Substituted bicyclic derivatives of piperidine useful as T cell activators

Abstract

Compounds of Formula (I): (see Formula) or a salt thereof are described, wherein: X is CR6 or N; Y is CR3 or N; R1, R2, R3, R4, R5, R6, R7, and m are as defined herein. Methods for using such compounds to inhibit the activity of one or both diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKα), and pharmaceutical compositions comprising such compounds, are also described. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.

Description

SUBSTITUTED BICYCLIC DERIVATIVES OF PIPERIDINE USEFUL AS T CELL ACTIVATORS Field of Invention The present invention generally relates to substituted bicyclic compounds that activate T cells, promote T cell proliferation and / or exhibit antitumor activity. Substituted bicyclic compounds, compositions comprising those compounds, and methods for their use are provided herein. The invention further relates to pharmaceutical compositions comprising at least one compound according to the invention that are useful for the treatment of proliferative disorders, such as cancer and viral infections. Background of the Invention 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, composed of T and B lymphocytes, has powerful anticancer potential, with a broad capacity and exquisite specificity to respond to various tumor antigens. Furthermore, the immune system demonstrates considerable plasticity and a memory component. The successful use of all these attributes Ref. 334520 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 considered self-reported and tolerated by the immune system. By contributing to this state of tolerance, tumors can exploit several distinct mechanisms to actively subvert antitumor 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 co-option of endogenous immune checkpoints, which serve to decrease 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, (2011) Nature 480:480-489). 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. Therefore, DGKs serve as intracellular checkpoints and inhibition of DGKs is expected to enhance T cell signaling pathways and T cell activation. Supporting evidence includes gene knockout mouse models either DGKa or DGK / showing a hyper-reactive T cell phenotype and enhanced antitumor immune activity (Riese M. J. et al., Journal of Biological Chemlstry, (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 patients with human renal cell carcinoma were observed to overexpress DGKa resulting in inhibited T cell function (Prinz, PU et al., J Immunology (2012) 12: 5990- 6000). Therefore, DGKa and DGK / are considered as targets for cancer immunotherapy (Riese M.J., Front Cell Dev Blol. (2016) 4: 108; Chen, S.S., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A., 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. There remains a need for compounds useful as inhibitors of one or both DGKa and DGK / . Additionally, there remains a need for compounds useful as inhibitors of one or both DGKa and DGK / that have selectivity over other diacylglycerol kinases, protein kinases and / or other lipid kinases. Accordingly, an agent that is safe and effective in restoring T cell activation, lowering the 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 TGFP, would be an important addition to the treatment of patients with proliferative disorders, such as cancer and viral infections. Brief Description of the Invention Applicants have found compounds that have activity as inhibitors of one or both DGKa and DGK / . Furthermore, applicants have found compounds that have activity as inhibitors of one or both DGKa and DGK / 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 for their treatability. The present invention provides substituted bicyclic compounds of Formula (I), which are useful as inhibitors of DGKa, DGK / , or both DGKa and DGK / , including salts and prodrugs thereof. The present invention also provides pharmaceutical compositions comprising a compound of the Formula (I) and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The present invention also provides a method for treating a disease or disorder associated with the activity of DGKa, DGK / , or both DGKa and DGK / , the method comprising administering to a mammalian patient a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof. The present invention also provides processes and intermediates for preparing the compounds of Formula (I) and / or salts thereof. The present invention also provides a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof, for use in therapy. The present invention also provides the use of the compounds of Formula (I) and / or their pharmaceutically acceptable salts, for the manufacture of a medicament for the treatment of proliferative disorders, such as cancer and viral infections. The compounds of Formula (I) and compositions comprising the compounds of Formula (I) can be used to treat, prevent or cure viral infections and various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful for treating, preventing or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as viral infections and cancer. These and other features of the invention will be set forth in expanded form as the description continues. Detailed description of the invention The first aspect of the present invention provides at least one compound of Formula (I): Re R2 or a salt thereof, where: X is CRe, or N; Y is CR3, or N; L is -O-, -S-, -S(O)2-, -NR4c-, or -NR4dC(O)-; Ri is H, F, Cl, Br, -CN, Ci-3 alkyl substituted by zero to 4 Ria, C3-4 cycloalkyl substituted by zero to 4 Ria, Ci-3 alkoxy substituted by zero to 4 R3a, -C(O)NRaRa, -NRaRa, S(O)nRe, or -P(O)ReRe; each Ria is independently F, Cl, -CN, -OH, OCH3, or -NRaRa; each Raes independently H or Ci-3 alkyl; each Reis independently C3-4 cycloalkyl or Ci-3 alkyl substituted by zero to 4 Rla; R2 is H, C1-3 alkyl substituted by zero to 4 R2a, C2-3 alkenyl substituted by zero to 4 R2a, or C3-4 cycloalkyl substituted by zero to 4 R2a; each R2a is independently F, Cl, -CN, -OH, O(Ci-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl; R3 is H, F, Cl, Br, -CN, Ci-3 alkyl, Ci-2 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, -NO2, or pyridinyl substituted by zero to 2 R3a; each R2a is halo, -CN, C1-3 alkyl, or C1-3 alkoxy; R4is R4a, -CH2R4a, or -CH2CH2R4a; R4a is C3-6 cycloalkyl, C5-14 heterocyclyl, Cg-io aryl, or C5-!4 heteroaryl, each substituted by zero to 4 R4bf each R4bes independently F, Cl, Br, -CN, -OH, Ci-6 alkyl , C1-3 fluoroalkyl, Ο2-4 hydroxyalkyl, - (CH2)2_2O (Ci-3 alkyl), C1-4 alkoxy, -O (C1-4 hydroxyalkyl), -O(CH)!3O (C1-3 alkyl) , C1-3 fluoroalkoxy, -O (CH) i-3NRaRc, -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 (Ci-4 alkyl)2, -NRCRC, -NRaS(O) 2(C2-3 alkyl), -NRaC (O) (Ci-3 alkyl), NRaC(O)O(C1-4 alkyl), -P(O) (Ci-3 alkyl)2, -S (O) 2(Ci3 alkyl), -O (CH2) i-2(C3_6 cycloalkyl), -O (CH2) !-2(morpholinyl), C3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CRcRc(phenyl); each Rces independently H or C1-2 alkyl; Ríe is H, Ci-g alkyl, or R4a; R4des H or Ci-e alkyl; each R5 is independently F, Cl, -CN, -OH, Ci-g alkyl substituted by zero to 4 Rg, C1-3 alkoxyl substituted by zero to 4 Rg, C2-4 alkenyl substituted by zero to 4 Rg, C2_4 alkynyl substituted by zero a 4 Rg, -(CH2)i2 (cic 1 oa 1 qui 1 o) i-2 (cic 1 oaIqui 1 or C3-4substituted by zero a 4 Rg), phenyl substituted by zero a 4 Rg, oxadiazolyl substituted by zero a 3 Rg, pyridinyl substituted by zero to 4 Rg, - (CH2) 1-2 (heterocyclyl substituted by zero to 4 Rg), (CH2) i-2NRcC (O) (C4_4 alkyl), - (CH2) ^NRcC (O ) O (Ci-4 alkyl), O (CH2) i-2(heterocyclyl substituted by zero to 4 Rg), -(CH2)i2NRcS (O)2(Ci-4 alkyl), -C(O)(Ci alkyl) -4), -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 =0; each Rges independently F, Cl, -CN, -OH, C1-3 alkoxy, C1-3 fluoroalkoxy, -0 (CH2) i-20 (C2-2alkyl), C3-s cycloalkyl, or -NRCRC; each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; R7is H or -CH3; m is zero, 1, 2, or 3; and n is zero, 1, or 2. The second aspect of the present invention X is CRe, or N; Y is CR3, or N; L is -O-, -S-, -S(O)2-, -NR4c-, or -NR4dC(O)-; Ri is H, F, Cl, Br, -CN, Ci-3 alkyl substituted by zero to 4 Ria, C3~4 cycloalkyl substituted by zero to 4 Ria, Ci-3 alkoxy substituted by zero to 4 R3a, -C(O)NRaRa, -NRaRa, S(O)nRe, or -P(O)ReRe; each Riais independently F, Cl, -CN, -OH, OCH3, or -NRaRa; each Raes independently H or Ci-3 alkyl; each Reis independently C3-4cycloalkyl or C4-3alkyl substituted by zero to 4 R4a; R2 is H, Ci-3 alkyl substituted by zero to 4 R2a, C2-3 alkenyl substituted by zero to 4 R2a, or C3-4 cycloalkyl substituted by zero to 4 R2a; each R2a is independently F, Cl, -CN, -OH, O(Ci-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl r R3 is H, F, Cl, Br, -CN, Ci-3 alkyl, Ci-2 fluoroalkyl, C3_4 cycloalkyl, C3_4 fluorocycloalkyl, -NO2, or pyridinyl substituted by zero to 2 R3a; each R3ais halo, -CN, Ci-3 alkyl, or Ci-3 alkoxy; R4is R4a, -CH2R4a, or -CH2CH2R4a; R4a is C3-s cycloalkyl, C5-14 heterocyclyl, Ce-io aryl, or C5_14 heteroaryl, each substituted by zero to 4 R4b; each R4bes independently F, Cl, Br, -CN, -OH, Ci-g alkyl, Ci-3 fluoroalkyl, Ci-4 hydroxyalkyl, -(CH2)i2O (Ci-3 alkyl), Ci-4 alkoxy, -O (hydroxyalkyl Ci-4), -O(CH)i3O (alkyl Ci~3), fluoroalkoxy Ci~3, -O (CH) !-3NRaRc, -OCH2CH=CH2, -OCH2CsCH, -C (O) (alkyl Ci -4) , -C(O)OH, -C (O) O (Ci-4 alkyl) , -C(O)NH2, -C (O) NH (Ci-4 alkyl) , -C(O)N (Ci-4 alkyl)2, -NRCRC, -NRaS (O)2(Ci-3 alkyl) , -NRaC(O) (Ci-3 alkyl) , NRaC (O) O (Ci-4 alkyl) , -P (O) (Ci-3 alkyl)2 / -S (O)2(Ci3 alkyl) , -O (CH2) i-2 (C3-6 cycloalkyl) , -O (CH2) i-2(morpholinyl) , C3 -6cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CRcRc(phenyl); each Rces independently H or C1-2 alkyl; R4ces H, C1-6 alkyl, or R4a; R4ci is H or Ci-6 alkyl, each R3 is independently F, Cl, -CN, -OH, Ci-g alkyl substituted by zero to 4 Rg, C1-3 alkoxy substituted by zero to 4 Rg, substituted C2-4 alkenyl by zero to 4 Rg, C2-4 alkynyl substituted by zero to 4 Rg, C3-4 cycloalkyl substituted by zero to 4 Rg, phenyl substituted by zero to 4 Rg, oxadiazolyl substituted by zero to 3 Rg, pyridinyl substituted by zero to 4 Rg, - (CH2) 1-2 (heterocyclyl substituted by zero to 4 Rg), - (CH2) i-2NRcC (O) (Ci-4 alkyl), -ΟΥ2NRcC (O) O (C1-4 alkyl), - (CH2)i-2NRcS (O)2(Ci-4 alkyl), C (O) (Ci-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) ; each Rges independently F, Cl, -CN, -OH, C1-3 alkoxy, C1-3 fluoroalkoxy, -O (CH2) i~2O (C3-2alkyl), C3-5 cycloalkyl, or -NRCRC; each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; R7is H or -CH3; m is zero, 1, 2, or 3; and n is zero, 1, or 2. In one embodiment, a compound of Formula (I) or a salt thereof is provided wherein X is CRe; and Y is CR3o N. The compounds of this modality have the structure of Formula (II): In one embodiment, a compound of the Formula (I) or a salt thereof wherein X is CRe or N; and Y is CR3. The compounds of this modality have the structure of Formula (III): One modality provides a compound of the Formula (I) or a salt thereof, where X is CRe and Y is CR3. The compounds of this modality have the structure of the Formula (IV): This modality includes compounds in which L is O. Also, this modality includes compounds in which X is CH. Additionally, this modality includes compounds in which each Re is H. One modality provides a compound of the Formula (I) or a salt thereof, where X is N and Y is CR3. The compounds of this modality have the structure of Formula (V): This modality includes compounds in which L is O. Also, this modality includes compounds in which each Rg is H. One embodiment provides a compound of Formula (I) or a salt thereof, where X is CRg and Y is N. Compounds of this embodiment have the structure of Formula (VI): This modality includes compounds in which L is O. Also, this modality includes compounds in which X is CH. Additionally, this modality includes compounds in which each Re is H. One modality provides a compound of the Formula (I) or a salt thereof, where X is N and Y is N. The compounds of this modality have the structure of Formula (VII): This modality includes compounds in which L is O. Also, this modality includes compounds in which each Rg is H. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: Ri is H, F, Cl, Br, -CN, C1-3 alkyl substituted by zero to 4 Rla, cyclopropyl substituted by zero to 3 Rla, C1-3 alkoxy substituted by zero to 3 Ria, -C(O)NRaRa, -NRaRa, -S(O)nCH3, or -P(O) (CH3)2; each Riais independently F, Cl, or -CN; each Raes independently H or Ci-3 alkyl; R2 is H, Ci-2 alkyl substituted by zero to 2 R2a, or C2-3 alkenyl substituted by zero to 2 R2a; each R2ais independently F, Cl, -CN, -OH, O (Ci-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 by zero to 1 R3a; R4aes 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, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 3 R4b / each R4bes independently F, Cl, Br, -CN, -OH, Ci-6 alkyl, Ci-2 fluoroalkyl, ¢4-3 hydroxyalkyl, - (CH2) 12O(C1-3 alkyl), C1-4 alkoxy, -O (C1-3 hydroxyalkyl), -Ο(ΟΗ)33O (C1-3 alkyl), fluoroalkoxy Ci-2, -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 (Ci-3 alkyl)2, -NRCRC, S (O) 2 (Ci alkyl) -2), C3-6 cycloalkyl, or -CRcRc(phenyl); R4ces H, Ci-4 alkyl, or R4a; R4des H or Ci-4 alkyl; house R5 is independently F, -CN, -OH, alkyl Ci-5 substituted by zero to 4 Rg, C1-3 alkoxyl substituted by zero to 3 Rg, C2-3 alkenyl substituted by zero to 4 Rg, C2-3 alkynyl substituted by zero to 4 Rg, -(CH2)i2 (cycloalkyl C3-4 substituted by zero to 4 Rg), phenyl substituted by zero to 3 Rg, oxadiazolyl substituted by zero to 3 Rg, pyridinyl substituted by zero to 3 Rg, -(CH2)i2 (heterocyclyl substituted by zero to Rg), - O(CH2)i2(heterocyclyl substituted by zero to 4 Rg) , -(CH2)i2NRcC(O)(0Ί_4 alkyl) , - (CH2) i-2NRcC (O) O (Ct-4 alkyl), -(CH2) i2NRcS (O) 2 (Ch-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); each Rg is H, F, or -CH3; and R7 is H or —CH3. This embodiment includes compounds in which R7 is H, D, -CH3, or -CD3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: Ri is H, F, Cl, Br, -CN, Ci-3 alkyl substituted by zero to 4 Ria, cyclopropyl substituted by zero to 3 Rla, Ci-3 alkoxy substituted by zero to 3 Ria, -C(O)NRaRa, -NRaRa , -S(O)nCH3, or -P(O) (CH3)2; each Riais independently F, Cl, or -CN; each Raes independently H or Ci-3 alkyl; R2 is H, C1-2 alkyl substituted by zero to 2 R2a, or C2-3 alkenyl substituted by zero to 2 R2a; each R2a is independently F, Cl, -CN, -OH, O(Ci-2 alkyl), cyclopropyl, C3-4 alkenyl, or C3-4 alkynyl; R3 is H, F, Cl, Br, -CN, Ci-2 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, -NO2, methylpyridinyl, or methoxypyridinyl; R4aes 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, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 3 R4b; each R4bes independently F, Cl, Br, -CN, -OH, C4-6 alkyl, Ci-2 fluoroalkyl, ¢4-3 hydroxyalkyl, -(CH2)12O (C1-3 alkyl), C1-4 alkoxy, -O (C1-3 hydroxyalkyl), -O(CH)!3O (C1-3 alkyl), Ci-2 fluoroalkoxy, -O (CH)4_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 (Ci-3 alkyl)2, -NRCRC, S(O)2(C1-2 alkyl), C3-6 cycloalkyl, or -CRcRc(phenyl); R4ces H, C1-4 alkyl, or R4a; R4des H or Ci-4 alkyl; each R5 is independently F, -CN, -OH, alkyl Ci-5 substituted by zero to 4 Rg, C1-2 alkoxy substituted by zero to 3 Rg, C2-3 alkenyl substituted by zero to 4 Rg, C2-3 alkynyl substituted by zero to 4 Rg, C3-4 cycloalkyl substituted by zero at 4 Rg, phenyl substituted by zero at 3 Rg, oxadiazolyl substituted by zero at 3 Rg, pyridinyl substituted by zero at 3 Rg, - (CH2) i-2(heterocyclyl substituted by zero at 4 Rg), - (CH2) i -2NRcC (O) (C1-4 alkyl), -(CH2)i2NRcC (O) O (C^ alkyl), - (CH2) i-2NRcS (O)2(C1-4 alkyl), C (O) (Ct-4 alkyl), -C(O)OH, -C (O) O (C1-4 alkyl), C (O) O (C3_4 cycloalkyl), -C(O)NRaRa, or - C(O)NRa(C3-4cycloalkyl) ; and each R6is H, F, or -CH3. This embodiment includes compounds in which R7 is H, D, -CH3, or -CD3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CH and Y is CR3; X is N and Y is CR3; either XesNyYesN; L is -O-, -NH-, -N(CH3)-, or -N(CH3)C(O)-; Ri is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2es -CH3; R3 is H, F, Cl, Br, -CN, -CH3, -NO2, methylpyridinyl, or methoxypyridinyl; R4is R4ao -CH2R4a; R4a 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 by zero a 3 R4b7 each R4bes 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, -CH2(phenyl), C(CH3)2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R3 is independently hydrogen, F, -OH, C^ alkyl, C1-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and each Re is H. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CH and Y is CR3; X is N and Y is CR3; or XesNyYesN; L is -O- or -NH-; Ri is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2es -CH3; R3 is H, F, Cl, Br, -CN, Ci-2 alkyl, Ci-2 fluoroalkyl, C3~4 cycloalkyl, -NO2, or pyridinyl substituted by zero to 1 R3a; R4is R4ao -CH2R4a; F , Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, CH2CH2CH2CH2CH3, —C (CH3) 2CH2CH3, -CF3, -OCH3, - OCH(CH3)2, OC(CH3)3, -OCF3, -C(O)N(CH3)2, -CH2(phenyl), -C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R5 is independently hydrogen, F, -OH, C4-2 alkyl, or each Re alkoxy is H C4-2; ; and R7 is H. This embodiment includes compounds where R7 is D. One embodiment provides a compound of Formula (I) OR a salt thereof, wherein: X is CH and Y is CR3; X is N and Y is CR3; 0 X is N and Y is N; L is -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, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero a 3 R4b; each R4bes 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, -CH2(phenyl), C(CH3)2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R5 is independently hydrogen, F, -OH, Ci~2 alkyl, Ci~3alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and each R6is H; and R7 is H or -CH3; This embodiment includes compounds in which R7 is H, D, -CH3, or -CD3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CH and Y is CR3; XesNyYes CR3; either XesNyYesN; L is -O-; Ri is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2es -CH3; R3 is H, F, Cl, Br, -CN, -CH3, -NO2, methylpyridinyl, or methoxypyridinyl; R4is R4ao -CH2R4a; R4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4b, each R4bes independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, CH2CH2CH2CH2CH3, —C (CH3)2ch2ch3, -cf3, -OCH3, -OCH(CH3)2, OC(CH3)3, -OCF3, -C (O) N (CH3)2, -CH2(phenyl), -C (CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R3 is independently hydrogen, F, -OH, Ci-2 alkyl, or Ci-2 alkoxy; each Rg is H; and R7 is H. This modality includes compounds in which R7 is D. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CH and Y is CR3; L is -O-; R4is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2 is CH3; R3 is H, F, Cl, Br, -CN, -CH3, -NO2, methylpyridinyl, or methoxypyridinyl; R4is R4ao -CH2R4a; R4a 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 by zero at 3 R^; each R4bes 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, -CH2(phenyl), C (CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R3 is independently hydrogen, F, -OH, Ci-2 alkyl, Ci-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3)2, OCH2 (cyclopropyl), or -OCH2CH2 (morpholinyl); and R7 is H. This modality includes compounds in which R7 is D. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CH and Y is CR3; L is -O-; Ri 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; R4is R4ao -CH2R4a; R4ais Phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4b; each R4b is independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -ch2ch2ch2ch2ch3, -C (CH3)2CH2CH3, - cf3, -och3, OCH(CH3)2, -OC(CH3)3, -OCF3, -C (O) N (CH3)2, -CH2(phenyl), C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each Rbes independently hydrogen, F, -OH, C1-2 alkyl, or Ci-2 alkoxy; each Re is H; and R7 is H. This modality includes compounds in which R7 is D. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is CR3; L is -O-; Ri 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; R4is R4ao -CH2R4a; R4ais Phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4b; each R4bes independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -c (CH3)2CH2CH3, -cf3 , -och3, OCH(CH3)2, -OC(CH3)3, -OCF3, -C(O)N(CH3)2, -CH2(phenyl), C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R3 is independently hydrogen, F, -OH, Ci-2alkyl, or Ci-2alkoxy; each Re is H; and R7 is H. This modality includes compounds in which R7 is D. One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N and Y is N; L is -O-; R1 is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2es -CH3; R3 is H, F, Cl, Br, -CN, -CH3, -NO2, methylpyridinyl, or methoxypyridinyl; R4 is R4ao -CH2R4a; R4ais Phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4b; each R4b is independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -ch2ch2ch2ch2ch3, -C (CH3)2CH2CH3, - cf3, -och3, OCH(CH3)2, -OC(CH3)3, -OCF3, -C(O)N(CH3)2, -CH2(phenyl), C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; each R5 is independently hydrogen, F, -OH, Ci-2alkyl, or Ci-2 alkoxy; each Rg is H; and R7 is H. This modality includes compounds in which R7 is D. One embodiment provides a compound of Formula (I) or a salt thereof, where L is -O-. One modality provides a compound of the Formula (I) or a salt thereof, where L is -S- or -S(O)2-. One modality provides a compound of the Formula (I) or a salt thereof, where L is -S-. One modality provides a compound of the Formula (I) or a salt thereof, where L is -S(O)2~· One modality provides a compound of the Formula (I) or a salt thereof, where L is -NR4c- or NR4dC (O) -. One modality provides a compound of the Formula (I) or a salt thereof, where L is -NR4c-. This modality includes compounds in which R4ces H or Ci-4 alkyl. Also, this modality includes compounds in which R4ces R4a. One embodiment provides a compound of Formula (I) or a salt thereof, where L is -NR4dC(O)-. This modality includes compounds in which R4des H or C1-2 alkyl. One embodiment provides a compound of Formula (I) or a salt thereof, wherein Rdes H, F, Cl, Br, -CN, Ct-3 alkyl substituted by zero to 4 Rla, C3-4 cycloalkyl substituted by zero to 4 Ria, Ci-3 alkoxy substituted by zero to 4 Ria, -C(O)NRaRa, -NRaRa, -S(O)nRe, or -P(O)ReRe. This embodiment includes compounds in which Ri is H, F, Cl, Br, -CN, Ci-3 alkyl substituted by zero to 4 Ria, cyclopropyl substituted by zero to 3 Ria, Ci-3 alkoxy substituted by zero to 3 Ria , -C(O)NRaRa, -NRaRa, -S(O)nCH3, or P (O) (CH3)2. Also, this embodiment includes compounds in which Ri is H, F, Cl, Br, -CN, Ci-2 alkyl substituted by zero to 4 Ria, cyclopropyl substituted by zero to 1 Ria, C1-3 alkoxy substituted by zero a 3 Ria, -C(O)NRaRa, NRaRa, -S(O)nCH3, or -P(O) (CH3)2. Additionally, this embodiment includes compounds in which Ri is F, Cl, Br, -CN, -OCH3, or -C(O)NH2. One embodiment provides a compound of Formula (I) or a salt thereof, wherein each Ria is independently F, Cl, -CN, -OH, or -OCH3. This embodiment includes compounds in which each Ria is independently F, Cl, -CN, or -OCH3. Also, this embodiment includes compounds in which each Ria is independently F, Cl, or -CN. One modality provides a compound of the Formula (I) or a salt thereof, wherein each Ra is independently H or C1-2 alkyl. This modality includes compounds in which each Ra is independently H or -CH3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R2 is H, Ci3 alkyl substituted by zero to 3 R2a, or C3-4 cycloalkyl substituted by zero to 2 R2a. This embodiment includes compounds in which R2 is H or C4-2alkyl substituted by zero to 2 R2a. Also, this modality includes compounds in which R2 is H or -CH3. Additionally, this modality includes compounds in which R2 is -CH3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein each R2a is independently F, Cl, -CN, -OH, -O (C1-2 alkyl), cyclopropyl, C3-4 alkenyl, or alkynyl C3-4. This embodiment includes compounds in which each R2a is independently F, Cl, -CN, -OH, -OCH3, or cyclopropyl. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is H, F, Cl, Br, -CN, C1-3 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, -NO2, or pyridinyl substituted by zero to 2 R3a. This embodiment includes compounds in which R3 is H, F, Cl, Br, CN, C1-2 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, -NO2, or pyridinyl substituted by zero to 1 R3a. Also included in this embodiment are compounds in which R3 is H, F, Cl, Br, -CN, —CH3, -NO2, methylpyridinyl, or methoxypyridinyl. Additionally, this modality includes compounds in which R3 is H, F, Cl, Br, -CN, -CH3, or -NO2. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is Cl; and R3es -CN. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And is CR3; Ri is Br; and R3es -CN. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3 is H. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is F; and R3 is -NO2. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -OCH3; and R3es -CN. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3es -CN. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3 is -NO2. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and And it's CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -C(O)NH2; and R3 is H. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3es -CH3. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3 is F. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3 is Cl. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is -CN; and R3es Br. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein X is CRg or N; And it is CR3; Ri is Cl; and R3 is H. This embodiment includes compounds in which X is CRg and Y is CR3. Also, this modality includes compounds in which X is N and Y is CR3. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4 is R4ao -CH2R4a. This modality includes compounds in which R4 is R4a. Also included in this embodiment are compounds in which R4a is C3-g 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 by zero to 3 R4b· One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4 is R4ao -CH2R4a. This modality includes compounds in which R4 is R4a. Also, this modality includes compounds in which R4 is -CH3R4a. Furthermore, this embodiment includes compounds in which R4a is C3-g 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 by zero to 3 R4b. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4 is R4a; and R4aes C3-g 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 by zero to 3 R4b. This embodiment includes compounds in which R4a 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 by zero to 3 R4b; and each R4bes 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, -CH2(phenyl), C(CH3) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl. One modality provides a compound of the Formula (I) or a salt thereof, wherein R4 is R4a; and R4aes 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, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 3 R4b. This embodiment includes compounds in which R4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4bz and each R4bes independently F, Cl, Br, -CN, -CH3, -ch2ch3, -CH2CH2CH3, -CH(CH3)2, -CH3CH3CH2CH3, -C (CH3)3, CH2CH2CH2CH2CH3, -C (CH3 ) 2CH2CH3, -cf3, -och3, -OCH(CH3)2, OC(CH3)3, -OCF3, -C (O) N (CH3) 2, -CH2(phenyl) , -C (CH3)2(phenyl ), cyclopropyl, cyclopentyl, or cyclohexyl. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4 is R4a, -CH2R4a, or -CH2CH2R4a; and R4aes 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, benzoxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 3 R4b. This modality includes compounds in which R4aes R4aes cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b] [1,4]dioxepinyl, each substituted by zero to 3 R4b; and 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, -CH2(phenyl), C(CH3)2(phenyl), cyclopropyl, cyclopentyl, or cyclohexyl. One modality provides a compound of the Formula (I) or a salt thereof, wherein R4 is R4a, -CH2R4a, or -CH2CH2R4a; and R4aes C3-g 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 by zero to 3 R4b- This embodiment includes the compounds in wherein R4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by zero to 2 R4b; and each R4bes independently F, Cl, Br, -CN, —ch3, -ch2ch3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, CH2CH2CH2CH2CH3, —c (ch3)2ch2ch3, -cf3 , -OCH3, -OCH(CH3)2, OC(CH3)3, -OCF3, -C (O) N (CH3)2, —CH2(phenyl), -C (CH3)2(phenyl), cyclopropyl, cyclopentyl , or cyclohexyl. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4a 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 by zero to 3 R4b; and 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, -CH2(phenyl), C(CH3) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl. One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7naphthyridinyl, or dihydrobenzo[b][1, 4]dioxepinyl, each substituted by zero to 2 R4b; and each R4b is independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -C (CH3)2ch2ch3, - cf3, 37 OCH3, -OCH(CH3)2, -OC(CH3)3, -OCF3, -C (O) N (CH3)2, -CH2(phenyl), -C(CH3) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl. One embodiment provides a compound of Formula (I) or a salt thereof, where m is 1, 2 or 3. Included in this embodiment are compounds where m is zero, 1 or 2. Also, in this embodiment Compounds in which m is 1 or 2 are included. One embodiment provides a compound of Formula (I) or a salt thereof, wherein m is 1, 2 or 3; and each R5 is independently F, -CN, -OH, C1-5 alkyl substituted by zero to 4 Rg, C1-3 alkoxyl substituted by zero to 3 Rg, C2-3 alkenyl substituted by zero to 4 Rg, C2_3 alkynyl substituted by zero to 4 Rg, - (CH2) i-2(C3-4 cycloalkyl substituted by zero to 4 Rg), phenyl substituted by zero to 3 Rg, oxadiazolyl substituted by zero to 3 Rg, pyridinyl substituted by zero to 3 Rg, - (CH2) 1-2 (zero-substituted heterocyclyl to Rg), -0 (CH2) 1-2 (zero-substituted heterocyclyl to 4 Rg), - (CH2) i-2NRcC (0) (C1-4 alkyl), - (CH2 ) 4-2NRcC (0) 0 (alkyl C1-4), - (CH2) i-2NRcS (0) 2 (¢4-4 alkyl), -C (0) (C1-4 alkyl), C (0) OH, -C (0) O (C1-4 alkyl), -C (0) 0 (C3-4 cycloalkyl), C(0)NRaRa, or -C (0)NRa(C3-4 cycloalkyl) ); This embodiment includes compounds in which each R5 is independently hydrogen, F, -OH, C1-2 alkyl, Ci-3 alkoxy, -CH2CF3, OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or OCH2CH2( morpholinyl). One modality provides a compound of the Formula (I) or a salt thereof, where m is 1, 2 or 3; and each R5 is independently F, -CN, -OH, C1-5 alkyl substituted by zero to 4 Rg, C1-2 alkoxy substituted by zero to 3 Rg, C2-3 alkenyl substituted by zero to 4 Rg, C2-3 alkynyl zero-substituted to 4 Rg, zero-substituted C3-4 cycloalkyl to 4 Rg, zero-substituted phenyl to 3 Rg, zero-substituted oxadiazolyl to 3 Rg, zero-substituted pyridinyl to 3 Rg, -(CH?)