263-264); (±)-cis-8-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (265-266); (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (267-268); (±)-trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-methoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (269-270); (±)-trans-6-chloro-4-(3 -hydroxy-4-(3 -(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (271-272); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (273-274); 6-chloro-4-((3R,4R)-3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (275); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (276-277); 4-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (278-279); 8-((2 S, SR)-4-((5-methoxypyridin-2-yl)amino)-2, 5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (280-281); N-((2S,5R)-1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (282-283) N-(1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (284-287); N-(1-(3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-N-methyl-4-(trifluoromethyl)benzamide (288-293). 8-((2S,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (294); 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (295); 8-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (296); 8-((2R,4R,SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (297); 8-((2R,4 S, SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (298); 8-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (299); 6-chloro-4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (300); 4-((2 S,4R, SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (302); 4-((2R,4R,SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (303); 6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (304); 4-((2R,4 S, SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (305); 6-chloro-4-((2S,4S,SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (306); 4-((2 S,4 S, SR)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (307); 8-((2S,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (308); 8-((2R,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (309); 8-((2R,4R,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (310); 8-((2R,4S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (311); 8-((2S,4R,5S)-2,5-dimethyl-4-(p-tolyloxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (312); 8-((2S,4R,5S)-4-(3-chlorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (313); 8-((2S,4R,5S)-4-(3-cyanophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (314); 8-((2S,4R,5S)-4-(4-fluorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (315); 8-((2S,5S)-2,5-dimethyl-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316A); 8-(2,5)-dimethyl-4-(methyl(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316-319); 8-((25,5 S)-2,5-dimethyl-4-(methyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (320-321); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (322-325); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (326-328); 8-(4-((4,4-difluorocyclohexyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (329-330); 8-((2 S, SR)-4-((4-fluorobenzyl)(methyl)amino)-2, 5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (331-332); 8-((2S,5S)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (333-334); 8-((2S,5S)-4-((5-Isopropoxypyridin-2-yl)oxy)-2,4,5-trimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (335-336); 5-methyl-6-oxo-8-((25,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (337-338); 1-methyl-2-oxo-4-((25,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (339-340); trans-8-(3-ethoxy-4-phenoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (341-342); 8-((3 S, 4 S)-3 -ethoxy-4-(4-(tri fluorom ethyl)phenoxy)pip eri din-1-yl)-5 -m ethyl-6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (343-344); 8-((3 S, 4 S)-3 -ethoxy-4-(2-(tri fluorom ethyl)phenoxy)pip eri din-1-yl)-5 -m ethyl-6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (345-346); 8-((3 S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (347-348); 8-((3 S,4S)-3-ethoxy-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (349-350); 8-((3S,4S)-3-ethoxy-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (351-352); 8-((3 S,4 S)-3-ethoxy-4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (353-354); 8-((3 S,4S)-3-ethoxy-4-((2-methylbenzo[d]oxazol-5-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (355-356); 8-((3 S,4 S)-4-(4-chloro-3-fluorophenoxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (357-358); 8-((3S,4S)-3-ethoxy-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (359-362); trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (363-364); 8-((3S,4S)-3-ethoxy-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (365-366); trans-8-(3-ethoxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (367-368); cis- 8-(3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (369-370); cis-8-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (371-372); trans-8-4-(benzo[d]thiazol-2-yloxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (373-374); 8-((3S,4S)-3-ethoxy-4-((6-isopropoxypyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (375-376); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrazin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (377-378); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrimidin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (379-380); 8-((3S,4S)-3-ethoxy-4-((3-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (381-382); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyridin-2-yl)methoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (383-384); 8-((3R,4R)-3-(2-(dimethylamino)ethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (385-386); 8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (387-388); 8-((3R,4R)-3-(2-methoxyethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (389-390); 5-methyl-8-((3R,4R)-3-(2-morpholinoethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (391-392); 5-methyl-6-oxo-8-((3R,4R)-3-(2,2,2-trifluoroethoxy)-4-(3-(trifluoromethyl)phenoxy) piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (393-394); trans-8-(3-isopropoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (395-396); trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (397-398); (±)-trans-6-chloro-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (399); trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (400-401); trans-4-(3-ethoxy-4-phenoxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (402-403); or 4-((3 S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (404-405).

11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1-10 or a pharmaceutically-acceptable salt thereof, for use in therapy.

13. A compound according to any one of claims 1-10 or a pharmaceutically-acceptable salt thereof, for use in the treatment of cancer or viral infections.

14. The compound or pharmaceutically-acceptable salt thereof for use according to claim 13, wherein said cancer is selected from cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.