ί-2 (zero substituted heterocyclyl to 4 Rg), (CH2) !-2NRcC (0) (C1-4 alkyl), - (CH2) i-2NRcC (0) 0 (C1-4 alkyl), (CH2) i-2NRcS (0) 2 (C1-4 alkyl), -C (0) (C1-4 alkyl), -C(O)OH, C (0) 0 (C1-4 alkyl), -C (0) 0 (cycloalkyl C3-4), -C(0)NRaRa, or C(0)NRa(cycloalkyl ¢3-4). Included in this embodiment are compounds in which each R5 is independently hydrogen, F, -CN, -OH, Ci~2 alkyl substituted by zero to 4 Rg, or C1-2 alkoxy. Also, this embodiment includes compounds in which each R5 is independently hydrogen, F, -OH, Ci-2 alkyl, or Ci-2 alkoxy. One embodiment provides a compound of Formula (I) or a salt thereof, where m is 1 or 2; and each Rs is independently hydrogen, F, -OH, Ci-2 alkyl, 04-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3)2, OCH2(cyclopropyl), or -OCH2CH2(morpholinyl). This embodiment includes compounds in which each R5 is independently F, -OH, Ci-2 alkyl, C1-3 alkoxy, -CH2CF3, OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or OCH2CH2(morpholinyl). One embodiment provides a compound of Formula (I) or a salt thereof, where m is 1; and R5 is hydrogen, F, -OH, Ci-2 alkyl, Ci-3 alkoxy, -CH2CF3, OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or OCH2CH2(morpholinyl). This embodiment includes compounds in which each R5 is independently F, -OH, Ci-2 alkyl, 0τ-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3)2, -OCH2(cyclopropyl), or -OCH2CH2( morpholinyl). One embodiment provides a compound of Formula (I) or a salt thereof, where m is 1 or 2; and each R5 is independently hydrogen, F, -OH, Ci-2 alkyl, or Ci-2 alkoxy. Included in this embodiment are compounds in which each R5 is independently hydrogen, F, -OH, Ci-2 alkyl, or Ci-2 alkoxy. One embodiment provides a compound of Formula (I) or a salt thereof, where m is 1; and R5hydrogen, F, -OH, Ci-2 alkyl, or Ci-2 alkoxy. Included in this embodiment are compounds in which each R5 is F, -OH, Ci-2 alkyl, or Ci-2 alkoxy. One embodiment provides a compound of Formula (I) or a salt thereof, having a structure selected from: One modality provides a compound of the Formula (I) or a salt thereof, having a structure selected from: One modality provides a compound of the Formula (I) or a salt thereof, wherein the compound is: 6fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-l-yl)-1-methyl3-nitroquinolin-2(1H)- ona (1); 6-fluoro-4-(4-(4isopropylphenoxy)piperidin-l-yl)-l-methyl-3-nitroquinolin41 2(lH)-one (2); 6-fluoro-l-methyl-3-nitro-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)quinolin-2(1H)-one (3) ; 6-fluoro-l-methyl-3-nitro-4-(4-(m-tolyloxy)piperidin-lyl)quinolin-2 (1H)-one (4); 4-(4-((lH-indazol-4yl)oxy)piperidin-l-yl)-6-fluoro-l-methyl-3-nitroquinolin2(lH)-one (5); 3-((1-(6-fluoro-l-methyl-3-nitro-2-oxo-l, 2dihydroquinolin-4-yl)piperidin-4-yl)oxy)benzonitrile (6); 4(4-(3-chlorophenoxy)piperidin-l-yl)-6-fluoro-l-methyl-3nitroquinolin-2(1H)-one (7); 6-fluoro-4-(4-(2-methoxy-5(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-3nitroquinolin-2(1H)-one (8); 6-fluoro-4-(4-(3fluorophenoxy)piperidin-l-yl)-l-methyl-3-nitroquinolin-2(1H)one (9); or 4-(4-(4-(tert-butyl)phenoxy)piperidin-l-yl)-1methyl-2-oxo-l,2-dihydroquinoline-6-carbonitrile (53). One modality provides a compound of the Formula (I) or a salt thereof, wherein the compound is: 4((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-l-yl)-l- methyl-2-oxo-l,2-dihydropyrido[3,2d]pyrimidine-6-carbonitrile (243 and 246); 4-((2R,5R)-4-((5isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-l-yl)-1methi1-2-oxo-1,2-dihydropyrido[3,2-d ]pyrimidine-6-carbonitrile (244-245) ; 4- ((2R,5S)-4-( (5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-l-yl)-l-methyl-2-oxo-l,2-dihydropyrido[3,2d ] pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-l-yl)-1 methi1-2-οχο-1,2-dihydropyrido[3,2- d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine -6-carbonitrile (251 and 253); 4((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine -6carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-1-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine -6-carbonitrile (256-257); 4((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine -6carbonitrile (255 and 258); (±)-trans-6-chloro-4-(3-hydroxy-4(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-1-methylpyrido[3,2d]pyrimidin-2(1H)-one ( 271-272); (+)-trans-4-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine-6 -carbonitrile (273-274); 6chloro-4- ((3R,4R)-3-methoxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-1-methylpyrido[3,2— d]pyrimidin-2(1H)-one ( 275); (±)-trans-4-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-1-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine-6 -carbonitrile (276-277); 4((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)l-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine- 6carbonitrile (278-279); 6-chloro-4-((2S,4R,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-1 methylpyrido[3,2-d] pyrimidin-2(1H)-one (300); 4-((2S,4R,5R)-5ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l11)-1-methyl-2-oxo-1,2-dihydropyrido[3 ,2-d]pyrimidine-6carbonitrile (301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-1methylpyrido[3,2-d]pyrimidin -2(1H)-one (302); 4-((2R,4R,5R)-5ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[ 3 ,2-d]pyrimidine-6carbonitrile (303); 6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-1methylpyrido[3,2-d]pyrimidin -2(1H)-one (304); 4-((2R,4S,5R)-5ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[3 ,2-d]pyrimidine-6carbonitrile (305); 6-chloro-4-((2S,4S,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-1methylpyrido[3,2-d]pyrimidin -2(1H)-one (306); 4-((2S,4S,5R)-5ethyl-4- ((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[3 ,2-d]pyrimidine-6carbonitrile (307); l-methyl-2-oxo-4-((2S,5S)-2,4,5-trimethyl4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2dihydropyrido[3,2-d] pyrimidine-6-carbonitrile (339-340); (±)trans-6-chloro-4-(3-ethoxy-4-((5-isopropoxypyridin-2yl)oxy)piperidin-l-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H )ona (399); trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2yl)oxy)piperidin-l-yl)-l-methyl-2-oxo-l,2-dihydropyrido[3,2 d]pyrimidine-6-carbonitrile (400-401); trans-4-(3-ethoxy-4phenoxypiperidin-1-yl)-1-methyl-2-oxo-l,2-dihydropyrido[3,2d]pyrimidine-6-carbonitrile (402-403); or 4-((3S,4S)-3-ethoxy4 - (4-(trifluorornetyl)phenoxy)piperidin-l-yl)-l-methyl-2-οχο1,2-dihydropyrido[3,2-d]pyrimidine-6 -carbonitrile (404-405). One embodiment provides a compound of Formula (I) or a salt thereof, wherein the compound is: 6-chloro-4(4-(3-methoxyphenoxy)piperidin-l-yl)-1-methi1-2-oxo- 1,2-dihydro1,5-naphthyridine-3-carbonitrile (10); 6-chloro-l-methyl-2-oxo-4(4-(2-(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (11); 6-chloro-4-(4-(3,4-difluophenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridine-3-carbonitrile (12); 6-chloro-l-methyl-2-oxo-4-(4(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (13); 6-chloro-4-(4-(4methoxyphenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (14); 4-(4-(4-(tert-butyl)phenoxy)piperidin-l-yl)-6-chloro-l-methyl-2-oxo-l,2dihydro-1,5-naphthyridine-3-carbonitrile (15); 6-chloro-4-(4-(4chlorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (16); 6-chloro-4-(4-(3-fluo o-4(trifluoromethoxy)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrile ( 17); 6-chloro-4-(4-(2chlorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (18); 6-chloro-l-methyl-2-oxo-4-(4 (4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (19); 6-chloro-4-(4-(4fluorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (20); 6-chloro-l-methyl-2-oxo-4-(4(p-tolyloxy)piperidin-l-yl)-1,2-dihydro-l,5-naphthyridine-3carbonitrile (21); 6-chloro-l-methyl-2-oxo-4-(4-(mtolyloxy)piperidin-l-yl)-1,2-dihydro-l,5-naphthyridine-3carbonitrile (22); 6-chloro-4-(4-(2-chloro-5fInorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (23); 6-chloro-l-methyl-2-oxo-4-(4(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (24); 4-((1-(6-chloro-3-cyano-lmethi1-2-oxo-1,2-dihydro-l,5-naphthyridin-4-yl)piperidin-4yl)oxy)-N,N-dimethylbenzamide ( 25); 4-(4-(4-bromo-2methylphenoxy)piperidin-l-yl)-6-chloro-1-methi1-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrile (26); 6-chloro-4-(4-(3chlorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (27); 6-chloro-4-(4-(3-chloro-5fInorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (28); -chloro-l-methyl-4-(4-(2methyl-4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-2-oxo-l,2dihydro-1,5-naphthyridine-3-carbonitrile (29); 6-chloro-l-methyl2-oxo-4-(4-(4-(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2dihydro-1,5-naphthyridine-3-carbonitrile (30); 4-(4-(4-(terebutoxy)phenoxy)piperidin-l-yl)-6-chloro-l-methyl1-2-oxo-1,2- 6-dihydro-1,5-naphthyridine-3-carbonitrile (31); 6-chloro-4-(4-(4cyanophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-1,5naphthyridine-3-carbonitrile (32); 6-chloro-l-methyl-2-oxo-4-(4(2-(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrile (33); 6-chloro-4-(4-(3cyanophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (34); 6-chloro-4-(4-(2methoxyphenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-1,5naphthyridine-3-carbonitrile (35); 6-chloro-4-(4-(4-fluoro-2methoxyphenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-1,5naphthyridine-3-carbonitrile (36); 6-chloro-4-(4-(4isopropylphenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2-dihydro1,5-naphthyridine-3-carbonitrile (37); 6-chloro-4-(4-(3-chloro-4cyanophenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (38); 6-chloro-4-(4-(4-chloro-3methoxyphenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-1,5naphthyridine-3-carbonitrile (39); 6-chloro-4-(4-(3-chloro-4methylphenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2-dihydro-l,5naphthyridine-3-carbonitrile (40); 6-chloro-4-(4-(2-chloro-4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1-methyl-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrile (41 ); 6-chloro-4-(4-(3chloro-4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-l-methyl-2oxo-1,2-dihydro-l,5-naphthyridine-3-carbonitrile (42) ; 6-chloro4-(4-(2-cyanophenoxy)piperidin-l-yl)-1-methi1-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrile (43); 6-chloro-4-(4-(247-fluorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridine-3-carbonitrile (44); 6-chloro-4-(4-(3fluorophenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridine-3-carbonitrile (45); 6-chloro-l-methyl-2-oxo-4-(4phenoxypiperidin-l-yl)-1,2-dihydro-l,5-naphthyridine-3carbonitrile (46); 6-bromo-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (47); 6-methoxy-l-methyl-2-oxo-4-(4(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile (48); l-methyl-2,6-dioxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2,5,6-tetrahydro1,5-naphthyridine-3-carbonitrile (49); 5-methyl-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2,7-dicarbonitrile (50); 5-methyl-7-nitro-6-oxo-8(4-(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro1,5-naphthyridine-2-carbonitrile (51); 5-methyl-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (52); 5-methyl-6-oxo-8-(4-(4-(tercpentyl)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5-naphthyridine-2carbonitrile (54); 8-(4-(4-benzylphenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (55); 8-(4-(4-butylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (56); 5-methyl-6-oxo-8(4-(4-propylphenoxy)piperidin-l-yl)-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (57) ; 8-(4-(448 cyclopentylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (58); 8-(4-(4cyclopropylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (59); 8-(4-(4-isopropyl-3methylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (60); 5-methyl-6-oxo-8-(4((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)piperidin-l-yl)-5,6dihydro-1,5-naphthyridine-2-carbonitrile (61); 5-methyl-6-oxo-8(4-(4-pentylphenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (62); 8-(4-(4cyclohexylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (63); 8-(4-(4-(2cyclohexylpropan-2-yl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (64); 8-(4-(4(tert-butoxy)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (65); 8-(4-((5isopropoxypyridin-2-yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (66); 8-(4-((5chloropyridin-2-yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-(4-((6-(tert-butyl)pyridazin-3-yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (68 ); 5-methyl-6-oxo-8(4-(quinoxalin-2-yloxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (69); 8-(4-((2,6-dimethylpyrimidin 4-yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,549 naphthyridine-2-carbonitrile (70); 5-methyl-6-oxo-8-(4(quinazolin-4-yloxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (71); 5-methyl-8-(4-((2methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (72); 8-(4-((7-chloro-4methoxyquinolin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (73) ; 8-(4-((1,7naphthyridin-8-yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (74); 5-methyl-6-oxo-8(4-(phthalazin-l-yloxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (75); 5-methyl-6-oxo-8-(4-((2(trifluoromethyl)pyrimidin-4-yl)oxy)piperidin-l-yl)-5,6dihydro-1,5-naphthyridine-2-carbonitrile (76) ; 5-methyl-6-oxo-8(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-l-yl)-5,6dihydro-1,5-naphthyridine-2-carbonitrile (77) ; 8-(4-((2isopropyl-6-methylpyrimidin-4-yl)oxy)piperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (78) ; ( + / )6-cyano-l-methyl-4-((3R,4R)-3-methyl-4-(4(trifluorornetoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2(1H )one (79); 6-cyano-l-methyl-4-((3R,4R)-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2(1H)one (80 ); 6-cyano-l-methyl-4-((3R,4R)-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2(1H)one (81 ); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tercpentyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,550 naphthyridine-2 -carbonitrile (82-84); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (85-87); 8-((3R,4R)-4(4-(tert-butyl)phenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2- carbonitrile (88-90); 8((3R,4R)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (OIOS); 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin-l-yl)5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (9496 ) ; 5-methyl-8-((3R,4R)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (97-99); 8-((3R,4R)-4-(4cyclopentylphenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (100-102) ; 8-((3R,4R) 4-(3,4-difluorophenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (103 -105); 8((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (106); 5-methyl-8-((3R, 4R)-3-methyl-4-(m-tolyloxy)piperidin-l-yl)-6oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (107 -109); 8((3R,4R)-4-(4-ethylphenoxy)-3-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (110); 8((3R,4R)-4-(4-cyclopropylphenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (111); 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3 methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (112); 8-((3R,4R)-4-(2,4difluorophenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (113- 115); 8-((3R,4R) 4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3-methylpiperidin-l-yl)5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (116-118); 5-methyl-8-((3R,4R)-3-methyl-4-(ptolyloxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile (119-121 ); 8-((3R,4R)-4-(3-isopropylphenoxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (122); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (123); 8-((3R,4R)-4(2-fluoro-6-(trifluoromethyl)phenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile ( 125127) ; 8- ((3R, 4R)-4- (4-fluorophenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (128130) ; 5-methyl-8-((3R,4R)-3-methyl-4-(2,4,6trifluorophenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (131); 8-((3R,4R)-4-((3,4-dihydro2H-benzo[b][1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-l-yl)-5methyl-6- oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (132); 5-methyl-8-((3R,4R)-3-methyl-4-(452 (trifluoromethoxy)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (133-135); 5-methyl-8-((3R,4R)3-methyl-4-(m-tolyloxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2,7-dicarbonitrile ( 136);8-((3R,4R)-3-ethyl-4-(3isopropylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro1,5-naphthyridine-2-carbonitrile (137-139 ); 8-((3R,4R)-3-ethyl4-(3-(triflucromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile ( 140-142); 8((3R,4R)-3-ethyl-4-(4-isopropylphenoxy)piperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (143- 145); 8-((3R,4R)-3-ethyl-4-(4-(trifluoromethyl)phenoxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2- carbonitrile (146-148); 8-((3R,4R)-3-ethyl-4-(4-(tercpentyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2- carbonitrile (149-151); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-ethylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (152-154); 8-((3R,4R) 4-(3-cyclopropylphenoxy)-3-ethylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (155-157 ); 8((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-ethylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2- carbonitrile (158160); 8-((3R,4R)-3-ethyl-4-(4-isopropoxyphenoxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (161 ); 8-((3R,4R)-3-ethyl-4-(3(trifluoromethoxy)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6 dihydro-1,5-naphthyridine-2- carbonitrile (162-163); 8-((3R, 4S)3-ethyl-4-(3-isopropylphenoxy)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (164) ; 8-((3R, 4S)4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2- carbonitrile (165-167); 5methyl-8-((3R,4 S)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidinl-yl)-6-oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (169171); 8- ((3R, 4S)-4- (4- (tert-butoxy)phenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile (172-174); 8-((3R, 4S)-4-(4-(tert-butyl)phenoxy)3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2- carbonitrile (175); 8-((3R,4S)-4-(4isopropylphenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (176-178) ; 8-((3R,4S)— 4-(3-cyclopropylphenoxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (179- 181); 8((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (182184); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l, 5naphthyridine-2-carboxamide (185);(+ / -) 5-methyl-8-((3R,4S)-3methi1-4 -(4-(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo- 5,6dihydro-1,5-naphthyridine-2-carbonitrile (186); 5-methyl-8((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-l-yl)δ-οχο-5,6-dihydro-l,5-naphthyridine-2- carbonitrile (187); 5-methyl-8-((3R, 4S)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile ( 188); 5-methyl-8-((3R,4S)-3-methyl4-(4-(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6dihydro-1,5-naphthyridine-2,7- dicarbonitrile (189-191); 8((3R,4R)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (192-194); 8-((3R,4R)-3-ethyl-4-(4-fluoro-3propylphenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (195); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (196-198); 8-((3R,4R) 4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (199201) ; 8-((3R,4S)-3-ethyl-4-((5-isopropoxlpyridin-2yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (202-204); 8-((3R,4S)-4-((5isopropylpyridin-2-yl)oxy)-3-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (205-207); 8((3R,4S)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine -2-carbonitrile (208-210); 8-((3R,4S)-4-((4isopropylpyridin-2-yl)oxy)-3-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (211-213); 8((3R,43)-4-((6-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-l yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (214-216); 5-methyl-8-((3R,4S)-3-methyl-4-(pyrimidin-2yloxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile (217 ); 8- ((3R,4S)-4-((4-methoxypyrimidin-2yl)oxy)-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (218); 5-methyl-8-((3R,4S)-3-methyl4-((5-propylpyrimidin-2-yl)oxy)piperidin-l-yl)-6-oxo-5,6dihydro-1,5-naphthyridine- 2-carbonitrile (219);5-methyl-8((3R,4 S)-3-methyl-4-((2-methylpyrimidin-4-yl)oxy)piperidin-lyl)-6-OXO-5,6-dihydro-l,5- naphthyridine-2-carbonitrile (220); 8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3-methylpiperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (221); 5-methyl-8-((3R,4S)-3-methyl-4-((5(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-l-yl)-6-oxo-5,6dihydro-1, 5-naphthyridine-2-carbonitrile (222); 8-((3R,4S)-4((5-cyclopropylpyrimidin-2-yl)oxy)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (223); 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (224); 5-methyl-8-((3R,4S)-3-methyl4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-l-yl)-6-oxo5,6-dihydro-l,5 -naphthyridine-2-carbonitrile (225-227); (+ / -); 8-((3R,4S)-4-((5-isopropoxypyridin-2-yl)oxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (228); (+ / -) 5-methyl-8-((3R,4R)-3 methi1-4-(4-(tert-pentyl)phenoxy)piperidin-l-yl)-6-oxo-5,6dihydro-1, 5-naphthyridine-2,7-dicarbonitrile (229); 5-methyl-8((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-l-yl)-6oxo-5,6-dihydro-l,5-naphthyridine-2 ,7-dicarbonitrile (230); 5methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidinl-yl)-6-oxo-5,6-dihydro-l,5-naphthyridine-2, 7-dicarbonitrile (231); ( + / -)8-(4-( (5-isopropoxypyridin-2-yl)oxy)-3,3dimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (232); 8-(4-((5-isopropoxypyridin2-yl)oxy)-3,3-dimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (233 ); 8-(4-((5isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (234 ); (+ / -)5-methyl-8-((3R,4S)-3-methi1-4-( (4(trifluchromethoxy)benzyl)oxy)piperidin-l-yl)-6-oxo-5,6dihydro-1 ,5-naphthyridine-2-carbonitrile (235); (+ / -)5-methyl-8( (3R,4 S)-3-methyl-4-((4-(trifluororethoxy)benzyl)oxy)piperidinl-yl)-6-OXO-5,6-dihydro- l,5-naphthyridine-2-carboxamide (236); 7-fluoro-5-methyl-6-OXO-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (237); 7-chloro-5-methyl-6-oxo-8-(4(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (238); 7-bromo-5-methyl-6-oxo-8-(4(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (239); 7-(6-methoxypyridin-3-yl)-5-methi1-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-l-yl)5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (240); 7-(2methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile (241); (+ / -) 6-bromo-l-methyl-4((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-l-yl)-2oxo-1,2- dihydro-l,5-naphthyridine-3-carbonitrile (242); 8((2S,5S)-4- ((5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (243 and 246); 8-((2R,5R)-4-((5isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (244245) ; 4- ((2R,5S)-4-( (5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-l-yl)-l-methyl-2-oxo-l,2-dihydropyrido[3,2d ]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-( (5isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-l-yl)-1methi1-2-oxo-1,2-dihydropyrido[3,2-d ]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine -6-carbonitrile (251 and 253); 4((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-lyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine -6carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine -6-carbonitrile (256-257); 8 ((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (255 and 258); (±)-trans-8-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (259-260); (±)-trans8-(3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile ( 261262); 8-((3R,4R)-3-ethoxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (263-264); (±)-cis-8(3-fluoro-4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (265266) ; (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2yl)oxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (267-268); (±)-trans-8-(4-((5isopropoxypyridin-2-yl)oxy)-3-methoxypiperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (269-270); 8-((2S,5R)-4-((5-methoxypyridin-2-yl)amino)-2,5dimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine -2-carbonitrile (280-281); N-((2S,5R)-1-(6-cyanol-methyl-2-oxo-l,2-dihydro-l,5-naphthyridin-4-yl)-2,5dimethylpiperidin-4-yl)-4- fluoro-N-methylbenzamide (282-283); N-(1-(6-cyano-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridin-4-yl)3-methylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (284-287); N-(1-(3,6-dicyano-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridin-459yl)-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-l-yl)-5methyl-6-oxo-5,6-dihydro- l,5-naphthyridine-2-carbonitrile (294); 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro -l,5naphthyridine-2-carbonitrile (295); 8-((2S,4R,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l ,5-naphthyridine-2-carbonitrile (296);8((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2methylpiperidin-l-yl)-5- methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (297); 8- ((2R,4S,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l ,5-naphthyridine-2-carbonitrile (298);8((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2methylpiperidin-l-yl)-5- methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (299); 8-((2S,4S,5R)-5-ethyl-2methyl-4-(3-(triflucromethyl)phenoxy)piperidin-l-yl)-5-methyl-6oxo-5, 6-dihydro-l,5- naphthyridine-2-carbonitrile (308);8((2R,4S,5R)-5-ethyl-2-methyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo -5,6dihydro-1,5-naphthyridine-2-carbonitrile (309); 8-((2R,4R,5R)5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5 -naphthyridine-2-carbonitrile (310); 8-((2R,4S,5R)-2,5-dimethyl-4-(360 (trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine -2-carbonitrile (311); 8-((2S,4R,5S)2,5-dimethyl-4-(p-tolyloxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2- carbonitrile (312); 8-((2S,4R,5S)4-(3-chlorophenoxy)-2,5-dimethylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (313); 8((2S,4R,5S)-4-(3-cyanophenoxy)-2,5-dimethylpiperidin-l-yl)-5methyl-β-οχο-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (314); 8-((2S, 4R, 5S)-4-(4-fluorophenoxy)-2,5-dimethylpiperidin-l-yl)5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2 -carbonitrile (315); 8- ((2S,5S)-2,5-dimethyl-4-( (4(trifluoromethyl)phenyl)amino)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5- naphthyridine-2-carbonitrile (316A); 8-(2,5)dimethyl-4-(methyl(4-(trifluoromethyl)phenyl)amino)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2- carbonitrile (316-319); 8- ((2S,5S)-2,5-dimethyl-4-(methyl(3(trifluoromethyl)phenyl)amino)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5 -naphthyridine-2-carbonitrile (320-321); 8-(4((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7-dicarbonitrile (322 -325); - (4-((4-fluorobenzyl)(methyl)amino)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (326-328); 8-(4-((4,4difluorocyclohexyl)(methyl)amino)-3-methylpiperidin-l-yl)-5methyl-δ-οχο-5,6-dihydro-l,5-naphthyridine-2,7-dicarbonitrile ( 329-330); 8-((2S,5R)-4-((4-fluorobenzyl)(methyl)amino)-2,5dimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (331-332); 8-((2S,5S)-4-((4fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (333334) ; 8- ((2S,5S)-4-((5-Isopropoxypyridin-2-yl)oxy)-2,4,5trimethylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l ,5naphthyridine-2-carbonitrile (335-336); 5-methyl-6-oxo-8((2S,5S)-2,4,5-trimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (337-338); trans-8-(3-ethoxy-4phenoxypiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (341-342); 8- ((3S,4S)-3-ethoxy-4(4-(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (343-344); 8-((3S,4S)3-ethoxy-4-(2-(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (345-346); 8-((3S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (347348 ); 8-((3S,4S)-3-ethoxy-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (349-350); 8-((3S,4S)3-ethoxy-4-(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)-5-methyl16-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (351-352); 8-((3S,4 S)-3-ethoxy-4-(4-(methylsulfonyl)phenoxy)piperidin-1yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (353-354); 8-((3S,4S)-3-ethoxy-4-((2-methylbenzo[d]oxazol-5yl)oxy)piperidin-l-yl)-5-methi1-6-oxo-5,6-dihydro- l,5naphthyridine-2-carbonitrile (355-356); 8-((3S,4S)-4-(4-chloro3-fluorophenoxy)-3-ethoxypiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile ( 357-358); 8-((3S,4S)3-ethoxy-4- ((2-(trifluoromethyl)pyridin-4-yl)oxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l, 5-naphthyridine-2-carbonitrile (35 9-3 62); trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2yl)oxy)piperidin-l-yl)-5-methi1-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (363-364); 8-((3S,4S)-3-ethoxy-4((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l, 5-naphthyridine-2-carbonitrile (365-366); trans-8-(3-ethoxy-4-((5-(trifluoromethyl)pyridin-2yl)oxy)piperidin-l-yl)-5-methi1-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (367-368); cis-8-(3-ethoxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (369-370 ); cis-8-(3ethoxy-4- ((5-isopropoxypyridin-2-yl)oxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile ( 371372) ; trans-8-4-(benzo[d]thiazol-2-yloxy)-3-ethoxypiperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (373 -374); 8- ((3S,4S)-3-ethoxy-4-((6-isopropoxypyridazin-3yl)oxy)piperidin-l-yl)-5-methi1-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (375-376); 8-((3S,4S)-3-ethoxy-4((5-isopropoxypyrazin-2-yl)oxy)piperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (377-378); 8((3S,4S)-3-ethoxy-4-((5-isopropoxypyrimidin-2yl)oxy)piperidin-l-yl)-5-methi1-6-oxo-5,6-dihydro-l,5naphthyridine-2 -carbonitrile (379-380); 8-((3S,4S)-3-ethoxy-4( (3-(trifluoromethyl)benzyl)oxy)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine- 2-carbonitrile (381-382); 8((3S,4 S)-3-ethoxy-4-((5-isopropoxypyridin-2yl)methoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile (383-384); 8-((3R,4R)-3-(2(dimethylamino)ethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l, 5-naphthyridine-2-carbonitrile (385-386); 8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2 -carbonitrile (387-388); 8-((3R,4R) 3-(2-methoxyethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-lyl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine -2-carbonitrile (389-390); 5-methyl-8-((3R,4R)-3-(2-mofolinoethoxy)-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l, 5naphthyridine-2-carbonitrile (391-392); 5-methyl-6-oxo-8((3R,4R)-3-(2,2,2-trifluoroethoxy)-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5,6-dihydro- l,5naphthyridine-2-carbonitrile (393-394); trans-8-(3-isopropoxy4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (395-396) ; trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-ethoxypiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile (397 -398). The present invention can be carried out in other specific ways without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention indicated herein. It is understood that any and all embodiments of the present invention may be taken together with any other embodiment or embodiments to describe additional embodiments. It should also be understood that each individual element of the modalities is intended to be combined with any and all other elements of any modality to describe an additional modality. DEFINITIONS The features and advantages of the invention can be more easily understood by those skilled in the art by reading the following detailed description. It should be appreciated that certain features of the invention which, for reasons of clarity, are 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, for the sake of brevity, are described in the context of a single embodiment, may also be combined to form subcombinations thereof. The exemplary or preferred embodiments identified herein are intended to be illustrative and not limiting. Unless otherwise specified herein, references made to the singular may also include the plural. For example, a and a can refer to one, or one, or more. 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 include 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). Unless otherwise noted, any atom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences. The definitions set forth herein take precedence over the definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference. 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 description (unless limited in specific cases) either individually or as part of a larger group. Throughout the description, one skilled in the art can choose groups and substituents thereof to provide stable moieties and compounds. In accordance with a convention used in the art it is used in the structural formulas herein to represent the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. The terms halo and halogen, as used herein, refer to F, Cl, Br and I. The term cyano refers to the CN group. The term amino refers to the NH2 group. The term oxo refers to the group =0. The term alkyl, as used herein, refers to groups of both straight-chain and branched saturated aliphatic hydrocarbons containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms and 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 more specifically the number of carbon atoms a particular group can contain. For example, Ci-¿ alkyl denotes straight-chain and branched alkyl groups with one to four carbon atoms. 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, Ci-4 fluoroalkyl is intended to include Ci, C2, C3 and C4 alkyl groups substituted by one or more fluoro atoms. Representative examples of fluoroalkyl groups include, but are not limited to, CF3 and CH2CF3. The term hydroxyalkyl includes both straight-chain and branched-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, hydroxyalkyl includes -CH2OH, -CH2CH2OH, and hydroxyalkyl Ci_4. The term alkenyl refers to a straight-chain or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethenyl or allyl. For example, C2_6 alkenyl denotes straight-chain and branched alkenyl groups with two to six carbon atoms. The term alkynyl refers to a straight-chain or branched hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-to-carbon triple bond. Examples of such groups include ethinyl. For example, C2_e alkynyl denotes straight-chain and branched alkynyl groups with two to six carbon atoms. The term cycloalkyl, as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by the removal of a 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 more specifically defines the number of carbon atoms that a particular cycloalkyl group can contain. For example, C3-6 cycloalkyl means cycloalkyl groups with three to six carbon atoms. The term fluorocycloalkyl as used herein is intended to include a cycloalkyl group substituted with one or more fluorine atoms. The term alkoxyl, as used herein, refers to an alkyl group attached to the precursor molecular moiety through an oxygen atom, for example, a methoxyl group (OCH3). For example, C1-3 alkoxy denotes alkoxy groups with one to three carbon atoms. The terms fluoroalkoxyl and O (fluoroalkyl) represent a fluoroalkyl group as defined above attached through an oxygen (O) bond. For example, C1-4 fluoroalkoxyl is intended to include Ci, C2, C3, and C4 fluoroalkoxyl groups. The terms carbocycle, carbocyclic or carbocyclyl can be used interchangeably and refer to cyclic groups having at least one saturated or partially saturated non-aromatic ring where all atoms of all rings are carbon. The carbocyclyl ring may be unsubstituted or may contain one or more substituents as valency permits. Thus, the term includes non-aromatic rings such as, for example, cycloalkyl, cycloalkenyl and cycloalkynyl rings. Exemplary bicyclic carbocyclyl groups include, indanyl, indenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, bicycloheptanyl, bicyclohaltanyllines, and bicyclononanyl. The term aryl, as used herein, refers to a group of atoms derived from a molecule containing one or more aromatic rings by the elimination of hydrogen that is attached 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 valency permits. 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 valency permits. The term heteroatom refers to oxygen (O), sulfur (S) and nitrogen (N). The terms heterocycle, heterocyclic or heterocycilium can be used interchangeably and refer to cyclic groups that have at least one saturated or partially saturated non-aromatic ring and where one or more of the rings have at least one heteroatom (O, S or N), the heteroatom-containing ring preferably has 1 to 3 heteroatoms independently selected from O, S and / or N. The ring of such a heteroatom-containing group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and also that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may optionally be quaternized. The heterocycle group can be attached to any available nitrogen or carbon atom. The heterocycle ring may be unsubstituted or may contain one or more substituents as valency permits. Exemplary monocyclic heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2oxoazepinyl, azepinyl, 4-piperidonyl, tetra hydropyranyl, morpholinyl, thiamorpholinyl, sulfoxide thiamorpholinyl, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1dioxothienyl, dihydroisoindolyl, and tetrahydroquinolinyl. The term heteroaryl refers to substituted or unsubstituted aromatic groups having at least one heteroatom (O, S or N) in at least one of the rings, the 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 may contain one or two oxygen or sulfur atoms and / or 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. 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 that complete the bicyclic group and the tricyclic heteroaryl group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic and tricyclic heteroaryl groups should include only aromatic rings. The heteroaryl group can be attached to any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents. Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyradinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, cromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazole yl, and pyrrolopyridyl. Exemplary tricyclic heteroaryl groups include acridinyl, benzoquinolinyl, benzoisoquinolinyl and benzonaphthyridinyl. The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity. irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio. Compounds of formula (I) can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to a compound of the invention is understood to include a 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. Additionally, the term salt(s) may include zwitterions (internal 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 amine and metal salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, for example, in isolation or purification steps that may be employed during preparation, and are therefore contemplated within the scope of the invention. Salts of compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt is precipitated or in an aqueous medium followed by freeze-drying. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipates, alginates, ascobates, aspartates, benzoates, benzenesulfonates, bisulfates, paraffins, butyrates, citrates, camphorates, camphorsulfonates. , cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, maleates (formed with maleic acid), 275 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. 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-p-phenethylamine, 1-ephenamine, N,N'dibenzylethylene-diamine, dehydroabietylamine, netylpiperidine, benzylamine, dicyclohexylamine or amines and similar pharmaceutically acceptable salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can 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), 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, hydrogen sulfate, methanesulfonate, phosphate or nitrate salts. The compounds of Formula (I) may be provided as amorphous solids or crystalline solids. Freeze-drying can be employed to provide the compounds of Formula (I) as a solid. Furthermore, it should be understood that the 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 bonds. In certain cases the solvate will be able to be isolated, for example when one or more solvent molecules are incorporated into the crystalline structure of the crystalline solid. Solvato encompasses both the solution phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates and ethyl acetate solvates. Solvation methods are known in the art. Various forms of prodrugs are well known in the art and are described in Rautio, J., Nature Review Drug Discovery, 17, 559-587 (2018). Furthermore, the 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. The term stable compound or stable structure is intended to indicate a compound that is sufficiently robust to survive isolation at a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent. The present invention aims to incorporate stable compounds. Therapeutically effective amount is intended to include an amount of a compound of the present invention alone or an amount of the combination of claimed compounds or an amount of a compound of the present invention in combination with other active ingredients effective to act as a DGKa inhibitor and / or or DGK / , or effective in treating or preventing viral infections and proliferative disorders, such as cancer. As used herein, treat or treatment covers the treatment of a disease state in a mammal, particularly in a human, and includes: (a) preventing the disease state from occurring in a mammal, in particular, when the mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibit the disease state, that is, stop its development; and / or (c) alleviate the disease state, that is, cause regression of the disease state. The compounds of the present invention are intended to include all isotopes of the atoms that occur in the present compounds. Isotopes include those atoms that have 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). Carbon isotopes include 13C and 14C. The isotope-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described herein, using an appropriate isotope-labeled reagent in place of the unlabeled reagent otherwise employed. . The compounds according to Formula (I) and / or their pharmaceutically acceptable salts may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or the amount of compound of the Formula (I) to be delivered. Also included within this invention is a class of pharmaceutical compositions comprising a compound of Formula (I) and / or its pharmaceutically acceptable salts thereof; and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively known 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 route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention may, for example, be administered orally, mucosally or parenterally including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal 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 can be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered for example as an oral dosage form or an infusion. 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 about 0.1 to about 1000 mg, preferably about 0.25 to about 250 mg, and more preferably about 0.5 to about 100 mg. An appropriate daily dose for a human or other mammal can vary widely depending on the patient's condition and other factors, but can be determined using routine methods. Any pharmaceutical composition contemplated herein may, for example, be administered orally via any acceptable and suitable oral preparation. 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 may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition according to the invention may contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants and preservative agents. A tablet may be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic excipient pharmaceutically 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, croscarmellose sodium, corn starch and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinylpyrrolidone and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid and talc. Additionally, a tablet may be uncoated or coated by known techniques to mask the bad taste of an unpleasant-tasting drug, or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effects of the active ingredient for a period of time. of more time. Exemplary water-soluble flavor masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate. Hard gelatin capsules may be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one of its salts with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin. Soft gelatin capsules may be prepared, for example, 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. An aqueous suspension may be prepared, for example, by mixing 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, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum of tragacanth and gum arabic; dispersing or wetting agents, such as, for example, a phosphatide of natural origin, e.g. , lecithin; condensation products of algylene 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 sobitol monooleate; and condensation products of ethylene oxide with partial asters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension may also contain at least one preservative, such as, for example, ethyl n-propyl phydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, sucrose, saccharin and aspartame. Oily suspensions may be prepared, for example, by suspending at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil, such as, for example, peanut oil; olive oil; Sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension may also contain at least one thickening agent, such as, for example, beeswax; hard paraffin and cetyl alcohol. In order to provide a palatable oil suspension, at least one of the sweetening agents already described above, and / or at least one flavoring agent can be added to the oil suspension. An oil suspension may further contain at least one preservative, including, but not limited to, an antioxidant, such as, for example, butylated hydroxyanisole and alpha-tocopherol. The dispersible powders and granules may be prepared, for example, by mixing 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 conservative. Suitable dispersing agents, wetting agents and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, eg, ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including, but not limited to, sweetening agents, for example; flavoring agents; and coloring agents. An emulsion of at least one compound of Formula (I) and / or at least one of its pharmaceutically acceptable salts may, for example, be prepared as an oil-in-water emulsion. The oil phase of emulsions comprising compounds of Formula (I) may be constituted by known ingredients in a known manner. The oil phase may 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. Although the phase may simply comprise an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally occurring phosphatides, eg, soy lecithin; esters or partial asters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial asters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that 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) form the so-called emulsifying wax, and the wax, together with oil and fat, form the so-called emulsifying ointment base that forms the dispersed oil phase of the cream formulations. An emulsion may 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 well materials. known in the art. The compounds of Formula (I) and / or at least one pharmaceutically acceptable salt thereof may also be administered intravenously, subcutaneously and / or intramuscularly via any suitable and pharmaceutically acceptable 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. Formulations for precursor administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the mentioned vehicles or diluents for use in the formulations for oral administration or using other suitable dispersing or wetting agents and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, gum tragacanth and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable vehicles including saline, dextrose or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose any soft fixed oil can be used including synthetic mono- or di-glycerides. Furthermore, fatty acids such as oleic acid find use in the preparation of injectables. A sterile injectable oil-in-water microemulsion can be prepared, for example, by 1) dissolving at least one compound of Formula (I) in an oil phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining Formula (I) containing the oil phase with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion. A sterile aqueous or oleaginous suspension can be prepared according to methods known in the art. For example, a sterile aqueous solution or suspension may be prepared with a non-toxic parenterally acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension may 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. Pharmaceutically acceptable carriers, adjuvants and vehicles that can 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). abbreviations) such as d-alpha-tocopherol succinate polyethylene glycol 1000, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil as a CREMOPHOR surfactant (BASF) or other similar polymeric delivery matrices, serum proteins, such as albumin human serum, buffer substances such as phosphates, glycine, sorbic acid, potassium sobate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride sodium, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. Cyclodextrins such as alpha, beta and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be used advantageously to improve the delivery of compounds of the formulas described herein. document. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may undergo 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 be additionally prepared with enteric coatings. The compositions may also comprise adjuvants, such as wetting agents, sweeteners, flavorings and perfuming agents. The amounts of compounds that are administered and the dosage regimen to treat a disease condition with the compounds and / or compositions of this invention depend on a variety of factors, including the age, weight, sex, medical condition of the subject, type of the disease, severity of the disease, route and frequency of administration, and particular compound used. Therefore, the dosage regimen can vary widely, but can be determined routinely using standard methods. A daily dose of 0.001 to About 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and more preferably between about 0.005 and about 10 mg / kg body weight. The daily dose may be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two-day cycle. For therapeutic purposes, the active compounds of this invention are typically combined with one or more adjuvants appropriate for the indicated route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, powdered starch, cellulose esters of alkanoic acids, alkyl esters of cellulose, 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. The capsules or tablets may contain a controlled release formulation which may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. The 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. Alternative compositions of this invention comprise a compound of Formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. UTILITY The compounds of Formula (I) are useful for the treatment of cancer. 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 agents for simultaneous use, e.g. separate or sequential in the treatment and / or prophylaxis of multiple diseases or disorders associated with the inhibition of the DGK target in T cells. In another aspect, the invention provides a method of treating a patient who suffers from or is susceptible to a medical condition that is associated with inhibition of the DGK target on T cells. A number of medical conditions can 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 can be used to treat or prevent viral infections and proliferative diseases such as cancer. Compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful for treating or preventing any disease or condition that is associated with inhibition of the DGK target in T cells. These include viral and other infections (eg, skin infections, GI infections, urinary tract infections, genitourinary infections, systemic infections) and proliferative diseases (eg, cancer). Compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) can be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably human beings. Any administration method can be used to administer the compound or pharmaceutical composition to the patient. In certain embodiments, the compound of Formula (I) or the pharmaceutical composition comprising at least the compound of Formula (I) is administered orally. In other embodiments, Formula (I) or the pharmaceutical composition comprising at least the compound of Formula (I) is administered parenterally. Compounds of Formula (I) can inhibit the activity of diacylglycerol kinase alpha and zeta (DGKa / ζ). For example, compounds of Formula (I) can be used to inhibit the activity of DGKa and DGK / in a cell or in an individual requiring modulation of DGKa and DGK / by administering an inhibitory amount of a compound of Formula (I) (I) or a salt thereof. The present invention further provides methods for treating diseases associated with the activity or expression, including abnormal activity and / or overexpression, of DGKa and DGK / in an individual (e.g., a 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. Exemplary diseases may include any disease, disorder or condition that is directly or indirectly linked to the expression or activity of the DGKa and DGK / enzyme, such as overexpression or abnormal activity. A disease associated with DGKa and DGK / may also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulating the enzymatic activity of DGKa and DGK / . Examples of diseases associated with DGKa and DGK / include cancer and viral infections, such as HIV infection, hepatitis B, and hepatitis C. In one aspect, the compound(s) of Formula (I) are administered sequentially prior to administration of the immuno-oncology agent. In another aspect, the compounds of Formula (I) are administered simultaneously with the immuno-oncology agent. In yet another aspect, the compounds of Formula (I) are administered sequentially after administration of the immuno-oncology agent. In another aspect, the compounds of Formula (I) can be co-formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, a small molecule drug, an antibody or other biological or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In one aspect, the immuno-oncological agent is (i) an agonist of a stimulating receptor (including a co-stimulator) or (ii) an antagonist of an inhibitory signal (including a co-inhibitor) in T cells, both of which result in the amplification of antigen-specific T cell responses (often known as immune checkpoint regulators). Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind costimulatory or coinhibitory receptors is the B7 family, which includes B7-1, B7-2, B7H1 (PD-L1), B7-DC (PD-L2), B7- H2 (ICOS-L), B7-H3, B7-H4, B7H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the TNF family of molecules that bind to members of the cognate TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRilo, BOMA, LTpR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, In one aspect, 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, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. 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 KIR antagonists, such as lirilumab. Still 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). In another aspect, the compounds of Formula (I) can be used with one or more agonist agents that bind positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome the various immunosuppressive 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 depletion of anti-CD25 beads ex vivo), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion and agents that trigger immune activation innate and / or inflammation at tumor sites. In one aspect, the immuno-oncological agent is a CTLA-4 antagonist, such as a CTLA-4 antagonist antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncological agent is a PD-1 antagonist, such as a PD-1 antagonist 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), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fe portion of IgGl, called AMP-224 In another aspect, the immuno-oncological agent is a PD-L1 antagonist, such as a PD-L1 antagonist antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174). In another aspect, the immuno-oncological agent is a LAG-3 antagonist, such as a LAG-3 antagonist antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273). In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as a CD137 agonist antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433). In another aspect, the immuno-oncology agent is a GITR agonist, such as a GITR agonist antibody. Suitable GITR antibodies include, for example, BMS986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK4166 (WO11 / 028683). In another aspect, the immuno-oncology agent is 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). In another aspect, the immuno-oncological agent is an 0X40 agonist, such as an 0X40 agonist antibody. Suitable 0X40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncological agent is a 100 OX40L antagonist, such as an 0X40 antagonist antibody. Suitable OX40L antagonists include, for example, RG-7888 (WOO6 / 029879). In another aspect, the immuno-oncology agent is a CD40 agonist, such as a CD40 agonist antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as a CD40 antagonist antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. In another aspect, the immuno-oncology agent is a CD27 agonist, such as a CD27 agonist antibody. Suitable CD27 antibodies include, for example, varlilumab. In another aspect, the immuno-oncology agent is MGA271 (a B7H3) (WO11 / 109400). Combination therapy is intended to encompass the administration of these therapeutic agents sequentially, that is, where each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form having a fixed proportion of each therapeutic agent or in single dosage forms and 101 multiple for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent may be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes and direct absorption through mucous membrane tissues. Therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination 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 may also encompass the administration of the therapeutic agents as described above in additional combination with other biologically active ingredients and non-pharmacological therapies (eg, surgery or radiation treatment). When the combination therapy further comprises a non-pharmacological treatment, the non-pharmacological treatment may be carried out at any suitable time as long as a beneficial effect is achieved from the joint action of the combination of the therapeutic agents and the non-pharmacological treatment. For example, in appropriate cases, the 102 beneficial effect is still achieved when the non-pharmacological treatment is temporarily withdrawn from the administration of the therapeutic agents, perhaps for days or even weeks. As used herein, the term cell refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism such as a mammal. As used herein, the term "contacting" refers to the joining of indicated moieties in an in vitro system or an in vivo system. For example, contacting the enzyme DGKa and DGK / with a compound of Formula (I) includes administering a compound of the present invention to an individual or patient, such as a human, who has DGKa and DGK / , as well such as, for example, by introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing the enzyme DGKa and DGK / . The term DGKa and DGK / inhibitor refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and / or diacylglycerol kinase zeta (DGKa and DGK / ) in T cells resulting in the stimulation of T cells. 103 The DGKa and DGK / inhibitor may be a reversible or irreversible DGKa and DGK / inhibitor. A reversible DGKa and DGK / inhibitor is a compound that reversibly inhibits the enzymatic activity of DGKa and DGK / at the catalytic site or at a non-catalytic site and an irreversible DGKay DGK / inhibitor is a compound that irreversibly destroys the enzymatic activity of DGKa and DGK / forming a covalent bond with the enzyme. The types of cancers that can 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, cancers prostate, colon cancer, blood cancers, lung cancer and bone cancer. Examples of such types of cancer include neuroblastoma, bowel carcinoma, such as rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary nonpolyposis colorectal cancer, esophageal carcinoma, labial carcinoma, laryngeal carcinoma, hypopharyngeal carcinoma, carcinoma tongue, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian carcinoma, cervical carcinoma, uterine corpus carcinoma, endometrial carcinoma, carcinoma chorion, pancreatic carcinoma, 104 prostate carcinoma, thoracic carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphatic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) chronic myeloid leukemia (CML), lymphoma / leukemia adult T cell, diffuse large B cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma , basalioma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyoscopesis, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. One or more additional pharmaceutical agents or treatment methods such as, for example, antiviral agents, chemotherapeutic or other anticancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors can be used optionally 105 in combination with the compounds of Formula (I) for the treatment of diseases, disorders or conditions associated with DGKa and DGK / . The agents may be combined with the present compounds in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms. Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobromane, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide. In the treatment of melanoma, agents suitable for use in combination with the compounds of Formula (I) include: dacarbazine (DTIC), optionally, together 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™. The compounds of Formula (I) can also be combined with immunotherapeutic drugs, which include cytokines such as interferon alpha, interleukin 2 and necrosis factor. 106 tumor cell (TNF) in the treatment of melanoma. The compounds of Formula (I) can also be used in combination with vaccine therapy in the treatment of melanoma. Melanoma vaccines are, in some ways, similar to antivirus vaccines 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 the melanoma cells. Melanomas that are limited to the arms or legs can 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 affected limb from the rest of the body and injects high doses of chemotherapy into the artery that feeds the limb, thus delivering high doses to the tumor area without exposing internal organs to these doses that would otherwise occur. could cause severe side effects. Typically, the fluid is heated to 38.9oC to 40°C. Melphalan is the most commonly used drug in this chemotherapy procedure. This is 107 can provide you with another agent called tumor necrosis factor (TNF). Suitable guimotherapeutic agents or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogues, purine analogues and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine , cytarabine, 6mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine. Suitable guimotherapeutic agents 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, deoxy-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide and teniposide. Other cytotoxic agents include navelbene, CPT11, anastrazole, letrazol, capecitabine, reloxafine, and droloxafine. Cytotoxic agents such as epidophyllotoxin are also suitable; an antineoplastic enzyme; a 108 topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors. Other anticancer agent(s) include antibody therapies such as trastuzumab (HERCEPTIN®), antibodies against costimulatory molecules such as CTLA4, 4-1BB and PD-1, or antibodies against cytokines (IL-10 or TGFβ). · Other anti-cancer agents also include those that block immune cell migration, such as chemokine receptor antagonists, including CCR2 and CCR4. Other anti-cancer agents also include those that boost the immune system, such as adjuvants or adoptive T cell transfer. Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. The pharmaceutical composition of the invention may optionally include at least one signal transduction inhibitor (STI). A signal transduction inhibitor is an agent that inhibits 109 selectively one or more vital steps in signaling pathways, in the normal function of cancer cells, 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, Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors, such as farnesyl transferase inhibitors (FTIs), such as, for example, L-744,832 (Kohl, Na t. Med., 1 (8): 792-797(1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as rapamycin (see, for example, Sekulic, 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) phosphatidylinositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos, 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 110 an STI can 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. Furthermore, when more than one compound of Formula (I) and / or STI is used, the compounds may be administered in any order. The present invention further provides a pharmaceutical composition for 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 vehicle. Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition. In a specific embodiment of the present invention, at least one compound of Formula (I) and at least one chemotherapeutic agent are 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 at least one STI may be administered at the same time. Furthermore, when 111 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 can also be administered at any point compared to the administration of the compound of Formula (I). Chronic viral infections that can be treated with the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). In particular, parasitic infections (e.g., malaria) can also be treated by the above methods where compounds known to treat parasitic conditions are optionally added in place of antiviral agents. Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) may comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNTRs). acronym in English), protease inhibitors and other antiviral drugs. 112 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 [(-)ETC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2',3'-dideoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU142721; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-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 (ABT538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378 and AG1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607. The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases or disorders associated with DGKa and DGK / , and other diseases mentioned herein that include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). 113 Such kits may further include, if desired, one or more of several 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 labels, indicating the quantities of the components to be administered, administration guidelines, and / or guidelines for mixing the components, may also be included in the kit. Combination therapy is intended to encompass the administration of these therapeutic agents sequentially, that is, where each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form having a fixed proportion of each therapeutic agent or in single and multiple dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent may 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 agents 114 therapeutics can be administered through the same route or through different routes. For example, a first therapeutic agent of the selected combination 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 may also encompass the administration of the therapeutic agents as described above in additional combination with other biologically active ingredients and non-pharmacological therapies (eg, surgery or radiation treatment). When the combination therapy further comprises a non-pharmacological treatment, the non-pharmacological treatment may be carried out at any suitable time as long as a beneficial effect is achieved from the joint action of the combination of the therapeutic agents and the non-pharmacological treatment. For example, in appropriate cases, the beneficial effect is still achieved when the non-pharmacological treatment is temporarily withdrawn from the administration of the therapeutic agents, perhaps for days or even weeks. The invention also provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds of the 115 Formula (I), formulated together with one or more pharmaceutically acceptable vehicles (additives) and / or diluents, and optionally, one or more therapeutic agents described above. The compounds of this disclosure may 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 controlled release formulations), pills. , powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; oral; parenteral, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by spray for inhalation; 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 will generally be administered with a pharmaceutical vehicle selected based on the chosen route of administration and standard pharmacy practice. The phrase pharmaceutically acceptable vehicle 116 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, magnesium talc, calcium or zinc stearate, or acid stearic), or solvent encapsulation 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 vehicle must be acceptable in the sense of being compatible with the other ingredients of the formulation, including, e.g., adjuvant, excipient or vehicle, such as diluents, preservative 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 harmful to the patient. The term pharmaceutical composition means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the 117 scope of those skilled in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to whom the composition containing the agent is to be administered; the intended route of administration of the composition; and the therapeutic indication to which it is directed. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semisolid dosage forms. Such carriers may include several 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 skilled 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, Alien, LV Jr. et al., Remlngton: The Science and Practice of Pharmacy (2 Volumes) , 22nd Edition (2012), Pharmaceutical Press. The dosage regimen for the compounds of the present invention will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, condition 118 medical, and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's kidney and liver function, and the desired effect. As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will range from about 0.001 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and more preferably from about 0.1 to 250 mg per day. mg approximately per day. Intravenously, the most preferred doses will range from approximately 0.01 to 10 mg / kg / minute during a constant rate infusion. The compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three, or four times a day. The compounds are typically administered in admixture with suitable diluents, excipients or pharmaceutical vehicles (collectively known herein as pharmaceutical vehicles) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs and syrups, and consistent with conventional pharmaceutical practices. Suitable dosage forms (pharmaceutical compositions) for administration may contain 1 119 milligram to approximately 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight based on the total weight of the composition. 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. A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) in a vial, lyophilizing and aseptically sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline solution, to produce an injectable preparation. 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, the compounds of the present invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents, e.g. , an anti-cancer agent or other material 120 pharmaceutically active. Regardless of the route of administration selected, the compounds of the present invention, which can 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 experts in the technique. The actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the therapeutic response for a particular patient, composition, and mode of administration, without being toxic. for the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound employed of the present invention, 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 used, the rate and extent of absorption, duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound used, age, sex, weight, condition, general health and history previous medical 121 patient treated, and factors of this type known in medical techniques. A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start with doses of the antibodies of the invention used in the pharmaceutical composition at levels lower than those required to achieve the therapeutic effect and gradually increase the dosage until the effect is achieved. In general, an adequate daily dose of a compound of the invention will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such effective dosage will generally depend on the factors described above. In general, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from approximately 0.01 to 50 mg per kilogram of body weight per day. 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, 122 the dosage is one administration per day. 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). The above other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as determined by one skilled in the art. In the methods of the present invention, such other therapeutic agents may be administered before, simultaneously with, or after administration of the compounds of the invention. PREPARATION METHODS The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry. General synthetic reaction schemes for preparing compounds of the present invention are described below. These reaction schemes are illustrative and are not intended to limit the possible techniques that one skilled in the art can use to prepare the compounds described herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Examples of compounds of the present invention 123 prepared by methods described in the general reaction schemes are given in the Examples section below. The preparation of homochiral examples can be carried out by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separation of racemic or diastereomeric products by chiral phase preparative HPLC. Alternatively, the example compounds can be prepared by known methods to give enantiomerically or diastereomerically enriched products. The reactions and techniques described in this section are carried out in appropriate solvents for the reagents and materials used and are suitable for the transformations carried out. Furthermore, in the description of the synthetic methods given below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and workup procedures, are chosen as standard conditions for that reaction, which should be easily recognized by one skilled in the art. An expert in the art of organic synthesis understands that the functionality present in various portions of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents that are 124 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 judgment to modify the order of synthetic steps or to select one particular process reaction scheme over another in order to obtain a compound of the invention. It will also be recognized that another important consideration in planning any synthetic route in this field is the judicious choice of a protecting group used for the protection of reactive functional groups present in the compounds described in this invention. An authoritative account that describes the many alternatives to the trained professional is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007). In a further enablement, intermediates and examples of the present invention can be prepared using stereoselective methodologies known in the art, examples of which are shown in the following reaction schemes. 125 REACTION SCHEME I Both antipodes of chiral oxazolidinones of the type represented can be reacted with acyl chlorides at low temperature to produce N-acyl derivatives. These can be converted to the related boron enolates and condensed with 2-(2-alkyl-l,3-dioxolan-2-yl)acetaldehydes to produce 4-benzyl-3-(2-alkyl-3-hydroxy-4-( 2-alkyl-l,3dioxolan-2-yl)butanoyl)oxazolidinones of known stereochemistry. Deprotection of the dioxolane product using, for example, ferric chloride in acetone can produce l—(4—benzyl-2-oxooxazolidin-3-yl)-2-alkyl-3-hydroxyalkyl-l,5diones. The subsequent reductive amination using benzylamine 126 with, for example, sodium triacetoxyborohydride can provide diastereomeric mixtures of 4-benzyl-3-(5(benzylamino)-2-alkyl-3-hydroxyalkanoyl)oxazolidinones. The resulting amines can be cyclized intramolecularly by heating in MeOH under microwave conditions to provide chromatographically separable l-benzyl-3-alkyl-4-hydroxy-6-alkylpiperidin-2ones. Successive reduction of the product piperidinones with, for example, borane or LAH can produce N-benzyl-2-alkyl-4-hydroxy-5alkylpiperidines. Removal of the benzyl moiety under hydrogenolysis conditions in the presence of di-tert-butyl dicarbonate can allow access to tere-butyl 4-hydroxy-2,5dialkylpiperidine-l-carboxylates which are useful intermediates in the synthesis of examples. of the present invention. In a further step, the stereochemistry of the 4-hydroxy moiety in these and other related intermediates can be reversed using standard Mitsunobu conditions employing p-nitrobenzoic acid to produce esters from which the desired alcohols can be released by base-catalyzed hydrolysis. The use of these methodologies with properly functionalized oxazolidinones and aldehydes can produce intermediates of known stereochemistry. An example of the use of these compounds to access additional modalities of the present invention is shown in the methodologies described 127 in the following reaction scheme. REACTION SCHEME II fice Bcc A CU nr *J Ar = aryl or heteroaryl X = CI or Triflate In these cases, N-boc-protected 2,5-dialkyl-4-hydroxypiperidines can be first deprotected under standard conditions and then reacted with 1alkylpyrido[3,2-d]pyrimidin-2(1H)-ones or l-alkyl- 1,5naphthyridin-2(1H)-ones to give product alcohols which can subsequently be reacted under Mitsunobu conditions, or with selected heterocycles under SNAr conditions to give examples of the present invention. 128 Alternatively, N-boc protected 2,5-dialkyl-4-hydroxypiperidines can be reacted first under Mitsunobu conditions with appropriately functionalized phenols, or with selected heterocycles under SNAr conditions to give additional intermediates of the type represented above. Subsequent reaction with suitable functionalized pyrido[3,2-d]pyrimidin-2(1H)-ones or pyridin-2(1H)-ones may provide access to additional examples. In some cases, 2,5-dialkyl-4hydroxypiperidines or their related ethers can be reacted with 4,6-dichloro-l-alkylpyrido[3,2-d]pyrimidin2(lH)-ones or 4,6-dichloro- l-alkyl-l,5-naphthyridin-2(1H)-ones to access the related 4-N-piperidinyl derivatives, thus facilitating the introduction of additional functionality in the 6-position of the bicyclic heterocyl, for example a nitrile group, which are additional embodiments of the present invention. EXAMPLES The following examples illustrate 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 used in 129 the Examples and elsewhere in this application. Common intermediaries are generally useful for the preparation of more than one Example and are identified sequentially (e.g., Intermediary 1, Intermediary 2, etc.) and abbreviated as Int. 1 or II, Int. 2 or 12, etc. Compounds in the Examples are identified by the example and step in which they were prepared (e.g., 1-A denotes Example 1, step A), or by the example alone where the compound is the title compound of the example (e.g. , 1 denotes the title compound of Example 1). In some cases, alternative preparations of intermediate products or examples are described. Often, chemists skilled in the art of synthesis can devise alternative preparations that may be desirable based on one or more considerations, such as shorter reaction time, less expensive starting materials, ease of operation or isolation, yield. improved, susceptible to catalysis, avoidance of toxic reagents, accessibility of specialized instrumentation, and decreased number of linear steps, etc. The intention of describing alternative preparations is to further enable the preparation of the examples of this invention. In some cases, some functional groups in the examples and claims outlined may be replaced by well-known bioisosteric replacements known in the art, e.g. 130 replacement of a carboxylic acid group with a tetrazole or phosphate moiety. NMR data collected in deuterated dimethyl sulfoxide used water suppression in data processing. The reported spectra are not corrected for the effects of water suppression. Protons adjacent to the water suppression frequency of 3.35 ppm show decreased signal intensity. In the examples, the use of wedge bonds and dotted lines implies relative stereochemistry. The designation (+ / -) preceding the name of a compound indicates a racemic mixture. The designation (reí) indicates that all stereochemical designations of the compound are relative and not absolute. The use of a bond without dashed lines at a chiral center implies unknown relative stereochemistry. In the following tables, 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 Anhydrous acetyl ac. anhydrous here aqueous BOP benzotriazole-1-hexafluorophosphate 131 yloxytris(dimethylamino)phosphonium Bu butyl DCM diolorornetham DEA diethylamine DIEA O DIPEA diisopropylethylamine DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene Et ethyl EtOAc ethyl acetate EtOH ethanol h, hours or hrs hour(s) HC1 acidic hydrochloric HPLC high pressure liquid chromatography LC liquid chromatography LCMS liquid chromatography mass spectrometry M molar mM millimolar Me methyl MeOH methanol Mesyl-Cl methanesulfonyl chloride MHz megahertz 132 mins minutes(s) M+l (M+H)+ MS mass spectrometry η o N normal NH4OAc ammonium acetate nM nanomolar NMP N-methylpyrrolidinone Pd2 (dba)3 tris-(dibenzylideneacetone)dipalladium pet ether petroleum ether Ph phenyl POCI3 phosphorus oxychloride ta 0 Ret time retention time sat. saturated TEA triethylamine TEA trifluoroacetic acid THE tetrahydrofuran The methodologies that can be employed in the synthesis of intermediates useful in the preparation of examples of the present invention are shown in the following reaction scheme. Benzoxazma-2,4 (1H)-diones of the type shown are They can be treated with a strong base and a methylation reagent such as methyl iodide to produce l-methyl-2Hbenzo[di[1,3]oxazine-2,4(1H)-diones. These can be treated, for example, with nitro-acetate to generate l-methyl-3133 nitroquinoline-2,4(1H,3H)-diones. Such compounds, in turn, can be converted to the related 4-chloro derivatives that can react with a variety of functionalized piperidines to provide examples of the present invention. In other methodologies, picolinic acids can be esterified under standard conditions and then treated with, for example, acetic anhydride to provide ethyl 3acetamidopicolinates. These can be alkylated under standard conditions and subsequently treated with a mixture of hydrogen peroxide and trifluoroacetic anhydride to access 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 which upon base treatment can cyclize to provide 1,5-naphthyridine-2,4(1H,3H)- dionas. Compounds of this type can be derived in a plurality of ways to access various useful intermediates. For example, treatment under standard nitration conditions can generate the related l-methyl-3-nitro-l,5-naphthyridine-2,4(1H, 3H) diones that can be converted under standard conditions to 4-chloro-intermediates. or 4-trifluoromethanesulfonate that can be reacted with a variety of functionalized piperidines to provide 134 additional examples of the present 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 variety of piperidines at the 4-position of the heterocycle , as well as an additional derivatization at the 3-position of naphthyridine. For example, aromatic and heteroaromatic moieties can be introduced into this vector by coupling chemistries known in the art. In a further methodology, ethyl 3-amino-6bromopicolinates generated from the related ethyl 3-aminopicolinates can be treated as described above to provide 6-bromo-l-methyl-l,5naphthyridine-2,4(1H, 3H)-diones that allow the introduction of a variety of moieties at position 6 of the naphthyridine heterocycle, an example being the introduction of the cyano function at this position as shown in Reaction Scheme 1. 135 REACTION SCHEME 1 h2o2 TFAA I JES DMF The following reaction scheme shows 136 additional methodologies that may be useful in the synthesis of intermediates of the present invention. Ethyl 3-amino-6-bromopicolinates under treatment with 2-cyanoacetyl chloride can be cyclized to generate 6-bromo-2,4-dioxo-l,2,3,4-tetrahydro-l,5naphthyridine-3- carbonitriles. These can be alkylated to NI under standard conditions and subsequently converted to the related 6-bromo-3-cyano-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridin-4-yl sulfonates that are useful in preparation of other examples. Alternatively, sequential treatments with POC13 and HC1 in dioxane give access to 4,6dichloro-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3carbonitriles which are also useful intermediates. SCHEME ? pm h í| A / AYO / I / 0. / —- í| 1 í Br N Y A A A II Br N ηρ CN O · N ..O í T T poc^ ΐ Ί Bt Ν' ί 'CN Bi N 0 °A / VNH? a_cn r — Γχ Br N Π TEA O PPAA ¿ OF REACTION 2 1 1 NaH / γΝγο (CF3SO2)2O ΜθΙ Br N / jUN TEA Br^N^y^CN O OTf N ..0 ' N .-O ir Cl - í i .r • c\ Cioxaroí cl N - CN Cl Cl f CN Y CN Pd2(dba)3 < f Zn / Zn(CN)2 NC 3 0 137 Other synthetic methods that may be useful for the introduction of a cyano motif at the 6-position of the examples of the present invention may involve the treatment of ethyl 6-bromo-3-(2-cyanoacetamido) picolinate intermediates with zinc and cyanide. of zinc under palladium catalyzed conditions to generate ethyl 3-(2cyanoacetamido)-6-cyanopicolinates. These can be derivatized using methodologies as described above to access 4-chloro-6-isocyano-l-methyl-2oxo-1,2-dihydro-l,5-naphthyridine-3-carbonitriles which can react with piperidines. variously functionalized to generate several examples of the present invention. Additional useful intermediates can be prepared by condensing suitably functionalized naphthyridinone and quinolone heterocycles with variously functionalized piperidines as indicated in the following reaction scheme. Such intermediates can be exemplified by the present invention by further elaboration using, for example, Mitsunobu or SNAr reactions with appropriately functionalized aromatic or heteroaromatic coupling partners. 138 REACTION SCHEME 3 Preparation of useful piperidine intermediates and additional examples is shown in the reaction scheme below. REACTION SCHEME 4 OH Ar In these cases, N-protected cis-4-hydroxy-3alkylpiperidines can be treated with acids. 139 carboxylic acids, for example under Mitsunobu conditions, to provide trans-4-benzoyloxy-3-alkylpiperidines. These can subsequently be hydrolyzed to access the related trans4-hydroxy-3-alkylpiperidines which can be used in a methodology analogous to that discussed above, whereby subsequent deprotection and condensation of the trans 4-hydroxy-3-alkylpiperidines intermediates with naphthyridinones or appropriately functionalized quinolones generates trans-4-hydroxy-3-alkylpiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine or related quinolone intermediates that can react again under Mitsunobu conditions or SNAr to provide additional examples of the present invention. In other cases, 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 reaction 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-alkylpiperidin-4-ols. 140 REACTION SCHEME 5 boc h:po4 NaBH OH dicartcratc di-tert-butylc OH The relative stereochemistry of the alkyl and hydroxyl substituents can be controlled by numerous methods, some examples being concurrent treatment with phosphoric acid and sodium borohydride to give 141 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 a strong base and appropriately functionalized heterocycles under SNAR conditions can result in the synthesis of N-protected cis- or trans-3-alkyl-4(heteroaryloxy)piperidines. These deprotection intermediates can be reacted with suitably functionalized naphthyridinones or quinolones to provide a variety of examples of the present invention. INTERMEDIATE 1 (+ / -) trans-l-benzyl-3-methylpiperidin-4-ol OH (Μ) Phosphoric acid (85%, 4.25 g, 36.9 mmol) was added dropwise to a solution of methanol (25 μl-benzyl-3methylpiperidin-4-one (7.5 g, 36.9 mmol) in water (50 mL) and L) at -10 °C. Sodium borohydride (2.79 g, 73.8 mmol) was then added portionwise and, after 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 adding hydroxide solution 142 of 5 M sodium. The resulting mixture was extracted with ethyl acetate (3 x 15 mL) and the combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product as a yellow oil. viscous (4.65 g, 22.65 mmol, 61.4% yield). LCMS (m / z) : (M+H)+= 206.3, 4H NMR (500 MHz, CHLOROFORM-d) δ 7.52-7.12 (m, 5H), 3.71-3.40 (m, 2H), 3.223.10 (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 (+ / -) tere-butyl trans-4-hydroxy-3-methylpiperidine-l-carboxylate boc H (1-2) A solution of (+ / -) (trans)-benzyl-3-methylpiperidin-4-ol (2.5 g, 12.18 mmol) and Boc anhydride (3.11 mL, 13.39 mmol) was degassed in methanol (50 mL) and washed with nitrogen (2 x) . 10% Pd-C (1.2 g, 1.128 mmol) was then added and the mixture was evacuated again and flushed with nitrogen (2x) before evacuating and filling with hydrogen to 1 atmosphere (balloon). The reaction mixture was stirred vigorously under a hydrogen atmosphere for 2 days. It was then filtered through celite, and the filtrate was 143 washed with methanol and the washings were combined with the original filtrate. The combined solutions were concentrated in vacuo to provide the product as a yellow viscous oil (1.71 g, 7.94 mmol, 65.2% yield). LCMS:(m / z) (M-tBu+ACN+H)+= 201.2. Η2NMR (500 MHz, CHLOROFORM-d) δ 4.10-3.85 (m, 2H), 3.40-3.24 (m, 1H), 2.932.71 (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-4yl)oxy)pyridine, TFA hi 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 (+ / -) tere-butyl trans-4-hydroxy-3-methylpiperidine-lcarboxylate ( 120 mg, 0.557 mmol) in THF (4 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-fluoro-5isopropoxypyridine (0.100 mL, 0.836 mmol) was added. The reaction mixture was then heated to 60 °C overnight. The reaction was then quenched by the addition of water and the resulting mixture was extracted with ethyl acetate. 144 The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give the crude product as a yellow oil. This material was purified by reverse phase preparative HPLC using a CN-H2O-TFA system as eluent. The homogeneous fractions were combined and concentrated under reduced pressure. Next, the residual material was treated with a mixture of TEA (0.5 mL) in DCM (2 mL) for 3 hours at room temperature. The resulting mixture was then concentrated in vacuo to provide the product as a brown oil (40 mg, 0.110 mmol, 19.70% yield). INTERMEDIATE 4 (+ / -) 2-((trans-3-ethylpiperidin-4-yl)oxy)-5isopropoxypyridine 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 (+ / -) tere-butyl trans-3-ethyl-4-hydroxypiperidine-lcarboxylate ( 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, 0.654 145 mmol) in THF (1 mL) and the reaction mixture was heated at 60 °C for 5 hours under nitrogen. The reaction mixture was cooled to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (3x). The organic layers were combined, washed with brine and then dried over MgSO4, filtered and evaporated under reduced pressure to provide the crude product as a yellow viscous oil. This material was purified by flash chromatography on silica gel using 20% ​​ethyl acetate in hexanes as eluent. The homogeneous fractions were combined and evaporated in vacuo to provide the product as a colorless, viscous oil. This was treated directly with TFA (1 mL) in DCM (3 mL) at room temperature overnight. The resulting mixture was then concentrated in vacuo to provide the TFA salt of the title compound as a brown oil (153 mg, 0.311 mmol, 71.3% yield). LCMS:(m / z) 265 : (M+H)+= 265.25. INTERMEDIATE 5 (+ / -) 5-isopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine 146 Sodium hydride (60% in mineral oil) (69.7 mg, 1.742 mmol) was added portionwise to a solution of (+ / -) tere-butyl cis-4hydroxy-3-methylpiperidine-l-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 (1 mL) was added. Then, the reaction mixture was heated to 60 °C overnight. The reaction was then quenched by the addition of water and the resulting mixture was extracted with ethyl acetate (3x). The organic layers were collected, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give a brown viscous oil. The crude product was purified by preparative reverse phase HPLC using the CH3CN-H2OTFA system. The homogeneous fractions were combined and evaporated in vacuo and the residue was treated with TFA (1 mL) in DCM (2 mL) for 3 hours at room temperature. The resulting solution was reduced in vacuo to provide the bis-TFA salt of the title compound as a yellow oil (58.3 mg, 0.126 mmol, 18.10% yield). LCMS: (m / z) : 235.1: (M+H)+. 147 INTERMEDIATE 6 (+ / -) 5-isopropoxy-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine h A 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THE was added dropwise to a solution of a 9:1 mixture of cis- and trans-tert-butyl-4-hydroxy-3-methylpiperidine- l-carboxylate (120 mg, 0.557 mmol) in THF (4 mL). The mixture was stirred at room temperature for 30 min, then 2-fluoro-5isopropoxypyridine (0.100 mL, 0.836 mmol) was added and the reaction mixture was heated to 60 °C overnight. The reaction was then quenched by the addition of water and the resulting mixture was extracted with ethyl acetate (3x). The extracts were combined, washed with brine, dried over MgSO4, 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 the CH3CN-H2O-TFA system. The homogeneous fractions were combined and concentrated under reduced pressure overnight. Then, the residue was dissolved in dichloromethane (2 mL) and 0.5 mL TFA was added. The solution was stirred at room temperature for 3 hours. 148 The mixture was then evaporated in vacuo to provide the TFA salt of the title compound as a brown viscous oil (40 mg, 0.110 mmol, 19.70% yield). LCMS: (π? / ζ) : (M+H)+= 251.3. INTERMEDIATE 7 ( + / -) 2 -((3,3-dimethylpiperidin-4-yl)oxy)-5isopropoxypyridine 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 tere-butyl 4-hydroxy-3,3-dimethylpiperidine-lcarboxylate (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 then quenched by addition of water. The resulting mixture was extracted with ethyl acetate (3x) and the combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to give the crude product as a brown oil. The product was purified by preparative reverse phase HPLC using the system 149 CN-H2O-TFA. 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 hours. The solution was then concentrated in vacuo to provide the TFA salt of the title compound as a brown viscous oil (24 mg, 0.063 mmol, 18.18% yield). (m / z) : (M+H)+= 251.3. INTERMEDIATE 8 (+ / -) 5-(difluoromethyl)-2-((cis-3-methylpiperidin-4yl)oxy)pyridine h F (1-8) 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 tere-butyl cis-4-hydroxy-3-methylpiperidine-lcarboxylate (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 (1 mL) was added and the mixture was heated to 60 °C overnight. . The reaction was stopped by adding water and the resulting mixture was extracted with ethyl acetate. The combined extracts 150 washed with brine, dried over MgSO4, 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 the CH3CN-H2O-TFA system. The homogeneous fractions were combined and concentrated under reduced pressure. Then, the residue was dissolved in dichloromethane (1 mL) and treated with TFA (0.5 mL) for 3 hours at room temperature. The mixture was then evaporated in vacuo to provide 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 Sodium hydride (69.7 mg, 1.742 mmol) (60% in mineral oil) was added portionwise to a solution of (+ / -) tere-butyl cis-4hydroxy-3-methylpiperidine-l-carboxylate (150 mg, 0.697 mmol) in anhydrous THF (2 mL). After addition, the reaction mixture was stirred at room temperature for 10 min, then 2-chloro-6-isopropylpyridine (163 mg, 1,045 mmol) in THF (1 mL) was added and the mixture was heated to 60 °C under 151 nitrogen during the night. The reaction was then quenched by the addition of water and the resulting mixture was extracted with ethyl acetate (3x). The extracts were combined, washed with brine, dried over MgSO4, 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 the CH3CN-H2O-TFA system. The 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 resulting mixture was stirred at room temperature for 3 hours before being concentrated in vacuo to provide the TFA salt of the title compound as a viscous oil of yellow color, (53 mg, 0.115 mmol, 16.4 5% yield). LCMS: (m / z) : (M+H)+.= 235.1. INTERMEDIATE 10 ( + / -) 2 -((cis-3-methylpiperidin-4-yl)oxy)-5(trifluoromethyl)pyridine Sodium hydride (69.7 mg, 1,742 mmol) (60% in mineral oil) was added to a solution of (+ / -) tere-butyl cis-4-hydroxy-3methylpiperidine-l-carboxylate (150 mg, 152 0.697 mmol) in anhydrous THF (2 mL). The mixture was stirred at room temperature for 10 min, then 2-chloro5-(trifluoromethyl)pyridine (190 mg, 1,045 mmol) in THF (1 mL) was added and the reaction mixture was heated to 60 °C for 3 hours. before cooling by adding water. The mixture was then extracted using ethyl acetate (3x), the extracts were combined and washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using preparative reverse phase HPLC using a CH3CN-H2O-TFA system. The homogeneous fractions were combined and concentrated in vacuo. The residue was then dissolved in dichloromethane (2 mL), TFA (1 mL) was added and the resulting mixture was stirred at room temperature for 3 hours before being concentrated in vacuo to provide the TFA salt of the title compound as a solid. white. (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 153 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 (+ / -) tere-butyl cis-4-hydroxy-3-methylpiperidine-lcarboxylate ( 150 mg, 0.697 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 30 min, then 2-chloro-4isopropylpyridine (163 mg, 1,045 mmol) in THF (1 mL) was added and the resulting mixture was heated to 60 °C, under nitrogen overnight. . The reaction was then stopped by adding water. The mixture was then extracted using ethyl acetate (3x), the extracts were combined and washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using preparative reverse phase HPLC using a CH3CN-H2O-TFA system. The 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 resulting mixture was stirred at room temperature for 3 hours before being concentrated in vacuo to provide the TFA salt of the title compound as a yellow viscous oil, (42 mg, 0.091 mmol, yield 13.04%). LCMS : {m / z):(M+H)+= 235.0. INTERMEDIATE 12 (+ / -) 5-cyclopropyl-2-((cis-3-methylpiperidin-4154yl)oxy)pyridine HE drip added a solution 1.0 M potassium bis(trimethylsilyl)amide (1.161 mL, 1.161 mmol) in THF to a solution of (+ / -) tere-butyl cis-4-hydroxy-3-methylpiperidine-lcarboxylate (100 mg, 0.464 mmol) in anhydrous THF (2 mL). The mixture was stirred at room temperature for 30 min. Next, 2-chloro-5cyclopropylpyridine (107 mg, 0.697 mmol) in THF (1 mL) was added and the reaction mixture was heated to 60 °C overnight. The reaction was stopped by adding water. The resulting mixture was extracted with ethyl acetate (3x) and the extracts were combined, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give the crude product as a viscous yellow oil. The product was purified using preparative reverse phase HPLC using a CH3CN-H2O-TFA system. The 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 resulting mixture was stirred at room temperature for 3 hours before being concentrated in vacuo to provide the TFA salt of the title compound. 155 as a viscous yellow oil, (10 mg, 0.043 mmol, 9.27% ​​yield). LCMS: (m / z) : (M+H)+= 232.55. Other related intermediates could be prepared by the methodology shown in the reaction scheme below, which involves the reaction of a potassium alkoxide salt of a deprotected hydroxypiperidine with a chloropyrimidine. INTERMEDIATE 13 (+ / -) 2-((cis-3-methylpiperidin-4-yl)oxy)pyrimidine Potassium bis(trimethylsilyl)amide (0.901 mL, 0.901 mmol) was added to a solution of (+ / -) cis-3-methylpiperidin4-ol (104 mg, 0.901 mmol) in THE (2 mL) and the mixture was stirred. at room temperature for 30 min. The amino alcohol did not completely dissolve in THE and a suspension was always observed, even after the addition of the base. A solution of 2-chloropyrimidine (86 mg, 0.751 mmol) in THE (1 mL) was then added and the mixture was left stirring 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. End %B: 100. Gradient Time: 3.00 min. Completion time: 156 3.50 min. Flow rate: 1.0 mL / min. Wavelength 1: 220nm. Solvent pair: AA S174 / S175. Solvent A: Al=10 mM NH4OAc in CH3CN: Water (5:95) S174. Solvent B: Bl = 10 mM NH4OAc in CH3CN:Water (95:5) S175. Column, Id: 3, name: 3 (AA SCP 3 min) Acquity BEH C18 1.7 qm 2.1 x 50 mm. Retention time = 1,213 min. (m / z): (M+H)+= 194.2. Similarly, the following intermediates were prepared. Het-CI KHMDS THF TABLE 1 Intermediate No. Heterocycle Intermediate LCMS TA (min.) (m / z)\ (M+H)+ 1-14 o I ω H N O^N CH T 1 । 3 1.63 236.3 1-15 ci^n^och3 Η Ύ H N O^N^OCH3 η Ύ 0.92 224.0 157 Intermediate No. Heterocycle Intermediate LCMS TA (min.) (m / z): (M+H)+ 1-16 Cl N^N Ϊ O—( zi <\ 2 o 7 / / I / ---' ω 1.02 234.0 1-17 Cl N^N cf3 H N γτ:Η3 O^N Η n^ch3 XX H N yACH3 O^N^CH3 XX 0.88 208.0 INTERMEDIARY 20 6-fluoro-l-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione A 60% dispersion of sodium hydride (0.530 g, 13.25 mmol) in mineral oil was added portionwise to 158 a solution of 6-fluoro-lH-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 2-fluoro-5-isopropoxypyridine (0.829 mL, 13.25 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was stopped by the addition of water and a yellow solid separated and was collected by filtration. The solid was suspended in ethyl acetate, the resulting mixture was filtered and the filtrate was concentrated in vacuo to give the product as a yellow solid (395 mg, 2,024 mmol, 18.33% yield). LCMS: (m / z) : (M+H)+= 196. 4H NMR (400 MHz, DMSO-d6) δ 7.83-7.74 (m, 2H), 7.55-7.46 (m, 1H). INTERMEDIARY 21 6-fluoro-l-methyl-3-nitroquinoline-2,4(1H,3H)-dione To a solution of ethyl 2-nitroacetate (293 mg, 2198 mmol) in NMP (5 mL) in a round-bottom flask at 0 °C, a 60% dispersion of sodium hydride (96 mg, 2,398 mmol) in mineral oil. The reaction mixture was stirred for 5 minutes at 0 °C and then for 15 minutes at room temperature. 159 Then 6-fluoro-l-methyl-lH-benzo[d][1,3]oxazine2,4-dione (390 mg, 1998 mmol) was added and the reaction mixture was heated to 120 °C for 2 hours. LC / MS showed completion of the reaction. The reaction was stopped with the addition of ice water. The mixture was acidified with a 1 N HC1 solution. Ethyl ether and 6-fluoro-lmethyl-3-nitroquinoline-2,4(1H,3H)-dione (140 mg, 0.588 mmol, 29.4% yield) were added as a yellow solid. LCMS: (m / z):(M+H)+= 239. INTERMEDIARY 22 4-chloro-6-fluoro-l-methyl-3-nitroquinolin-2(1H)-one CH3 Cl (1-22) In a sealed tube, 6-fluoro-l-methyl-3nitroquinoline-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 hours. The mixture was poured into ice water, neutralized with saturated NaHCO3 solution and extracted with dichloromethane (2 x 20 mL). The organic layers were combined, dried (MgSO4) and concentrated to provide 4-chloro-6-fluoro-1methyl-3-nitroquinolin-2(1H)-one (140 mg, 0.546 mmol, 93% yield) as a solid orange color. LCMS:(m / z) 257 (MH+). 160 INTERMEDIATE 23 Ethyl 3-Aminopicolinate NH2o (1-23) To a stirred suspension of 3-aminopicolinic acid (150 g, 1086 mmol) in ethanol (1500 mL) at 0-5 °C was added H2SO4 (463 mL, 8688 mmol) via a 1 L addition funnel for 60 min. After the addition was complete, the light brown solution was heated under reflux at 90 °C for 24 hours. 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 NH4OH 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 a Buchner funnel, washed with water (1 L) and dried under vacuum to yield 60 g of product as a 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 Na2SO4, filtered and concentrated under reduced pressure to produce ethyl 3-aminopicolinate (116 g , 691 mmol, 63.6% yield). LCMS: m / z = 167.2 (m / z):(M+H); TA 0.78 min; Method: Column-KINETEX-XB-Cl8 (75 X 3 mm-2.6 pm); 161 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. Intermediary 24 Ethyl 3-Acetamidopicolinate ΟγΟΗ3NH or (1-24) To a stirred solution of ethyl 3-aminopicolinate (115 g, 692 mmol) in THF (1000 mL) was added Ac20 (588 mL, 6228 mmol) at room temperature. The reaction mixture was heated at 60 °C under a nitrogen atmosphere for ~7-8 hours. The reaction mixture was cooled to room temperature and the volatile compounds were evaporated at water bath temperature (~50 °C) under line vacuum, followed by removal of acetic acid under high vacuum at 50 °C to produce a solid. whitish. 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 hours to produce 3 162 ethyl acetamidopicolinate (139 g, 641 mmol, 93% yield) as an off-white solid; LCMS: m / z = 209.3 (m / z) : (M+H); ta 0.76 min; LC-MS Method: Column-KINETEX-XB-Cl8 (75 X 3 mm-2.6 pm) ; 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. INTERMEDIARY 25 Ethyl 3-(N-methylacetamido)picolinate 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 was observed). The resulting partial brown mixture was stirred at room temperature for approximately 8 hours. The reaction was stopped with water (1500 mL) [slight exotherm observed] and extracted with DCM (3 x 1000 mL). The combined extracts were washed with water (2 x 163 1000 mL) and the aqueous layer was extracted again with DCM (2 x 500 mL). The combined organic solutions were washed with brine (2 x 1000 mL), dried over Na2SO4, filtered and concentrated at ~50 °C, and then dried under vacuum at ~60 °C to give a brown solution ( contains some DMF). The material was dried under high vacuum to remove DMF at 58°C for 25 minutes to produce a brown solid which was dissolved in petroleum ether (1000 mL), stirred for 30 minutes at room temperature, filtered through a Buchner funnel and washed with petroleum ether (500 mL) After filtration, dried under vacuum for 8 hours to provide ethyl 3-(Nmethylacetamide)picolinate (70 g, 302 mmol, 84% yield) as a solid brown; LCMS: m / z = 223.2 (m / z) : (M+H); ta 0.64 min; LC-MS Method: Column-KINETEX-XB-Cl8 (75 X 3 mm-2.6 pm) ; 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. 164 INTERMEDIARY 26 2-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide To a stirred clear brown solution of ethyl 3-(Nmethylacetamido)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 of trifluoroacetic anhydride (66.7 mL, 472 mmol) slowly over 40 minutes through a 100 mL addition funnel. The reaction mixture solidified during the addition of trifluoroacetic anhydride. After the addition was complete, the reaction mixture was stirred at room temperature for approximately 2 hours. The reaction was stopped with a 10% NaHCCg 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 Na2SO4, and concentrated to provide 2-(ethoxycarbonyl)-3-(Nmethylacetamido)pyridine 2-oxide (70 g, 285 mmol, 90% yield)) as a light yellow solid; LCMS m / z = 239.0 (m / z): (M+H); ta 0.48 min; LC-MS Method: Column-KINETEX-XB-C18 (75 X 3 mm2.6 pm) ; 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 during 165 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. INTERMEDIARY 27 Ethyl 6-cyano-3-(N-methylacetamido)picolinate o^ch3 or (1-27) To a stirred pale yellow solution of 2-(ethoxycarbonyl)-3-(Nmethylacetamido)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 via a 50 mL addition funnel over 15 minutes, followed by TEA (41.0 mL, 294 mmol) through a 50 mL addition funnel slowly over 20 minutes. . An exothermic reaction was observed during the addition of TEA. The reaction mixture became cloudy (TEA salt) and stirring was continued for 2.5 hours at the same temperature. The reaction was stopped with the addition of a 10% NaHCOg solution (500 mL). The mixture was extracted with DCM (3 x 300 mL). The combined organic solution was washed with brine 6 (2 χ 250 mL), then dried over Ν&2504 and concentrated to produce a light yellow crude material. The crude material was purified through a normal phase RediSep silica column in ISCO® using EA / petroleum ether as eluent. The product was isolated with 65-70% EA / petroleum ether, the fractions were concentrated to give ethyl 6-cyano-3-(N-methylacetamido)picolinate (43 g, 83% yield) as a light brown liquid. ; LCMS: m / z = 2 48.0 {m / z) :(M+H); ta 1.26 min. LC-MS Method: Column-KINETEX-XB-Cl8 (75 X 3 mm-2.6 pm); 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. INTERMEDIARY 28 8-Hydroxy-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile Ethyl methylacetamido)picolinate (0.9 g, 3.64 mmol) in 167 tetrahydrofuran (10 mL) KHMDS (4.80 mL, 4.37 mmol) was added at -78 °C for 10 minutes. The reaction mixture was stirred for 15 minutes. The reaction mixture was slowly warmed to room temperature for 30 minutes and then stirred for another 90 minutes. 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 xlOO mL). The aqueous layer was collected and acidified with 1.5 N HC1 to adjust the pH to − 3.0. The mixture was stirred for 15 minutes to form a solid mass, which was filtered through a Buchner funnel to provide 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile 550 . mg, 75% yield) as a brown solid. LCMS: m / z = 202.0 (m / z) : (M+H) ; ta 0.36 min. LC-MS Method: Column-KINETEX-XB-C18 (75 X 3 mm-2.6 pm); 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. 168 INTERMEDIARY 29 8-Chloro-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2 carbonitrile CH3 NC N (1-29) To a stirred solution of 8-hydroxy-5-methyl-6-oxo 5,6-Dihydro-l,5-naphthyridine-2-carbonitrile (0.55 g, 2.73 mmol) in acetonitrile (10 mL) POCI3 (1.53) was added. mL, 16.4 mmol). The reaction mixture was heated to 85 °C for 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 adding saturated sodium bicarbonate solution (50 mL). The resulting 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 provide 8-chloro-5-methyl-6-oxo-5, 6-dihydro-l,5-naphthyridine-2-carbonitrile (0.25 g, 29.1% yield) as a brown solid. LCMS: m / z = 220.2 (m / z) : (M+H); ta 1.53 min. LC-MS Method: Column-KINETEX-XB-Cl8 (75 X 3 mm 2.6 pm); 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 during 169 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 100% 1.5 mL / min flow rate; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. INTERMEDIARY 30 6-cyano-l-methyl-2-oxo-l,2-dihydro1,5-naphthyridin-4-yl trifluoromethanesulfonate To a mixture of 8-hydroxy-5-methyl-6-oxo-5,6dihydro-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) trifluoromethanesulfonic anhydride (0.269 mL, 1.640 mmol) in DCM (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to provide 6-cyano-l-methyl2-oxo-l,2-dihydro-trifluoromethanesulfonate. l,5-naphthyridin-4-yl (0.45 g, 81% yield) as a pale yellow solid; LCMS: ra / z = 334.2 (m / z) : (M+H) ; ta 1.40 min. LC-MS Method: AQUITY UPLC BEH C18 Column (3.0 x 50 mm) 1.7 pm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: 170 Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B for 2.0 minutes, then a 0.2 minute hold at 100% B, flow rate 0.7 mL / min. INTERMEDIARY 31 8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-l, 5-naphthyridine- To a stirred solution of 8-hydroxy-5-methyl-6-oxo5,6-dihydro-l,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 at 80 °C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water, stirred for 10 minutes and the resulting solid was filtered to provide 8-hydroxy-5-methyl-7nitro-6-oxo-5,6-dihydro-l, 5-naphthyridine-2-carbonitrile (0.805 g, 65.1% yield) as a pale yellow solid; LCMS: m / z = 247.2 (M+H) ; ta 1.19 min.LC-MS Method: Column-KINETEX-XB-C18 (75 x 3 mm- 2.6 pm) ; 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 for 4 minutes, 1.0 mL / min flow rate, then a 0.6 minute hold at 171 100% flow rate of 1.5 mL / min; then Gradient: 100-20% B for 0.1 minute, flow rate 1.5 mL / min. INTERMEDIARY 32 8-chloro-5-methyl-7-nitro-6-oxo-5,6-dihydro-l,5-naphthyridine-2- 8-Hydroxy-5-methyl-7-nitro-6-oxo-5,6dihydro-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 provide a yellow solution. POCl3 (0.131 mL, 1.404 mmol) was then added and the mixture was stirred under nitrogen at room temperature for 1 hour. Benzyltriethylammonium chloride (200 mg, 0.878 mmol) was added and the mixture was heated to 65 °C for 1 hour. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and the resulting solution was poured onto ice. This was left for approximately 1 hour, 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 1.5 M K2HPO4 solution, saturated NaHCO3 solution, and then with brine. The mixture was then dried over MgSO4, filtered and then evaporated in vacuo to 172 provide a brown crystalline solid (204 mg, 90% yield). LCMS: (m / z) : (M+H)+= 2 64.9. NMR]H (CHLOROFORM-d) δ 8.03 (d, J=8.8 Hz, 1H), 7.89-7.97 (m, 1H), 3.82 (s, 3H). INTERMEDIARY 33 6-cyano-l-methyl-3-nitro-2-oxo-l,2dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate To a suspension of 8-hydroxy-5-methyl-7-nitro-6oxo-5,6-dihydro-l,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 a nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with DCM, washed with water, the organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to provide 6-cyano-l-methyl3-nitro-2-oxo-1 trifluoromethanesulfonate, 2-dihydro-l,5-naphthyridin-4-yl (0.25 g, 48.8% yield) as a light brown solid; LCMS: m / z = 379.2 (m / z):(M+H); ta 1.66 min. LC-MS Method: AQUITY UPLC BEH C18 Column (3.0 x 50 mm) 1.7 pm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Shock absorber: acetonitrile (5:95), Shock absorber: acetate 173 ammonium 10 mM; Gradient: 20-100% B for 2.0 minutes, then a 0.2 minute hold at 100% B, flow rate 0.7 mL / min. INTERMEDIARY 34 7-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine 2-carbonitrile ch3 NC'X'yFr OH (1-34) To a stirred solution of 8-hydroxy-5-methyl-6-oxo To 5,6-dihydro-l,5-naphthyridine-2-carbonitrile (1000 mg, 4.97 mmol) in dry DMF (10 mL) NBS (973 mg, 5.47 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give a residue. The residue was dissolved in water and stirred for 10 min. The solid material was filtered and washed with petroleum ether to provide 7-bromo-8-hydroxy-5methi1-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.8 g, 56.9% yield) as a whitish solid; LCMS: m / z = 282 (M+H); ta 1.60 min. Method: Column-KINETEX-XB-Cl8 (75 x 3 mm- 2.6 pm); 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 for 4 minutes, flow rate 1.0 mL / min, then a 0.6 minute hold at 100% flow rate 1.5 174 mL / min; then gradient: 100-20% B for 0.1 min, flow rate 1.5 mL / min. INTERMEDIARY 35 3-Bromo-6-cyano-l-methyl-2-oxo-l,2dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate To a stirred solution of 7-bromo-8-hydroxy-5methi1-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (0.175 g, 0.625 mmol) and TEA (0.131 mL, 0.937 mmol) In dry DCM (10 mL), trifluoromethanesulfonic anhydride (0.137 mL, 0.812 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and washed with water, followed by washing with brine, the organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 3-bromo-6-cyano-l-trifluoromethanesulfonate. methyl-2-oxo-l,2dihydro-1,5-naphthyridin-4-yl (190 mg, 53.9% yield) as a pale yellow solid; LCMS: m / z = 414 (m / z) : (M+H) ; TA 1.61 min; Method: Column- AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 pm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B for 2.0 minutes, then a 0.3 minute hold at 175 100% B, flow rate 0.7 mL / min. INTERMEDIARY 36 Ethyl 3-amino-6-bromopicolinate „ / CH3 Br N Yo Or (1-36) Ethyl 3-aminopicolinate (8.0 g, 48.1 mmol) in water (66 mL) in a 250 mL three-neck round-bottom flask equipped with a mechanical stirrer, an addition funnel, and a thermocouple temperature probe. Sulfuric acid (1.7 mL, 31.9 mmol) and acetic acid (3.31 mL, 57.8 mmol) were slowly added while the flask was immersed in a water bath at room temperature to control the 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 for 15 minutes at room temperature with vigorous stirring while maintaining the internal temperature of the reaction mixture for below 23°C. The water bath was removed and the reaction mixture was stirred at room 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 provide ethyl 3amino-6-bromopicolinate (9.305 g) as a yellow solid. LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm particles, 1.7 qm; Mobile phase A: 100% water with 0.05% trifluoroacetic acid; Mobile phase B: 176 100% acetonitrile with 0.05% trifluoroacetic acid; Temperature: 40°C; Gradient: 2-98% B for 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. Aduchos: [M+H]; Obs. Masses: 245.0. 7H NMR (DMSO-d6) 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). INTERMEDIARY 37 Ethyl 3-acetamido-6-bromopicolinate ΟγΟΗ3NH Br N γúO (1-37) Ethyl-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 hours. The volatile reaction compounds 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 and dried under vacuum to provide 3-acetamido-6-bromopicolinate. 177 ethyl (787 mg). LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm particles, 1.7 μπι; 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 for 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. NMR (DMSO-d6) 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=1.1 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J=7.2 Hz, 3H). Removal of the solvent from the filtrate provided an additional 695 mg of product (87% purity). INTERMEDIARY 38 Ethyl 6-bromo-3-(N-methylacetamido)picolinate ΟγΟΗ3 / ^s^N-CHa í T Br N yóo (1-38) A solution was prepared by dissolving ethyl 3-acetamido-6bromopicolinate (5 g, 17.41 mmol) in 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. The solvent was removed in vacuo using a rotary evaporator / vacuum pump combination. Acetate was added 178 ethyl and DCM to the reaction residue together with chloroform and toluene. The mixture was filtered through a celite pad to remove salts. The solvents were again removed in vacuo using a rotary evaporator. The reaction residue was redissolved in chloroform and toluene and filtered through a bed of celite to remove any insoluble particles still present. Removal of the 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 pm 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 for 2 minutes, then 1 minute hold at 100% B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection volume: 1 pL. Retention time 1.07 min.; Obs. Adducts: [M+H]; Obs. Masses: 301.1. proton NMR shows features of restricted rotation (rotamers); 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.OH), 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). 179 INTERMEDIARY 39 6-bromo-4-hydroxy-l-methyl-l,5-naphthyridin-2(1H)-one CH3 or (1-39) A 25 mL round bottom flask was charged with KHMDS (4.3 mL, 2,150 mmol) (0.5 M in toluene), was placed under nitrogen and cooled to −78 °C. A solution of ethyl 6-bromo-3-(Nmethylacetamido)picolinate (215 mg, 0.714 mmol) in THF (2.5 mL) was slowly added to the KHMDS solution over approximately 3 minutes. The reaction mixture was warmed to room temperature and a 1:1 mixture of ethyl acetate and water was 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 shaken in an Erlenmeyer flask with 7 mL of water. A yellow solid was collected and dried in vacuo to give the title compound (130.2 mg, 72%). LCMS; Column: Waters Acquity UPLC BEH C18 2.1 mm x 50 mm, 1.7 pm particles; Mobile phase A: 100% water with 0.05% TFA; Mobile phase B: 100 0.05% TFA acetonitrile; Temperature: 40°C; Gradient 2% B to 98% B for 1.5 minutes, then 1 minute hold at 100% B; Flow: 0.8 mL / min; Detection: MS and UV (220 nm). Injection volume: 3 180 pl. Retention time 0.8 min.; Obs. Adducts: [M+H]; Obs. Masses: 254.9, 256.9. INTERMEDIARY 40 6-Bromo-l-methyl-2-oxo-l,2-dihydrol,5-naphthyridin-4-yl trifluoromethanesulfonate In a round bottom flask, 6-bromo1-methyl-l,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 that the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by chromatography with 1:1 hexane:ethyl acetate on a 24 g silica gel column to provide the product as a white solid (260 mg, 86%). LC\MS analytical conditions: Injection Vol = 1 pL, Start %B 0 end B 100. Gradient time 2 minutes, Flow rate 1 mL / min, Wavelength 220 nm, Acetonitrile / water / TEA solvent pair, Solvent A 10% Acetonitrile / 90% Water / 0.1% TEA, 181 Solvent B 90% acetonitrile / 10% water / 0.1% TFA, Acquity BEH C18 Column 21. X 50 mm 1.7 pm, Oven temperature = 40 °C. LC\MS results; retention time 1.5 minutes, observed mass 386.7.388.7 (M+). INTERMEDIARY 41 2-cyanoacetyl chloride Or (1-41) A few drops of DMF were added to a solution of 2-cyanoacetic acid (500 mg, 5.88 mmol) in CH2C12 (5 mL). A solution of 2 M oxalyl chloride (3.23 mL, 6.47 mmol) in methylene chloride was then added dropwise. The reaction mixture was stirred at room temperature for 2 hours and concentrated. INTERMEDIARY 42 6-bromo-2,4-dioxo-l,2,3,4-tetrahydro-l,5-naphthyridine-3carbonitrile h ΒΓ^ΙψγΌΝ O (1-42) To a solution of ethyl 3-amino-6-bromopicolinate (1.3 g, 5.0 mmol) in DCM (10 mL), DIPEA (2.8 mL, 15.1 mmol) was added. 2-Cyanoacetyl chloride (0.09 g, 5.8 mmol) in DCM (10 mL) was then slowly added. The reaction mixture was stirred at room temperature for 10 min. 182 LC / MS showed the formation of ethyl 6-bromo-3-(2cyanoacetamido)picolinate (MS at 312). The reaction was stopped with water and the resulting mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to provide a thick brownish oil as crude product. The crude product was triturated with ethyl acetate / hexanes to give a yellow solid. 4H NMR confirms its structure as a cyclized product with DIPEA. The product was washed with a solution of 1 N HC1 and 6-bromo-2,4-dioxo1,2,3,4-tetrahydro-l,5-naphthyridine-3-carbonitrile (650 mg, 2,443 mmol, 46.1% yield ) as a whitish solid. Η4NMR(DMSO-dg). LCMS: (m / z) >90% pure, 266.268 (MH+). INTERMEDIATE 43 6-bromo-l-methyl-2,4-dioxo-l,2,3,4-tetrahydro-l,5-naphthyridine3-carbonitrile CH3 O (1-43) To a solution of 6-bromo-2,4-dioxo-l,2,3,4tetrahydro-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 portionwise. The reaction mixture was stirred at room temperature for 30 min and iodomethane (0.176 mL, 2.82 mmol) was added. The reaction mixture is 183 stirred at room temperature overnight. INTERMEDIATE 44 6-Bromo-3-cyano-l-methyl-2-oxo-l,2dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate ch3 OTf (1-44) To a stirred solution of 6-bromo-l-methyl-2,4dioxo-1,2,3,4-tetrahydro-l,5-naphthyridine-3-carbonitrile (0.6 g, 2.14 mmol) in DCM (8 mL) TEA (0.896 mL, 6.43 mmol) and DMAP (0.026 g, 0.214 mmol) were added at 0 °C. °C, followed by the addition of trifluoromethanesulfonic anhydride (0.724 mL, 4.28 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was stopped 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 give a brown solid. The crude compound was triturated with DCM and hexane (1:4) to produce 6bromo-3-cyano-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridin-4-yl trifluoromethanesulfonate (700 mg , 79% yield) as a brown solid; LCMS: m / z = 414.1 (m / z) : (M+H); ta 0.65 min. LC-MS Method: AQUITY UPLC BEH C18 Column (3.0 x 50 mm) 1.7 pm; Mobile phase A: Buffer: acetonitrile (95:5); Mobile phase B: 184 Buffer: acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B for 2.0 minutes, then a 0.3 minute hold at 100% B, flow rate 0.7 mL / min. INTERMEDIATE 45 6-bromo-4-chloro-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3- To a 500 mL round bottom flask charged with 6-bromo-l-methyl-2,4-dioxo-1,2,3,4-tetrahydro-l,5-naphthyridin3-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. POCl3 (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. Next, the mixture was initially concentrated online under vacuum, then under high vacuum. The residue was then poured onto a mixture of ice and a 1.5 M K2HPO4 solution. After 30 min, the mixture was extracted using chloroform (3x). The combined extracts were washed sequentially with K2HPO4 solution, 1 N HC1 solution, and then with brine. 185 The organic solution was then dried over Na2SO4, filtered and concentrated in vacuo to provide the crude product as a brown solid (3.1 g). The product was purified by flash chromatography on silica gel using 2% ethyl acetate in DCM as eluent. The homogeneous fractions were combined and evaporated under reduced pressure to provide the product as a yellow solid, 1,922 g (yield 72%). LCMS:(m / z):(M+H)+= 298.05. RMNXH (500 MHz, CHLOROFORM-d) δ 7.83 (d, J=8.8 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H). INTERMEDIARY 46 4,6-dichloro-l-methi1-2-oxo-1,2-dihydro-l,5-naphthyridine-3- mL, 80 mmol) to 6-bromo-4-chloro-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridine-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 in vacuo. 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 solid (0.78 g, 2.68 mmol, 186 80% performance). (LCMS: (m / z) : (M+H)+= 254.15, 4H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=9.0 Hz, 1H) , 8.00 (d, J=9.0 Hz, 1H ), 3.66 (s, 3H). INTERMEDIARY 47 Ethyl 6-bromo-3-(2-cyanoacetamido)picolinate To a stirred solution of ethyl 3-amino-6-bromopicolinate (2.0 g, 8.16 mmol) in DMF (15 mL) was added 2-cyanoacetic acid (1.388 g, 16.32 mmol) and TEA (2.84 mL, 20.40 mmol) followed by anhydride 1-propanephosphonic acid (10.78 mL, 17.95 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched by careful addition of water (100 mL). The resulting mixture was stirred for 15 min, during which time a solid separated and was collected by filtration to provide pride as a yellow solid (2.45 g, 7.85 mmol, 96% yield). INTERMEDIARY 48 Ethyl 6-cyano-3-(2-cyanoacetamido) picolinate To a stirred solution of ethyl 6-bromo-3-(2187 cyanoacetamido)picolinate (200 mg, 0.641 mmol) in NMP (8 mL) was 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 Pd2(dba)3 (58.7 mg, 0.064 mmol) were added and the purge was continued for a further 3 min. The reaction mixture was then heated to 80 °C for 5 min and the mixture was stirred for an additional hour before being allowed to cool to room temperature. The reaction was then stopped by adding water and the resulting mixture was filtered through a pad 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 Na2SO4, 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 / petroleum ether as eluent. The homogeneous fractions were combined and evaporated in vacuo to give the product as a brown solid, (70 mg, 0.271 mmol, 42.3% yield) LCMS method; buffer: 10 mM Ammonium Acetate pH -5 adjusted with HCOOH Mobile phase A: Buffer: ACN (95:5) Mobile phase B: buffer: ACN (5:95) Description: Method: %B: Omin-5%: 1.1 min -95%: 1.7 min-95% Column name: Acquity BEH C18 188 (2.1 χ 50 mm) 1.7 pm Method:C:\MassLynx\BMS_2013. Flow: 0.8 mL / min LCMS TA =1.10 min (M-H)- = 257.2). INTERMEDIARY 49 6,8-dioxo-5,6,7,8-tetrahydro-l,5-naphthyridine-2,7dicarbonitrile (1-49) To a stirred solution of ethyl 6-cyano-3-(2cyanoacetamido)picolinate (70 mg, 0.271 mmol) in DCM (5 mL) was added triethylamine (0.113 mL, 0.813 mmol). The reaction mixture was heated to 45 °C and then stirred for hours. The mixture was concentrated under reduced pressure and the residue was triturated with ethyl acetate for 15 min. The resulting suspension was filtered and the filtrate was dried under reduced pressure to provide the product as a brown solid (54 mg, 0.255 mmol, 94% yield). LCMS: (m / z) :(M+H)+= 213.2 INTERMEDIARY 50 5-methyl-6,8-dioxo-5,6,7,8-tetrahydro-l,5-naphthyridine-2,7dicarbonitrile CH3o (1-50) NaH (28.3 mg, 0.707 mmol) was added to a solution 189 stirred 6,8-dioxo-5,6,7,8-tetrahydro-l,5-naphthyridine-2,7dicarbonitrile (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 continued under a nitrogen atmosphere for 3 hours. The reaction was stopped by adding water (10 mL). The pH of the mixture was adjusted to ~6 using 1.5 N HC1. The resulting mixture was stirred for 15 min, during which time a solid separated and was collected by filtration and then dried under reduced pressure to provide the product as a brown solid (20 mg, 0.088 mmol, 37.5% performance). LC-MS: Method information: Ascentis Express C8 Column (50 -2 % H2O-10 mM NH4COOH), Flow= ImL / min, Time %B (0.0 0.0), (1.5 100.0), (3.2 100.0). LC-MS TA = 1.301 min (m / z) : (M+H)+= 225.0 . INTERMEDIARY 51 8-chloro-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7- The starting material, the hydrochloride salt of 5methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridin-2,7 190 dicarbonitrile, 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-tetrahydro1,5-naphthyridine-2,7-dicarbonitrile (10 g, 38.1 mmol) in acetonitrile (100 mL ) DIPEA (19.95 mL, 114 mmol) was added. The resulting cloudy brown solution was cooled to 0-5 °C and POCI3 (40.8 mL, 438 mmol) was added slowly over approximately 20 min, after which the mixture was heated to 90 °C for approximately 1 hour. The reaction mixture was cooled to room temperature and then concentrated under high vacuum to produce a pale brown residue. Ice pellets were added and the suspension was stirred for ~15 min, during which time a free-flowing solid formed. The mixture was neutralized by the addition of a saturated NaHCOs solution and the product was extracted using DCM (4 x 500 mL). The combined extracts were washed with brine (1 x 500 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide the crude product as a brown solid. This was triturated with acetone (50 mL) and the product was collected by filtration and dried in vacuo to provide 6 g of a solid. The filtrate was concentrated and the residue was triturated again with acetone to provide an additional 2.4 g of a solid. The solids were combined to provide the title compound as a colored solid. 191 brown (8.4 g, 33.8 mmol, 89% yield). INTERMEDIARY 52 6-chloro-4-(4-hydroxypiperidin-l-yl)-l-methyl-2-oxo-l,2dihydro-1,5-naphthyridine-3-carbonitrile Piperidin-4-ol (110 mg, 1,084 mmol) was added to a solution of 4,6-dichloro-l-methyl-2-oxo1,2-dihydro-l,5-naphthyridin-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. Upon stirring, a yellow 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, NMR3Η (500 MHz, DMSO-d6) 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). 192 INTERMEDIATE 53 (+ / -) 6-bromo-4-(cis-4-hydroxy-3-methylpiperidin-l-yl)-1methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrile To a solution of 6-bromo-4-chloro-l-methyl-2-oxo1,2-dihydro-l,5-naphthyridine-3-carbonitrile (1.0 g, 3.35 mmol) in DMF (8 mL), ( + / -) cis-3-methylpiperidin-4-ol (0.05 g, 3.2 mmol) and triethylamine (1.67 mL, 8.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water was then added and an orange solid separated and was collected by filtration. The crude product was triturated with methanol / dichloromethane and the final product was obtained by filtration as a yellow solid (0.82 g, 2.174 mmol, 64.9% yield). LCMS: (m / z) : (M+H)+= 376.9. 3H NMR (400 MHz, DMSO-d6) δ 7.97-7.87 (m, 1H), 8.027.79 (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=9.1, 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-l-methyl-4-(trans-3-methyl-4-(4-(tere 193 pentyl)phenoxy)piperidin-l-yl)-2-oxo-l,2-dihydro-l,5naphthyridine-3-carbonitrile To a solution of 4-(tert-pentyl)phenol (65.3 mg, 0.398 mmol) in THF (8 mL), triphenylphosphine (194 mg, 0.583 mmol) was added on a solid support. The reaction mixture was stirred at room temperature for 5 min. Then di-tert-butyl (E)-diazen-1,2-dicarboxylate (98 mg, 0.424 mmol) and (+ / -) 6-bromo-4-(cis-4-hydroxy-3methylpiperidin-l-) were added. yl)-l-methyl-2-oxo-l,2-dihydro-l,5naphthyridine-3-carbonitrile (100 mg, 0.265 mmol). The reaction mixture was stirred at room temperature for 6 days. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give a yellow solid. The product was purified using a reverse phase preparative HPLC column using a CH3CNH2O-TFA solvent system as eluent. Homogeneous fractions were collected and concentrated in vacuo to provide the TFA salt of the title compound as a yellow solid. 194 clear (31 mg, 0.049 mmol, 18.34% yield). LCMS: (m / z) : (M+H)+= 523.0. NMRΊΗ (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). Complete assignment was not performed due to obfuscation of certain compound-associated peaks by solvent impurities. INTERMEDIARY 55 8-chloro-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7dicarbonitrile To a stirred suspension of 8hydroxy-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7dicarbonitrile hydrochloride (10 g, 38.1 mmol) in acetonitrile (100 mL) was added DIPEA (19.95 mL, 114 mmol). The cloudy brown solution was cooled to 0-5 °C. POCI3 (40.8 mL, 438 mmol) was then added slowly over ~20 min via a dropping funnel. The resulting mixture was heated at 90 °C for 1 min and then allowed to cool to room temperature. The mixture was concentrated under high vacuum to provide a 195 pale brown 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 a saturated NaHCO3 solution and then extracted with DCM (4 x 500 mL). The combined extracts were washed with brine solution (1 x 500 mL), dried over Na2SO4, filtered and then concentrated to give a brown 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 was crushed again with acetone and additional product was obtained. The combined filtrates were dried under vacuum to provide the title compound as a brown solid (8.4 g, 33.8 mmol, 89% yield). LCMS: (M+H+ H2O)+= 262.0. NMR (300MHz, DMSO-d6) δ 8.49-8.37 (m, 2H), 3.72-3.61 (m, 3H). INTERMEDIARY 56 8-(4-hydroxypiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile OH (1-56) 196 6-cyano-lmethyl-2-oxo-l,2-dihydro-l,5-naphthyridin-4-yl trifluoromethanesulfonate (0.600 g, 1,800 mmol) and 4-hydroxypiperidine (0.266 g, 2.63 mmol) were added to the 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 hour. The heterogeneous mixture was then cooled in an ice bath to 0 °C, and the resulting yellow precipitate was collected by filtration and then dried under vacuum to provide the product as a yellow solid (473 mg, 92%). 1H 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, 1.0 H), 3.94-3.85 (m, 2.OH), 3.64 (s, 3.OH), 3.27 (ddd, J=12.5, 9.1, 3.3 Hz, 2.OH), 2.15-2.07 (m, 1.9H) , 1.87-1.76 (m, 2.OH). INTERMEDIATE 57 (+ / -) 4-(cis-4-hydroxy-3-methylpiperidin-l-yl)-6-cyano-lmethyl-1,5-naphthyridin-2(1H)-one Cis-3-methylpiperidin-4-ol (34.6 mg, 0.300 mmol) was added to a solution of 6-cyano-lmethyl-2-oxo-l,2-dihydro-l,5-naphthyridin-4-yl trifluoromethanesulfonate ( 100 mg, 0.300 197 mmol) and Hunig base (0.105 mL, 0.600 mmol) in DMF (4 mL). The mixture was heated to 85 °C overnight. The solvent was removed under high vacuum and the residue was dissolved in EtOAc. The resulting solution was washed with water (2x) and once with brine. The mixture was then dried over MgSO4, filtered and concentrated in vacuo to provide 89 mg of a yellow solid (100%). LCMS: TA = 1.01 (m / z) : (M+H)+= 299.03. 3Η NMR (400 MHz,) δ 8.02 (d, J=1.8 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 (dgt, 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). INTERMEDIARY 58 (+ / -)terebutyl cis-4-hydroxy-3-methylpiperidine-l-carboxylate Boc i OH (1-58) To a suspension of (+ / -)cis-3-methylpiperidin-4-ol (1 g, 8.68 mmol) and triethylamine (1.452 mL, 10.42 mmol) in DCM (15 mL), Boc-anhydride (2.419 mL, 10.42 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with DCM and acidified with a 198 1 N HC1 solution at pH ~6. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure of the solvent to give a yellowish oil. The crude product was then purified by flash chromatography using ethyl acetate / hexanes up to (10-40%) as eluent. Homogeneous fractions were collected and evaporated under reduced pressure to provide the product as a colorless viscous oil (1.35 g, 6.27 mmol, 72.2% yield). LCMS: 216 (m / z):(M+H)+= 216. 4H NMR (500 MHz, CHLOROFORM-d) δ 3.983.81 (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). INTERMEDIARY 59 (+ / -)Tere-butyl trans-4-(benzoyloxy)-3-methylpiperidine-l-carboxylate To a solution of (+ / -) tere-butyl cis-4-hydroxy-3-methylpiperidine1-carboxylate (0.982 g, 4.56 mmol) in THF (8 mL), triphenylphosphine (1.675 g, 6.39 mmol) and acid were added. benzoic acid (0.780 g, 6.39 mmol). Next, it 199 added ditero-butyl (E)-diazen-1,2-dicarboxylate (1.470 g, 6.39 mmol) in THE 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 was purified by flash chromatography using ethyl acetate in hexanes (10-30%) as eluent. The homogeneous fractions were combined and evaporated in vacuo to provide the product as a colorless, viscous oil (0.77 g, 2.411 mmol, 52.9% yield). 3H 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 (+ / -) trans-4-hydroxy-3-methylpiperidine-l-carboxylate tere-butyl Boc i N. T^CH3 ¿H (1-60) To a solution of (+ / -) tere-butyl trans-4-(benzoyloxy)-3methylpiperidine-l-carboxylate (0.761 g, 2.383 mmol) in MeOH (10 mL), sodium hydroxide (0.476 g, 11.91 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Then the mixture is 200 was 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 MgSO4, filtered and evaporated in vacuo to provide the product as a colorless, viscous oil (446 mg, 2,072 mmol, 87% yield). . 4H NMR (500 MHz, CHLOROFORM-d) δ 4.16-3.88 (m, 2H), 3.37-3.19 (m, 1H), 2.932.75 (m, 1H), 2.67-2.34 (m, br, 1H), 2.00- 1.84 (m, 1H), 1.551.40 (m, 11H), 1.02 (d, J=6.6 Hz, 3H). INTERMEDIATE 61 (+ / -) trans-3-methylpiperidin-4-ol H£CH3ÓH (1-61) To a solution of (+ / -)tere-butyl trans-4-hydroxy-3methylpiperidine-l-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 provide the TFA salt of the title compound as an oil. colorless viscous. 201 INTERMEDIATE 62 (+ / -) 8-(trans-4-hydroxy-3-methylpiperidin-l-yl)-5-methyl-6oxo-5,6-dihiro-l,5-naphthyridine-2-carbonitrile (+ / -) trans-3-methylpiperidin-4-ol, trifluoroacetate (468 mg, 2,044 mmol) was added to a solution of 6-cyano-l-methyl-2-oxo-l,2-dihydro1,5 trifluoromethanesulfonate -naphthyridin-4-yl (487 mg, 1.460 mmol) and Hunig's base (1.275 mL, 7.30 mmol) in DMF (5 mL). The reaction mixture was heated to 85 °C overnight. The mixture was diluted with water and a yellow solid separated which was collected by filtration and dried under vacuum to provide the product as a solid (385 mg, 1,290 mmol, 88% yield). LCMS: (m / z) : (M+H)+= 299. 2H NMR (500 MHz, DMSO-d6) 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 63 6-cyano-l-methyl-4-(5-methyl-3,6-dihydropyridin-l(2H)-yl)-1,5 202 naphthyridin-2(1H)-one A 20 mL dry scintillation vial equipped with a septum was charged with 3 mmol / g triphenylphosphane (polymer supported) (2.212 mL, 0.664 mmol) and then evacuated and flushed with nitrogen. THF (2 mL) was then added, followed after ~1 minute by 4-(trifluoromethoxy)phenol (0.039 mL, 0.302 mmol). The resulting 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 into a single portion. The mixture was stirred on an orbital shaker for 3 minutes, after which a solution of 8-(trans-4hydroxy-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro was added. -l,5naphthyridine-2-carbonitrile (90 mg, 0.302 mmol)) in THF (2 mL) in a single serving. The vial was then shaken at room temperature overnight. Subsequently, the reaction mixture was filtered and evaporated to dryness. The residue was dissolved in 2 mL of DMF and the resulting solution was fractionated by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 pm particles; Mobile phase A: 5:95 acetonitrile: water with acetate 203 ammonium 10 mM; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: a 0 minute hold at 31% B, 31-71% B for 25 minutes, then 5 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 32.9 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 minutes, then a 0.50 minute hold at 100% B; Fluid: 1 mL / min; 204 Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 281.11; Retention time: 1.69 min. NMR (500 MHz, DMSO-d6) 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). INTERMEDIARY 64 (+ / -)butyl ether cis-3-ethyl-4-hydroxypiperidine-l-carboxylate A 1 M solution of LSelectride (16.50 mL, 16.50 mmol) in THE was added dropwise to a solution of tere-butyl 3ethyl-4-oxopiperidine-l-carboxylate (2.5 g, 11.00 mmol) in THE (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 a 1 M NaOH solution (5 mL) at the same temperature. Then the reaction mixture was heated to 0 °C and a 30% aqueous solution was added. H2O2 (5 mL) was added dropwise. The cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours, after which it was diluted with EtOAc. 205 An insoluble white solid precipitated and was removed by filtration. The filtrate was collected, washed sequentially with a saturated solution of NaHCOs and brine, and then dried over MgSO4, filtered and evaporated under reduced pressure to provide 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 provide the product as a colorless oil (1.6 g, 6.98 mmol, 63.4% yield). LCMS: (M-(t-Bu)+ACN+H)+= 215.35. 4H NMR (500 MHz, CHLOROFORM-d). All signs were very broad. INTERMEDIATE 65 (+ / -) cis-3-ethylpiperidin-4-ol, TFA salt H tea NlhA OH (1-65) TFA (2 mL, 26.0 mmol) was added to a solution of tere-butyl cis-3-ethyl-4-hydroxypiperidine-l-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 give the product as a pale yellow viscous oil, TFA salt (1.65 g, 6.78 mmol, 97% yield). . RMNXH (500 MHz, CHLOROFORM-d) δ 9.03-8.82 (m, 1H), 8.82-8.60 (m, 1H), 206 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 (+ / -) tere-butyl trans-4-(benzoyloxy)-3-etolpiperidine-l-carboxylate Boc i CH3(1-66) To a solution of (+ / -)tere-butyl cis-3-ethyl-4-hydroxypiperidine-lcarboxylate (1.5 g, 6.54 mmol) in THF (10 mL), triphenylphosphine (2.402 g, 9.16 mmol) was added. and benzoic acid (1.118 g, 9.16 mmol). (E)-Di-tert-butyldiazene1,2-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 was purified by flash chromatography using ethyl acetate in hexanes (0-20%) as eluent. The homogeneous fractions were combined and evaporated in vacuo to provide the product as a colorless, viscous oil (1.70 g, 5.10 mmol, 78% yield). 207 INTERMEDIARY 67 (+ / -)Terebutyl trans-3-ethyl-4-hydroxypiperidine-l-carboxylate To a solution of (+ / -) tere-butyl trans-4-(benzoyloxy)-3ethylpiperidine-l-carboxylate (1.7 g, 5.10 mmol) in MeOH (15 mL), sodium hydroxide (1.020 g, 25.5 mmol) was added. mmol). The reaction mixture was stirred at room temperature for 3 hours. 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 MgSO4, filtered and evaporated in vacuo to provide 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. The homogeneous fractions were combined and evaporated under reduced pressure to provide tere-butyl trans-3ethyl-4-hydroxypiperidine-l-carboxylate (0.68 g, 2.97 mmol, 58.2% yield) as a viscous colorless oil. 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), 1.971.87 (m , 1H), 1.75 (br d, J=1.6 Hz, 1H), 1.51-1.40 (m, 11H), 208 1.40-1.30 (m, 1H), 1.25-1.15 (m, 1H), 0.99 (t, J=7 . 4 Hz, 3H). The spectrum was broad and could not be fully allocated. INTERMEDIATE 68 (+ / -) trans-3-ethylpiperidin-4-ol, TFA OH (1-68) To a solution of (+ / -) tere-butyl trans-3-ethyl-4-hydroxypiperidin1-carboxylate (0.3 g, 1.308 mmol) in dichloromethane (3 mL), 1 mL of TFA was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. INTERMEDIATE 69 (+ / -) 8-(cis-3-ethyl-4-hydroxypiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridine-2-carbonitrile (+ / -) cis-3-ethylpiperidin-4-ol TFA salt (1.2 g, 4.93 mmol) was added to a solution of 6-cyano-l-methyl-2-oxo-l,2-dihydro-trifluoromethanesulfonate. l,5-naphthyridin-4-yl (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 to 85 °C for 209 the night in nitrogen. The resulting mixture was diluted with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried over MgSO4, filtered and evaporated under reduced pressure to provide the crude product as an orange solid. The product was triturated with methanol and the residual solid was collected by filtration and air dried to provide the product as a light yellow 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 pm 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 for 22 minutes, then 4 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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% 210 B at 100% B for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 99.3%; Observed mass: 313.13; Retention time: 1.22 min. NMR (500 MHz, DMSO-dg) 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), .00-0.86 (m, 3H). The full spectrum was not completely assigned due to the water suppression technique used. INTERMEDIARY 70 4- (3-chlorophenoxy)piperidine (70) 211 Triphenylphosphine (156 mg, 0.596 mmol) was added to a solution of terebutyl 4-hydroxypiperidine-l-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 resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to provide 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 hours and then concentrated to give a yellow viscous oil. The mixture was purified using reverse phase preparative HPLC using a CH3OH-H2O-TFA buffer system. The homogeneous fractions were combined and evaporated under reduced pressure to provide 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. NMR (400 MHz, METHANOL-d4) δ 7.30 (t, J=8.2 Hz, 1H), 7.087.06 (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). 212 INTERMEDIARY 71 4- (3-fluoro-5-methylphenoxy)piperidine ΟΗ3(1-71) Triphenylphosphine on solid support (3 mmol / g) (289 mg, 1.1 mmol) was added to a 20 mL dry scintillation vial which 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 was further stirred briefly, after which di-tert (E)-diazene-1,2-dicarboxylate was added. -butyl (183 mg, 0.795 mmol). The mixture was then stirred for a further 3 min, and then tere-butyl 4-hydroxypiperidin1-carboxylate (100 mg, 0.497 mmol) was stirred and the resulting mixture was stirred at room temperature overnight. The suspension was filtered and the resin was washed with DCM. The washes and filtrates were combined and evaporated under reduced pressure. The residue was treated with 6 mL of a mixture of DCM and TEA, 1:1 for 30 min, and the resulting mixture was evaporated to dryness. The residue was dissolved in DCM and 5N NaOH solution was added. The mixture was extracted using DCM. The extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give the 213 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, To a solution of tere-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (100 mg, 0.464 mmol) in THE (2 mL), 1.0 M solution of potassium bis(trimethylsilyl)amide (1.161 mL, 1.161 mmol )) in THE. The reaction mixture was stirred at room temperature for 30 min, then l-fluoro-4-(trifluoromethyl)benzene (114 mg, 0.697 mmol) in THF (1 mL) was added. Then the reaction mixture was heated at 60 °C for 4 hours. The reaction was then quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give an oil. The product was fractionated using preparative HPLC using a CH3CN-H2O-TFA system as eluent. The homogeneous fractions were combined and concentrated under reduced pressure for 24 hours. The residue was dissolved in DCM (3 mL) and 1 mL of TFA was added. The mixture of 214 reaction was stirred at room temperature overnight and then concentrated in vacuo to provide 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. NMR (CD3OD) : NMR4Η (500 MHz, METHANOL-d4) δ 7.63 (br d, <7=8.5 Hz, 2H), 7.19 (d, 7=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, 7=6.9 Hz, 3H). The following method (Method A) was used to prepare several of the following examples of the present invention. EXAMPLE 1 6-fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-l-yl)-1methyl-3-nitroquinolin-2(1H)-one 4-(3-fluoro-5-methylphenoxy)piperidine (20 mg, 0.096 mmol) was added to a solution of 4-chloro-6-fluoro-l-methyl-3nitroquinolin-2(1H)-one (20.44 mg, 0.080 mmol) and Hunig's base (0.028 mL, 0.159 mmol) in DMF and the resulting mixture was stirred at room temperature overnight. Then mix 215 crude reaction was filtered, subsequently purified by preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 pm 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 for 25 minutes, then held for 6 minutes at 100% B; Fluid: 20 ml\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 22.1 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 216 minutes, then maintained 0.75 minutes at 100% B; Fluid: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 429.95; Retention time: 2.33 min. RMNXH (500 MHz, DMSO-de) δ 7.76-7.57 (m, 3H), 6.75-6.62 (m, 2H), 6.64-6.55 (m, 1H), 4.68 (dt, J=1.1, 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 complete assignment of all peaks in the spectrum was not achieved due to the water suppression technique employed in the NMR experiment. The following examples were prepared according to Method B. EXAMPLE 2 6-fluoro-4 - (4 - (4-isopropylphenoxy)piperidin-l-yl)-1-methi1-3nitroquinolin-2(1H)-one Triphenylphosphane on solid support 3 mmol / g (82.0 mg, 0.313 mmol) was added to a 20 mL dry scintillation vial. The resin was suspended in anhydrous DCM (3 mL) for 217 a period of 2 min under nitrogen. 4-Isopropylphenol (12.72 mg, 0.093 mmol) was added, followed after 5 min by the addition of (E)-diazene-1,2-dicarboxylate ditert-butyl (22.93 mg, 0.100 mmol). The resulting suspension was stirred on an orbital shaker for 3 minutes, and 6-fluoro-4-(4-hydroxypiperidin-l-yl)-l-methyl-3nitroquinolin-2(1H)-one (20 mg, 0.062 mmol) was added. ) in a single serving. Stirring continued at room temperature overnight. Then the reaction mixture was concentrated in vacuo and the residue was triturated with 2 mL of DMF. The suspension was then filtered and the crude product was fractionated using preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 pm 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 for 20 minutes, then held for 6 minutes at 100% B; Fluid: 20 mL\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 8.8 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% acid 218 trifluoroacetic; Temperature: 50°C; Gradient: 0% B to 100% B for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 440.18; Retention time: 2.54 min. 1H NMR (600 MHz, DMSO-dg) 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 spectrum acquisition. Similarly, the following examples were prepared. 219 Method A CH;. H CH; N ·. :', · N. · N ·. . < 0 J .1 . BasedeHunigo Et-N J .1 F NC- y _____________ ' F Cl 0 [}Mf. and . 1 T °Λ. Method B: CH3 CH:. / A ^.o y ,e _ Á Λ PPh,.DBAD J. JL. J Λ F - Y NO- Ar_()(1--F - - NO- 0 N j Q— PPh, .DBAD [ ] Y OH O. Ar TABLE 2 Ex- No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z).· (M+H)+ Synthesis method: 3 A 1 2.40 482.0 B 4 A 1 2.34 412.1 B 5 A 1 1.76 438.1 B 6 A 1 2.10 423.1 B 7 A 1 2.39 432.1 B 220 Ex. No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)\ (M+H)+ Synthesis method: 8 och3 cf3 A 1 2.32 496.1 B 9 A 1 2.26 416.1 B Method A was used to prepare several of the following examples. EXAMPLE 10 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-l-yl)-l-methyl-2-οχο 1,2-dihydro-l,5-naphthyridine-3-carbonitrile To a solution of 4,6-dichloro-lmethyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrile hydrochloride (15 mg, 0.052 mmol) in DMF (1.5 mL), hydrochloride was added of 4-(3methoxyphenoxy)piperidine (13.84 mg, 0.057 mmol) and triethylamine (0.036 mL, 0.258 mmol). The reaction mixture was stirred at room temperature for 2 hours. It was then diluted with methanol (2 mL), filtered and the crude mixture was purified. 221 by preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 pm 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 for 20 minutes, then held for 4 minutes at 100% B; Fluid: 20 mL\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 16.5 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 minutes, then held 0.75 minutes at 100% B; Fluid: 1 222 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 425.1; Retention time: 2.09 min. 1H NMR (600 MHz, DMSO-dg) 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=1.4, 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 spectrum acquisition. The following method (Method B) was used to prepare several of the following examples of the present invention. EXAMPLE 11 6-chloro-l-methyl-2-oxo-4-(4-(2(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile 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) was added. 223 1-yl)-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrile (15 mg, 0.047 mmol) and the reaction mixture was stirred for 15 min before adding DIAD ( 0.037 mL, 0.188 mmol) in a single serving. The resulting mixture was stirred at room temperature under nitrogen overnight. It was then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of CAN and DMF (1.8 mL). This crude mixture was then purified by preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 pm 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 for 20 minutes, then held for 5 minutes at 100% B; Fluid: 20 mL\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 8.0 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 Results: Purity: 100.0%; Observed mass: 463.02; 224 Retention time: 2.20 min. Injection conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 463.01; Retention time: 2.24 min. 4H NMR (500 MHz, DMSO-d6) 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). Similarly to the previous two methods, the following examples can be prepared. Method C: CU: μ CHS. . N... O .· N N . EITHER J ..J í.aBasedeHunigo EtN í ,.J J CI ' N ' 'f' C N Y _____________CI - N ' 'Y C N Cl L, DMf u 0,._ 225 Method D: CH:. . N... PPh-. ' DADC T OH T DADC d:azod;carboxylate dialquHo O Ar TABLE 3 Ex- No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)\ (M+H)+ Method: 12 A 1 2.14 431.1 B 13 A 1 2.31 479.0 B 14 A 1 2.00 425.1 B 15 A 1 2.53 451.0 A 16 A 2 4.22 428.9 A 17 A 1 2.38 497.1 B 18 A 1 2.16 429.1 A 19 A 1 2.30 478.9 A 226 Ex. No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)\ (M+H)+ Method: 20 i—f A 1 2.10 413.1 B 21 1— A 2 4.11 408.9 A 22 A^^CH3 A 1 2.21 409.1 B 23 Cl F A 2 4.12 446.9 A 24 X^ / CF3 uj A 1 2.30 463.1 B 25 26.9 A 29 ch3 vlX ^^ocf3 A 1 2.47 493.1 B 227 Ex- No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method: 30 A 1 2.32 463.1 B 31 h3c ί Λ. 3<CH3 A 1 2.31 467.1 B 32 i—Ocn A 1 1.93 420.1 B 33 ocf3 A 1 2.27 479.1 B 34 z^cn A 1 1.97 420.1 B 35 och3 57 A 1 1.98 425.1 B 36 och3 'YX A 1 1.95 443.0 B 37 / =\ ch3 ΓΥ^(3Η3 A 1 2.47 437.1 B 38 Á / ^CI Y T A 1 2.16 454.0 B 39 Á^,och3 1 Y A 1 2.27 459.1 B 40 / O^a 1 Y ^^ch3 A 1 2.49 443.1 B 228 Ex. No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)i (M+H)+ Method: 41 Cl nA ^^ocf3 A 1 2.46 513.1 B 42 I T ^^ocf3 A 1 2.49 513.0 B 43 CN A 1 1.86 420.0 B 44 F di ) A 1 2.07 413.1 B 45 A 1 2.08 413.1 B 46 i— A 1 2.07 395.1 B EXAMPLE 47 6-bromo-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-3-carbonitrile OCF3(47) 229 To a solution of 6-bromo-4-chloro-l-methyl-2-oxo1,2-dihydro-l,5-naphthyridine-3-carbonitrile (50 mg, 0.167 mmol) in DMF (4 mL), 4 was added. -4(trifluoromethoxy)phenoxy)piperidine (48.1 mg, 0.184 mmol) and triethylamine (0.093 mL, 0.670 mmol). The reaction mixture was stirred at room temperature for 2 hours and then quenched by addition of water. A white solid separated and 85 mg was collected by filtration. 20 mg of this material was dissolved in a 1:1 mixture of DMF and methanol, and this solution was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 pm 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 for 15 minutes, then held for 5 minutes at 100% B; Fluid: 20 mL\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 9.5 mg and its purity estimated by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 during 230 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 98.8%; Observed mass: 523.03; Retention time: 2.36 min. 7H NMR (500 MHz, DMSO-d6) 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 spectrum acquisition. 231 EXAMPLE 48 6-methoxy-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyrldine-3-carbonitrile CH3h3c-0^n^y^cn 9 °CF3(48) 6-bromo-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridin-3-carbonitrile (30 mg, 0.057 mmol), 5-[di(ladamantyl)phosphino]-l',3',5'-triphenyl-l'h-[l,4']bipyrazole (3.80 mg, 5.73 pmol), cesium carbonate (18.68 mg , 0.057 mmol) and Pd(OAc)2 (0.644 mg, 2.87 pmol) in 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 to 80 °C overnight. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 pm 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: 0 minute hold at 41% B, 41-81% B 232 for 25 minutes, then held for 4 minutes at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 14.4 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 475.05; Retention time: 2.18 min. Η4NMR (500 MHz, DMSO-dg) δ 233 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 50 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-lyl)-5,6-dihydro-l,5-naphthyridine-2,7-dicarbonitrile 6-Bromo-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5naphthyridine-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) dichloromethane complex (7.80 mg, 9.55 pmol) into a dry microwave vial that was sealed, evacuated, and then flushed with nitrogen. NMP (4 mL) was added and the resulting mixture was irradiated in the microwave at 75 °C for 4.5 hours. The reaction mixture was then cooled to room temperature, diluted with acetonitrile and filtered. The filtrate was fractionated using phase preparative HPLC. 234 reverse using a CH3CN-H2O-TFA system. The homogeneous fractions were combined, neutralized with a saturated NaHCO3 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) TA = 4.39 min. (m / z) :(M+H)+= 470.1. 4H NMR (400 MHz, DMSO-d6) 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=1.4, 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 51 5-methyl-7-nitro-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-5,6-dihydro-l,5naphthyridine-2-carbonitrile To a solution of 8-chloro-5-methyl-7-nitro-6-oxo 5,6-dihydro-l,5-naphthyridin-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). The reaction mixture 235 was stirred at room temperature over the weekend. The resulting solution was purified by preparative HPLC with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 qm 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 for 20 minutes, then held for 4 minutes at 100% B; Fluid: 20 mL\min. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 19.1 mg and its purity estimated by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity. Injection conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 qm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 qm 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 during 236 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 99.1%; Observed mass: 490.1; Retention time: 2.25 min. 4H NMR (500 MHz, DMSO-ds) 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 spectrum acquisition. The following method (Method A) was used to prepare several of the following examples of the present invention. EXAMPLE 52 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-lyl)-5,6-dihydro-l,5-naphthyridine-2-carbonitrile 8-Chloro-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (22 mg, 0.100 mmol) was dissolved in DMF (1 mL) contained in a one-dram pressure vial. 4-[4trifluoromethoxy)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, 237 was sealed and then heated in an oil bath at 90 °C for 5 hours. The reaction mixture was allowed to cool before diluting it to a volume of 2 mL by adding acetonitrile and two drops of water. This 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 pm 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 for 25 minutes, then 4 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 26.1 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.75 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 Results: Purity: 100.0%; Observed mass: 445.12; 238 Retention time: 2.19 min. Injection conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 minutes, then held 0.75 minutes at 100% B; Fluid: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 445.14; Retention time: 2.12 min. 4H NMR (500 MHz, DMSO-d6) 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.OH), 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.OH). The reported chemical shifts are not corrected for the effects of water suppression. The following method (Method B) was used to prepare several of the following examples of the present invention. 239 EXAMPLE 53 4-(4-(4-(tert-butyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2dihydroquinoline-6-carbonitrile Triphenylphosphine resin (56.6 mg, 0.217 mmol) (70 mg @ -3 mmol / g) was placed in an oven, dried in a 1 dram flask, cooled under vacuum, loading) and suspended in NMP (0.5 mL ) under nitrogen, and the mixture was allowed to stand for 2 min. Then 4-tert-butylphenol (23.0 mg, 0.153 mmol) and di-tert-butyl azodicarboxylate (43 mg, 0.187 mmol) were added and the mixture was stirred for an additional 5 min. A solution of 8-(4-hydroxypiperidin-l-yl)-5-methyl-6-oxo5,6-dihydro-l,5-naphthyridin-2-carbonitrile in N-methyl-2pyrrolidinone (1.0 mL, 28 mg) was added. , 0.098 mmol) and the resulting suspension was kept under nitrogen and stirred at room temperature overnight. The mixture was then filtered and the filtrate volume was adjusted to 2 mL by adding more NMP. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge 240 C18, 200 mm x 19 mm, 5 pm 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 for 20 minutes, then 7 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS and UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 0.6 mg and its purity estimated by LCMS analysis was 96%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 241 minutes, then a hold of 0.50 minutes at 100% B; Fluid: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 96.4%; Observed mass: 417.06; Retention time: 2.27 min. RMNXH (500 MHz, DMSO-dg) δ 8.16 (d, J=8.9 Hz, 1.0H), 8.08 (d, J=8.9 Hz, 1.OH), 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), 4.664.55 (m, 1.0H), 3.82-3.71 (m, 2.OH), 3.54 (s, 1.8H ), 2.162.02 (m, 2.OH), 1.88-1.73 (m, 1.9H), 1.25 (s, 9.OH). Similarly, the following examples can be prepared. Method A 242 TABLE 4 Ex. No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)'. (M+H)+ Method: 54 πΓΐ h3c ch3 A 1 2.51 431.1 B 55 A 1 2.26 451.2 B 56 xCH3 A 1 2.40 417.1 B 57 JH3 A 1 2.33 403.3 B 58 í— A 1 2.54 429.1 B 5 9 A 1 2.10 401.0 B 60 A^^CH3 XX^CH3 ch3 A 1 2.38 417.0 B 61 6qq A 1 2.27 415.0 B 62 ch3 OJ A 1 2.57 431.1 B 63 | A 1 2.55 443.1 B 243 Ex. No. Stereo Ar Structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method: 64 hQljO h3c ch3 A 1 2.48 479.1 B 65 ήη h3YcH3 A 1 2.18 433.3 B The following method (Method A) was used to prepare several of the following examples of the present invention. EXAMPLE 66 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-l-yl)-5-methyl6-oxo-5,6-dihydro-l,5-naphthyridin-2-carbonitrile In a dry dram vial, 8-(4hydroxypiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-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 pL, 0.142 mmol) was added. Stirring was continued at room temperature for 244 the night. The reaction was then stopped 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 pm 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 for 20 minutes, then 4 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 9.3 mg and its purity estimated by LCMS analysis was 97%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: 245 Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 98.8%; Observed mass: 420.32; Retention time: 1.85 min. 4H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1.OH), 8.078.00 (m, 1.0H), 7.79 (d, J=3.1 Hz, 1.OH), 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 . OH), 3.853.71 (m, 1.7H), 3.30 (br t, J=9.6 Hz, 1.8H), 2.18-2.04 (m, 2.OH), 1.87-1.71 (m, 2.OH), 1.23 (d, J=5.8 Hz, 6.OH). Water suppression at 3.57 ppm decreases the intensity of adjacent signals. Similarly, the following examples can be prepared. ch3ch? JL NaH NMP 1 . ..either NC N and heteroaryl halide NG N । OH O heteroaryl 246 TABLE 5 Ex. No. Heteroaryl Structure Stereo Chemistry LCMS Method LCMS TA (m / z)·. (M+H)~ Method: 67 N=\ 1— / 7 Cl A 1 1.97 396.0 A 68 ω m T T O O I A Z 7 A 1 1.64 419.3 A 69 Ύν A 1 1.92 413.3 A 70 / ^n^ch3 XX ch3 A 1 1.14 391.1 A 71 A 1 1.46 413.0 A 72 / L.n^ / Ch3 IX A 1 1.10 377.1 A 73 o / 7 \\ σ> \ / T )--< ° O ' z A—O A 1 2.30 476.1 A 74 aJO ΎΥ A 1 1.46 413.0 A 247 Ex. No. Heteroaryl Structure Stereo Chemistry LCMS Method LCMS TA (m / z)\ (M-HQ Method: 75 to A 1 1.28 412.9 A 76 / . .N. ,CF3 U A 1 1.80 431.3 A 77 b z / A 1 2.11 430.2 A 78 ch3 ΟγΝγΟβΗ3 ch3 A 1 1.34 419.3 A EXAMPLE 79 (+ / -) 6-cyano-l-methyl-4-(trans-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2(1H) - A 20 mL dry scintillation vial equipped with a septum was loaded with triphenylphosphane (polymer supported). 248 mmol / g (2.212 mL, 0.664 mmol) and then evacuated and washed abundantly with nitrogen. THF (2 mL) was then added, followed after ~1 minute by 4-(trifluoromethoxy)phenol (0.039 mL, 0.302 mmol). The resulting 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 into a single portion. The mixture was stirred on an orbital shaker for 3 minutes, after which a solution of 8-(cis-4hydroxy-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro was added. -l,5naphthyridine-2-carbonitrile (90 mg, 0.302 mmol)) in THF (2 mL) in a single serving. The bottle was then shaken at room temperature overnight. Subsequently, the reaction mixture was filtered and evaporated to dryness. The residue was dissolved in 2 mL of DMF and the resulting solution was fractionated by preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 pm 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 for 25 minutes, then 5 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by UV signals. The fractions containing the product were combined and dried by evaporation 249 centrifuge. The yield of the product was 13.3 mg and its purity estimated by LCMS analysis was 100%. Analytical LC / MS was used to determine purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 minutes, then a 0.50 minute hold at 100% B; Fluid: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 459.08; Retention time: 2.28 min. Η3NMR (500 MHz, DMSO-d6) 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) , 2.24 250 1.99 (m, 2H), 1.73-1.58 (m, 1H), 1.07 (br d, J=6.4 Hz, 3H). The above racemic mixture was resolved by a chiral SFC separation method. Approximately 10.1 mg of racemate was resolved into two peaks collected in IPA with 0.1% DEA. The chiral purity of the isolates was estimated based on the preparative chromatogram below. Isolate Chiral purity elution peak >95% 2nd elution peak >95% Preparative Chromatographic Conditions: Instrument: Waters 100 Prep SFC Column: Chiral AD, 30 x 250 mm. 5 microns Mobile phase: 75% CO2 / 25% IPA w / 0.1%DEA Flow Conditions: 100 mL / min Detector wavelength: 220nm Injection Details: 1500 pL 10.1 mg dissolved in 4 mL MeOH Analytical chromatographic conditions (before preparation): Instrument: Shimadzu Nexera UC SFC Column: Chiralpak AD, 4.6 x 100 mm, 5 micron Mobile phase: 75% CO2 / 25% IPA w / 0.1%DEA Flow Conditions: 2 mL / min Detector wavelength: 220 nm Example 80: Isolate 1: First elution peak 251 Example 81: Isolate 2: Second elution peak EXAMPLE 80 6-cyano-l-methyl-4-(trans-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2 (1H)- Analytical LC / MS was used to determine purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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% from B to 252 100% B for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 96.3%; Observed mass: 459.1; Retention time: 2.26 min. 1H NMR (500 MHz, DMSO-d6) 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 81 6-cyano-l-methyl-4-(trans-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2 (1H)one (rei) Analytical LC / MS was used to determine purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, then a 0.50 min hold at 100% B; Flow: 1 mL / min; 253 Detection: MS and UV (220 nm). Injection 1 Results: Purity: 99.3%; Observed mass: 459.08; Retention time: 2.2 min. Injection conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 97.8%; Observed mass: 459.24; Retention time: 2.26 min. 1H NMR (500 MHz, DMSO-d6) 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). Using similar methodology and purification techniques, the following examples were prepared. Quinal HPLC separation 254 TABLE 6 Ex- No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)\ (M+H)+ Method 82 πΓχ h3c ch3 R 1 2.60 445.2 A 83 ηΠι ^ / ^ch3 h3c ch3 H 1 2.60 445.3 A 84 hQl h3c ch3 H 1 2.60 445.3 A 85 h3Vh3 ^^ctoh3 R 1 2.27 447.1 A 86 ch3 H 3 2.23 447.1 A 87 CH3 H 3 2.23 447.1 A 88 / ==^ ch3 hOh1^3 ch3 R 1 2.46 431.0 A 89 , / =. ch3 πΟη^3 ch3 H 3 2.40 431.1 A 90 , ch3 hCIm1^3 ch3 H 3 2.40 431.1 A 255 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method 91 R 3 2.25 415.2 A 92 H 3 2.22 415.3 A 93 H 3 2.22 415.3 A 94 / =\CH3 R 1 2.53 417.2 A 95 / =^ / CH3 CHg H 1 2.405 417.3 A 96 ^= \CH3 bH3 H 1 2.40 417.3 A 97 |— R 1 2.44 443.1 A 98 |-^J^CF3 H 1 2.26 443.2 A 99 |-H^^Cf3 H 1 2.25 443.2 A 100 i——O R 1 2.60 443.3 A 101 |— H 3 2.57 443.4 A 102 i—C H 3 2.57 443.3 A 103 ϊ T R 1 2.11 411.1 A 256 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method 104 Ϊ T H 1 2.10 411.1 A 105 T T \^F H 1 2.10 411.1 A 106 |— R 3 2.69 457.1 A 107 Λ^χ,ΟΗ3 R 3 2.14 389.2 A 108 / ^^CH3 XX H 4 2.13 389.1 A 109 XX H 4 2.107 389.3 A 110 ^XX^ch3 R 1 2.26 403.2 A 111 í—c —xi R 1 2.24 415.2 A 112 F R 1 2.06 411.1 TO 257 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method 114 F H ​​1 2.05 411.1 A 115 F AA H 1 2.05 411.1 A 116 cf3 AA ^^F R 1 2.24 461.1 A 117 cf3 aa H 3 2.20 461.2 A 118 cf3 AA H 3 2.20 461.2 A 119 HA^ H'vCH' R 1 2.42 431.2 A 258 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method 124 cf3 Yj F^^ R 1 2.22 461.1 A 125 F Yj F^^ R 1 2.06 411.1 A 126 F Yj F^ / H 3 2.01 411.1 A 127 F Yj F^^ H 3 2.01 411.2 A 128 KY R 1 2.00 393.3 A 129 KY H 3 1.96 393.0 A 130 H 3 1.96 393.4 A 131 Á R 1 2.12 429.1 A 132 oz / χΛ^jj R 1 1.91 447.2 A Using a methodology related to that presented in the reaction scheme and table above and 259 which uses (+ / -) 8-(cis-4-hydroxy-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-2,7-dicarbonitrile as coupling partner with appropriately 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 7 Ex- No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z): (M+H)+ Method: 136 Αχ^0Η3 R 1 2.12 414.2 A Using related methodology and employing (+ / -)8(cis-3-ethyl-4-hydroxypiperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile as partner coupling with appropriately 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. 260 TABLE 8 Ex- No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)'. (M+H)+ Method: 137 ch3 ch3 R 3 2.44 431.2 A 138 ch3 H 5 2.48 431.1 A 139 ch3 H 5 2.48 431.1 A 140 Á^ / CF3 R 3 2 .41 457.1 A 141 A^^CF3 XX H 3 2.31 457.3 A 142 / ^y / CF3 XX H 3 2.30 457.2 A 143 / =\ / ch3 ch3 R 1 2.53 431 .1 A 144 j / =\ zch3 ch3 H 3 2.48 431.0 A Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method: 145 / =y / CH3 ch3 H 3 2.48 431.4 A 146 R 1 2.38 457.0 A 147 H 3 2.39 457.3 A 148 |-^J^Cf3 H 3 2.39 457.3 A 149 A / 7 PCH3 ch3 R 1 2.73 459.1 A 150 A # TCH3 ¿h3 H 3 2.73 459.1 A 151 A / 7 TCH3 ch3 H 3 2.74 459.1 A 152 ch3 R 3 2.54 445.1 A 153 U^k^cH3 ch3 H 3 2.61 445.1 A 154 / =\ CH3 M^y^cH3 ch3 H 3 2.62 445.1 A 155 R 3 2.32 429.2 A 156 H 1 2.35 429.2 A 262 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ Method: 157 H 1 2.35 428.9 A 158 aOlH3Ych3 R 1 2.36 460.9 A 159 H 3 2.40 461.1 A 160 H 3 2.39 461.2 A 161 CH3 R 3 2.38 447.1 A 162 / ^^.OC F3 H 3 2.35 472.9 A 163 Z^.OCF3 LJ H 3 2.35 473.3 A Using a methodology related to that presented in the previous table and using (+ / -) 8-(trans3-ethyl-4-hydroxypiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro1, 5- Naphthyridine-2-carbonitrile as a coupling partner with appropriately functionalized phenols in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers was achieved using preparative HPLC techniques as described 263 above. TABLE 9 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)'. (M+H)+ 164 ch3 / S^r^CH3 R 3 2.58 431.1 165 , H3%ch’ R 3 2.54 445.3 166 , hXch3 H 3 2.54 445.0 167 Z Η3ν^ H 3 2.66 445.1 168 R 1 2.37 457.1 Using a methodology related to that presented in the previous table and employing (+ / -) 8-(trans-4hydroxy-3-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-l, 5naphthyridin-2-carbonitrile as a coupling partner with 264 phenols appropriately functionalized in the Mitsunobu reaction, the following examples can be prepared. Isolation of specific enantiomers was achieved using preparative HPLC techniques as described previously. TABLE 10 Ex- No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)\ (M+H)+ 169 ch3 h3cch3 R 1 2.64 444.9 170 Yy ?H3 h3c ch3 H 3 2.62 445.0 171 ?H3 h3c CH3 H 3 2.62 445.2 172 R 1 2.28 446.9 173H 3 2.31 447.1 265 Ex. No. Stereo aril structure. Chemistry LCMS Method LCMS TA (m / z)·. (M+H)+ 174 H 3 2.32 447.1 175 / =\ ch3 γΛ Z^CH3 λ' ch3 R 1 2.52 431.0 176 ch3 R 1 2.40 417.3 177 ch3 H 3 2.43 417.0 178 ch3 H 3 2.43 417.3 179 R 3 2.24 415.0 180 H 1 2.26 415.3 181 H 1 2.26 415.3 182 ^CH3 ch3 R 1 2.43 417.3 183 y=\ / ch3 ch3 H 3 2.46 417.1 184 / CH3 ch3 H 3 2.46 417.3 266 EXAMPLE 185 (+ / -) 5-methyl-8-(cis-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-1,5naphthyridine- 2-carboxamide A suspension of sodium hydride (3.54 mg, 0.074 mmol) and (+ / -) 8-(cis-4-hydroxy-3-methylpiperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l ,5-Naphthyridine-2-carbonitrile (20 mg, 0.067 mmol) in DMF (2 mL) was heated at 80 °C under nitrogen for 15 minutes. Then l-fluoro-4(trifluoromethyl)benzene (9.36 μΐ, 0.074 mmol) was added in a single portion and continued to heat overnight, and the reaction mixture was left at room temperature for 48 h. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 pm 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 for 20 minutes, then 5 minute hold at 100% B; Rate 267 flow: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by UV signals. The fractions containing the product were combined and dried by centrifugal evaporation. The yield of the product was 14.1 mg and its purity estimated by LCMS analysis was 92%. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 91.8%; Observed mass: 317.14; Retention time: 1.12 min. 4H NMR (500 MHz, DMSO-dg) δ 8.21-8.14 (m, 1H), 8.08-8.01 (m, 1H), 7.82-7.74 (m, 1H), 268 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-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine- 2-carbonitrile 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-cyanol-methyl-2-trifluoromethanesulfonate. oxo-l,2-dihydro-l,5-naphthyridin-4-yl (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 to 85 °C overnight. The crude material was purified by preparative LC / MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 pm 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; 269 Gradient: a 0 minute hold at 40% B, 40-80% B for 20 minutes, then 4 minute hold at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was triggered by MS signals. The fractions containing the product were combined and dried by centrifugal evaporation. Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 100.0%; Observed mass: 443.21; Retention time: 2.33 min. A NMR (500 MHz, DMSO-d6) δ 8.20-8.11 (m, 1H), 270 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 used. The racemic product was further fractionated using SEC chiral chromatography. The following two enantiomers were obtained and characterized. EXAMPLE 187 5-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidinl-yl)-6-ΟΧΟ-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (rei) Analytical LC / MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, then a 0.50 min hold at 100% B; Flow: 1 mL / min; Detection: MS and UV (220 nm). Injection 1 results: 271 Purity: 97.5%; Observed mass: 442.84; Retention time: 2.25 min. Injection conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 qm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 99.4%; Observed mass: 443.07; Retention time: 2.25 min. NMR (500 MHz, DMSO-d6) 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 used. EXAMPLE 188 5-methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidinl-yl)-6-OXO-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (rei) Analytical LC / MS was used to determine purity 272 end. Injection Conditions 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 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 conditions 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm 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 for 3 min, followed by a 0.50 min hold at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm). Injection 2 Results: Purity: 98.6%; Observed mass: 443.07; Retention time: 2.25 min. NMR (500 MHz, DMSO-d6) 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), .06-0.92 (m, 3H). The full spectrum was not assigned due to the water suppression t...

Claims

1. A compound of Formula (I): or a salt thereof, characterized in that: X is CR6, or N; Y is CR3, or N; L is -O-, -S-, -S(O)2-, -NR4c-, or -NR4dC(O)-; Ri is H, F, Cl, Br, -CN, zero-substituted C4-3 alkyl at 4 Ria, zero-substituted C3-4 cycloalkyl at 4 Ria, zero-substituted Ci-3 alkoxy at 4 R2a, -C(O)NRaRa, -NRaRa, S(O)nRe, or -P(O)ReRe; each R4a is independently F, Cl, -CN, -OH, OCH3, or -NRaRa; each Ra is independently H or Ci-3 alkyl; each Re is independently C3-4 cycloalkyl or zero-substituted C4-3 alkyl at 4 Rla; R2 is H, Ci-3 alkyl zero-substituted to 4 R2a, C2-3 alkenyl zero-substituted to 4 R2a, or C3-4 cycloalkyl 529 zero-substituted to 4 R2a; each R2a is independently F, Cl, -CN, -OH, O (Ci-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl; R3 is H, F, Cl, Br, -CN, C1-3 alkyl, Ci-2 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, -NO2, or pyridinyl zero-substituted to 2 R3a;each R3a is halo, -CN, C1-3 alkyl, or Ci-3 alkoxy; R4 is R4s, -CH2R4a, or -CH2CH2R4a; R4a is C3-6 cycloalkyl, C5-14 heterocyclyl, Cg-io aryl, or C5-14 heteroaryl, each substituted by zero to 4 R4bZ each R4b is independently F, Cl, Br, -CN, -OH, C4-g alkyl, C1-3 fluoroalkyl, C4-4 hydroxyalkyl, -(CH2)i2O (C1-3 alkyl), Ci-4 alkoxy, -O (C4-4 hydroxyalkyl), -O(CH)i3O (C1-3 alkyl), Ci-3 fluoroalkoxy, -O (CH) i-3NRaRc, -OCH2CH=CH2, -OCH2C=CH, -C (O) (C1-4 alkyl), -C (O) OH, -C (O) O (C1-4 alkyl), -C(O)NH2, -c (O) NH (C4-4 alkyl) , -C (O) N (C4-4 alkyl)2, -NRCRC, -NRaS (O) 2 (C4-3 alkyl) , -NRaC(O) (C4-3 alkyl) , NRaC(O)O(C4-4 alkyl), -P (O) (C3-3 alkyl)2, -S (O) 2 (C3 alkyl), -O (CH2) 1-2 (C3-6 cycloalkyl) , -O (CH2) i-2 (morpholinyl) , C3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CRcRc (phenyl);each Rc is independently H or Ci-2 alkyl; 530 R4c is H, Ci-g alkyl, or R4a; R4d is H or ciscada alkyl. R5 is independently F, Cl, -CN, -OH, Ci-g alkyl substituted by zero at 4 Rg, C1-3 alkoxyl substituted by zero at 4 Rg, C2-4 alkenyl substituted by zero at 4 Rg, C2-4 alkynyl substituted by zero at 4 Rg, -(CH2)i2 (cycloalkyl!) 1-2 (C3-4 cycloalkyl substituted by zero at 4 Rg), phenyl substituted by zero at 4 Rg, oxadiazolyl substituted by zero at 3 Rg, pyridinyl substituted by zero at 4 Rg, -(CH2)i-2 (heterocyclyl substituted by zero at 4 Rg), (CH2)i-2NRcC(O) (C1-4 alkyl), -(CH2)4-2NRcC(O)O (C1-4 alkyl), O (CH2) 1-2 (heterocyclyl zero substituted to 4 Rg) , -(CH2)i2NRCS (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 =0;each Rg is independently F, Cl, -CN, -OH, Ci-3 alkoxy, Ci-3 fluoroalkoxy, -0 (CH2) i-20 (C2-2 alkyl), C3-3 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; yn is zero, 1, or 2.; 2. The compound according to claim 1 or a salt thereof, characterized in that: Ri is H, F, Cl, Br, -CN, zero to 4 substituted C1-3 alkyl Ria, zero to 3 substituted cyclopropyl R4a, zero to 3 substituted C1-3 alkoxy Ria, -C(O)NRaRa, -NRaRa, -S(O)nCH3, or -P(O)(CH3)2; each Ria is independently F, Cl, or -CN; each Ra is independently H or Ci-3 alkyl; R2 is H, zero to 2 substituted Ci-2 alkyl R2a, or zero to 2 substituted C2-3 alkenyl 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, Ci-2 alkyl, Ci-2 fluoroalkyl, C3-4 cycloalkyl, -NO2, or zero-substituted pyridinyl to 1 R3a;R4a is C3-g cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxazolyl, triazolyl, tridolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1], each with a certain substituent a 3 R4b; 532 each R4b is independently F, Cl, Br, -CN, -OH, alkyl Ci-g, fluoroalkyl C4-2, hydroxyalkyl C1-3, -(CH2)i~ 2O(alkyl C1-3) , alkoxy C4-4, -O (hydroxyalkyl C1-3) C1-3) , fluoroalkoxy C1-2, -O (CH) 1_2NRCRC, C (O) (alkyl C4-3) , -C(O)OH, -C (O) O (alkyl C1-3) , -C(O)NH2, C (O) NH (alkyl C1-3) , -C(O)(O) NH (O) 2 (alkyl C1-2) , cycloalkyl C3-6, o -CRcRc (phenyl) ;R4c is H, C4-4 alkyl, or R4a; R4d is H or Οί-4 alkyl; each R5 is independently F, -CN, -OH, C1-5 alkyl substituted by zero at 4 Rg, C1-3 alkoxyl substituted by zero at 3 Rg, C2-3 alkenyl substituted by zero at 4 Rg, C2-3 alkynyl substituted by zero at 4 Rg, -(CH2)i2 (C3_4 cycloalkyl substituted by zero at 4 Rg), phenyl substituted by zero at 3 Rg, oxadiazolyl substituted by zero at 3 Rg, pyridinyl substituted by zero at 3 Rg, -(CH2)i2 (heterocyclyl substituted by zero at Rg), -O(CH2)i2 (heterocyclyl substituted by zero at 4 Rg), -(CH2)i2NRcC (O) (C4_4 alkyl), - (CH2) i-2NRcC (O) O (alkyl C4-4) , -(CH2)i2NRCS (O) 2 (C4-4 alkyl), -C (O) (C4_4 alkyl) , -C(O)OH, C (O) O (C4-4 alkyl) , -C (O) O (C3-4 cycloalkyl) , -C(O)NRaRa, or C (O) NRa (C3-4 cycloalkyl); and each Rg is H, F, or -CH3.; 3. The compound according to any of claims 1-2 or a salt thereof characterized in that: X is CH and Y is CR3; X is N and Y is CR3; or X is N and Y is N; L is -O-, -NH-, -N(CH3)-, or -N(CH3)C(O)-; Ri 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-naphthiridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each substituted by 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, -CH2 (phenyl), C(CH3)2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl;each R3 is independently hydrogen, F, -OH, C4_2 alkyl, Ci-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N (CH3) 2, —OCH2(cyclopropyl), or -OCH2CH2 (morpholinyl) ; and each Rg is H. 534; 4. The compound according to any of claims 1-3 or a salt thereof, characterized in that: X is N; and Y is CR3.

5. The compound according to any of claims 1-3 or a salt thereof, characterized in that: X is CRg; and Y is CR3.

6. The compound according to any of claims 1-3 or a salt thereof, characterized in that: X is N; and Y is N.

7. The compound according to any of claims 1-6 or a salt thereof, characterized in that L is -O-.

8. The compound according to any of claims 1-6 or a salt thereof, characterized in that L is -NR4C-.

9. The compound according to any of claims 1-6 or a salt thereof, characterized in that L is -NR4dC(O)-.

10. The compound according to claims 1-6 or a salt thereof, characterized in that it has a structure selected from: R4 and R4 11. The composition of compliance with the indication 1 or a similar salt, characterized by being 6-fluoro-4-(4-(3-flúoro-5-methylfenoxi)piperidin-l-il)-l-methyl-3-nitroquinolin-2(1H)-ona (1) ; 6-fluoro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1methyl-3-nitroquinolin-2(1H)-one (2); 6-fluoro-l-methyl-3-nitro-4- (4- (4(trifluoromethoxy)phenoxy)piperidin-l-yl)quinolin-2(1H)-ona (3) ; 6-fluoro-l-methyl-3-nitro-4-(4-(mtolyloxy)piperidin-l-yl)quinolin-2(1H)-one (4); 4- (4 - ( (lH-indazol-4-yl)oxi)piperidin-l-yl)-6- fluoro-l-methyl-3-nitroquinolin-2(1H)-one (5); 3-((1-(6-fluoro-l-methyl-3-nitro-2-oxo-l,2dihydroquinolin-4-yl)piperidin-4-yl)oxi)benzonitrile (6); 4-(4-(3-chlorophenoxy)piperidin-l-yl)-6-fluoro-l-methyl-3-nitroquinolin-2(1H)-one (7); 536 6-fluoro-4-(4-(2-methoxy-5(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methy1-3nitroquinolin-2(1H)-one (8); 6-fluoro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1methyl-3-nitroquinolin-2(1H)-one (9);6-Chloro-4-(4-(3-methoxyphenoxy)piperidin-l-yl)-1methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrile (10); 6-Chloro-l-methyl-2-oxo-4-(4-(2(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5-naphthyridine-3-carbonitrile (11); 6-Chloro-4-(4-(3,4-difluorophenoxy)piperidin-l-yl)-1methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrile (12); 6-chloro-1-methyl-2-oxo-4-(4-(3(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrilo (13); 6-chloro-4-(4-(4-methoxyfenoxy)piperidin-1-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrilo (14); 4-(4-(4-(terc-butyl)phenoxy)piperidin-1-yl)-6-chlorol-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrilo (15) ; 6-Chloro-4-(4-(4-chlorophenoxy)piperidin-l-yl)-1-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (16); 6-Chloro-4-(4-(3-fluoro-4(trifluorornethoxy)phenoxy)piperidin-l-yl)-1-methyl-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrilo (17);537 6-chloro-4-(4-(2-chlorophenoxy)piperidin-l-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (18) ; 6-chloro-l-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrile (19); 6-chloro-4-(4-(4-fluorophenoxy)piperidin-l-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20); 6-chloro-l-methyl-2-oxo-4-(4-(p-tolyloxy)piperidin-lyl) — 1,2-dihydro-l,5-naphthyridine-3-carbonitrile (21); 6-chloro-l-methyl-2-oxo-4-(4-(m-tolyloxy)piperidin-lyl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (22); 6-chloro-4-(4-(2-chloro-5-fluorophenoxy)piperidin-lyl)-l-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (23) ; 6-chloro-l-methyl-2-oxo-4-(4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrile (24); 4-((1-(6-chloro-3-cyano-l-methyl-2-oxo-1,2-dihydro1,5-naphthyridin-4-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide (25) ;4-(4-(4-bromo-2-methylphenoxy)piperidin-l-yl)-6chloro-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (26); 6-chloro-4-(4-(3-chlorophenoxy)piperidin-l-yl)-1methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (27); 538 6-chloro-4-(4-(3-chloro-5-fluorophenoxy)piperidin-lyl)-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (28); 6-chloro-1-methyl-4-(4-(2-methyl-4(trifluoromethoxy)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro1,5-naphthyridine-3-carbonitrilo (29); 6-chloro-1-methyl-2-oxo-4-(4-(4(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrilo (30); 4-(4-(4-(tero-butoxy)phenoxy)piperidin-1-yl)-6chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3carbonitrilo (31); 6-Chloro-4-(4-(4-cyanophenoxy)piperidin-l-yl)-1methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (32); 6-Chloro-l-methyl-2-oxo-4-(4-(2(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,2-dihydro-l,5-naphthyridine-3-carbonitrilo (33);6-chloro-4-(4-(3-cyanophenoxy)piperidin-1-yl)-1methyl-2-oxo-1, 2-dihydro-1,5-naphthyridine-3-carbonitrilo (34); 6-chloro-4-(4-(2-methoxyfenoxy)piperidin-1-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrilo (35) ; 6-chloro-4-(4-(4-fluoro-2-methoxyfenoxy)piperidin-lyl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrilo (36) ; 6-Chloro-4-(4-(4-isopropylphenoxy)piperidin-l-yl)-1 539 methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (37) ; 6-Chloro-4-(4-(3-chloro-4-cyanophenoxy)piperidin-lyl)-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (38) ; 6-Chloro-4-(4-(4-chloro-3-methoxyphenoxy)piperidin-lyl)-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (39) ; 6-chloro-4-(4-(3-chloro-4-methylphenoxy)piperidin-lyl)-l-methyl-2-oxo-l,2-dihydro-l,5-naphthyridine-3-carbonitrilo (40); 6-chloro-4-(4-(2-chloro-4(trifluoromethoxy)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l, 2dihydro-1,5-naphthyridine-3-carbonitrilo (41);6-chloro-4- (4-(3-chloro-4(trifluoromethoxy)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-1,2dihydro-1,5-naphthyridine-3-carbonitrile (42); 6-chloro-4-(4-(2-cyanophenoxy)piperidin-l-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (43) ; 6-chloro-4-(4-(2-fluorophenoxy)piperidin-l-yl)-1methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (44); 6-chloro-4-(4-(3-fluorophenoxy)piperidin-l-yl)-1methyl-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-(4540 (trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrile (47); 6-methoxy-1-methyl-2-oxo-4-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5naphthyridine-3-carbonitrile (48); 1-methyl-2,6-dioxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2,5,6-tetrahydro1,5-naphthyridine-3-carbonitrile (49);5-methyl-6-OXO-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthyridine-2,7-dicarbonitrile (50); 5-methyl-7-nitro-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthyridine-2-carbonitrile (51); 5-methyl-6-OXO-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthyridine-2-carbonitrile (52); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-1-methyl2-oxo-1,2-dihydroquinoline-6-carbonitrile (53); 5-methyl-6-OXO-8-(4-(4-(terpenyl)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 541 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-methyl6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (58);8 - (4 - (4-cyclopropylphenoxy)piperidin-l-yl)-5-methylδ-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (59) ; 8-(4-(4-isopropyl-3-methylphenoxy)piperidin-l-yl)-5methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (60); 5-methyl-6-OXO-8-(4-((5,6,7,8-tetrahydronaphthalen-2yl)oxy)piperidin-l-yl)-5,6-dihydro-l,5-naphthyridine-2carbonitrile (61); 5-methyl-6-oxo-8-(4-(4-pentylphenoxy)piperidin-l-yl)5, 6-dihydro-l, 5-naphthyridine-2-carbonitrile (62); 8-(4-(4-cyclohexylphenoxy)piperidin-1-yl)-5-methyl-6oxo-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)-5methyl-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)-5 542 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-2carbonitrile (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-lyl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70) ; 5-methyl-6-oxo-8-(4-(quinazolin-4-yloxy)piperidin-lyl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71); 5-methyl-8-(4 -( (2-methylpyrimidin-4-yl)oxy)piperidinl-yl)-6-ΟΧΟ-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (72) ; 8-(4-((7-chloro-4-methoxyquinolin-2-yl)oxy)piperidinl-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (73); 8 - (4 - ( (1,7-naphthyridin-8-yl)oxy)piperidin-1-yl)-5methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-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-4yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (78); (+ / -)6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridine-2(1H)one (7 9); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridine-2(1H)one (80); 6-cyano-l-methyl-4-((3R,4R)-3-methyl-4-(4(trifluoromethoxy)phenoxy)piperidin-l-yl)-1,5-naphthyridin-2(1H)one (81); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tertpentyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (82-84);8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (85-87); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (88-90); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (91-93); 544 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (94-96); 5-methyl-8-((3R,4R)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (97-99); 8-((3R,4R)-4-(4-cyclopentylphenoxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (100-102); 8-((3R,4R)-4-(3,4-difluorophenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (103-105); 8-((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (106);5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107109) ; 8-((3R, 4R)-4-(4-ethylphenoxy)-3-methylpiperidin-l-yl)5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110); 8-((3R,4R)-4-(4-cyclopropylphenoxy)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (111) ; 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3 545 methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((3R,4R)-4-(2,4-difluorophenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (113-115); 8-((3R,4R)-4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3methylpiperidin-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-yl)-6-OXO-5,6-dihydro-l,5-naphthyridine-2-carbonitrile (119121) ; 8-((3R,4R)-4-(3-isopropylphenoxy)-3-methylpiperidin-yl)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2carbonitrile (122);8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (123); 8-((3R,4R)-4-(2-fluoro-6-(trifluoromethyl)phenoxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (125-127); 8-((3R, 4R)-4-(4-fluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile 546 (128-130); 5-methyl-8-((3R, 4R)-3-methyl-4-(2,4,6trifluorophenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (131); 8-((3R, 4R)-4-((3,4-dihydro-2Hbenzo[bj [1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-1-yl)-5methyl-6-oxo-5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (132); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidinl-yl)-6-OXO-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (136);8-((3R,4R)-3-etil-4-(3-isopropylfenoxi)piperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5-naftiridina-2-carbonitrilo (137-139); 8-((3R,4R)-3-etil-4-(3(trifluorometil)fenoxi)piperidin-l-il)-5-metil-6-oxo-5,6dihidro-1,5-naftiridina-2-carbonitrilo (140-142); 8-((3R,4R)-3-etil-4-(4-isopropylfenoxi)piperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5-naftiridina-2-carbonitrilo (143-145); 8-((3R,4R)-3-etil-4-(4(trifluorometil)fenoxi)piperidin-l-il)-5-metil-6-oxo-5,6dihidro-1,5-naftiridina-2-carbonitrilo (146-148); 8-((3R,4R)-3-etil-4-(4-(tercpentil)fenoxi)piperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (149-151); 547 8-((3R,4R)-4-(4-(terc-butil)fenoxi)-3etilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (152-154); 8-((3R,4R)-4-(3-ciclopropylfenoxi)-3-etilpiperidin1-il)-5-metil-6-oxo-5,6-dihidro-l,5-naftiridina-2carbonitrilo (155-157);8-((3R,4R)-4-(4-(terc-butoxi)fenoxi)-3etilpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (158-160); 8-((3R,4R)-3-etil-4-(4-isopropoxifenoxi)piperidinl-il)-5-metil-6-oxo-5,6-dihidro-l,5-naftiridina-2-carbonitrilo (161); 8-((3R,4R)-3-etil-4-(3(trifluorometoxi)fenoxi)piperidin-l-il)-5-metil-6-oxo-5,6dihidro-1,5-naftiridina-2-carbonitrilo (162-163); 8-((3R,4S)-3-etil-4-(3-isopropylfenoxi)piperidin-lil)-5-metil-6-oxo-5,6-dihidro-l,5-naftiridina-2-carbonitrilo (164); 8-((3R,4S)-4-(3-(terc-butil)fenoxi)-3etilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (165-167); 5-meti1-8-((3R,4S)-3-metil-4-(4-(tercpentil)fenoxi)piperidin-l-il)-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (169-171); 8-((3R,4S)-4-(4-(terc-butoxi)fenoxi)-3 548 metilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (172-174); 8-((3R,4S)-4-(4-(terc-butyl)fenoxi)-3methylpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (175);8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin1-yl)-5-methyl-δ-χο-5,6-dihydro-l,5-naphthyridine-2carbonitrile (176-178); 8-((3R,4S)-4-(3-cyclopropylphenoxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (179-181); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin1-yl)-5-methyl-6-oxo-5,6-dihydro-l,5naphthyridine-2carbonitrile (182-184); ( + / -) 5-methyl-8-((3R,4S)-3-methyl-4- (4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2-carboxamide (185); ( + / -) 5-methyl-8-((3R,4S)-3-methyl-4- (4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2-carbonitrile (186); 5-methyl-8-((3R,4S)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (187); 5-methyl-8-((3R,4S)-3-methyl-4-(4(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5 549 naphthyridine-2-carbonitrile (188);5-meti1-8-((3R,4S)-3-methyl-4-(4(trifluorometil)fenoxy)piperidin-l-il)-6-oxo-5,6-dihidro-l,5naftiridina-2,7-dicarbonitrilo (189-191); 8-((3R,4R)-3-etil-4-((5-isopropoxipiridin-2il)oxi)piperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (192-194); 8-((3R,4R)-3-etil-4-(4-fluoro-3propilfenoxi)piperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (195); 8-((3R,4R)-4-(3-(terc-butil)fenoxi)-3etilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (196-198); 8-((3R,4R)-4-((5-isopropoxipiridin-2-il)oxi)-3methylpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (199-201); 8-((3R,4S)-3-etil-4-((5-isopropoxipiridin-2-il)oxi)piperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (202-204); 8-((3R,4S)-4-((5-isopropilpiridin-2-il)oxi)-3methylpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (205-207);8-((3R,4S)-4-((5-(difluorometil)piridin-2-il)oxi)3-methylpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (208-210); 550 8-((3R,4S)-4-((4-isopropilpiridin-2-il)oxi)-3metilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (211-213); 8-((3R,4S)-4-((6-isopropilpiridin-2-il)oxi)-3methylpiperidin-l-il)-5-methyl-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (214-216); 5-methyl-8-((3R,4S)-3-metil-4-(pirimidin-2iloxi)piperidin-l-il)-6-oxo-5,6-dihidro-l,5-naftiridina-2carbonitrilo (217); 8-((3R,4S)-4-((4-metoxipirimidin-2-il)oxi)-3metilpiperidin-l-il)-5-metil-6-oxo-5,6-dihidro-l,5naftiridina-2-carbonitrilo (218); 5-metil-8-((3R,4S)-3-metil-4-((5-propylpirimidin-2il)oxi)piperidin-l-il)-6-oxo-5,6-dihidro-l,5-naftiridina-2carbonitrilo (219); 5-methyl-8-((3R,4S)-3-methyl-4-((2-methylpirimidin-4il)oxi)piperidin-l-il)-6-oxo-5,6-dihidro-l,5-naftiridina-2carbonitrilo (220);8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (221) ; 5-methyl-8-((3R,4S)-3-methyl-4-( (5(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (222) ; 8-((3R,4S)-4-((5-cyclopropylpyrimidin-2-yl)oxy)-3 551 methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (223) ; 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (224); 5-methyl-8-((3R,4S)-3-methyl-4-( (5(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6dihydro-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-1,5naphthyridine-2-carbonitrile (228); (+ / -) 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tertpentyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-l,5naphthyridine-2,7-dicarbonitrile (229);5-methyl-8-((3R,4R)-3-methyl-4-(4-(terpenyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2,7-dicarbonitrile (230); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(terpenyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-2,7-dicarbonitrile (231); (+ / -)8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (232); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5552 naphthyridine-2-carbonitrile (233); 8-(4-( (5-isopropoxypyridin-2-yl)oxy)-3,3dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (234); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (235); (+ / -)5-methyl-8-((3R,4S)-3-methyl-4-((4(trifluoromethoxy)benzyl)oxy)piperidin-l-yl)-6-oxo-5,6dihydro-1,5-naphthyridine-2-carboxamide (236);7-fluoro-5-metil-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthiridina-2-carbonitrile (237); 7-chloro-5-metil-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthiridina-2-carbonitrile (238); 7-bromo-5-metil-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthiridina-2-carbonitrile (239); 7-(6-methoxypyridin-3-yl)-5-methyl-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthyridin-2-carbonitrile (240); 7-(2-methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5naphthyridin-2-carbonitrile (241); 553 (+ / -) 6-bromo-1-methyl-4-((3R,4R)-3-methyl-4-(4(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5naphthyridin-3-carbonitrile (242); 8-( (2S,5S)-4-( (5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-l-yl)-5-metil-6-oxo-5,6-dihydro-l,5naphthiridina-2-carbonitrilo (243 y 246);8-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2dihydropyrido[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-1,2dihydropyrido[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-1,2dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 8-((2S,5S)-2,5-dimethyl-4-(3554 (trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (255 y 258);(±)-trans-8-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridin-2-carbonitrile (259-260); (±)-trans-8-(3-methoxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridin-2-carbonitrile (261-262); 8-((3R,4R)-3-ethoxy-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridin-2-carbonitrile (263-264); (±)-cis-8-(3-fluoro-4-(3(trifluorometil)phenoxy)piperidin-1-yl)-5-metil-6-oxo-5,6dihydro-1,5-naphthiridina-2-carbonitrilo (265-266); (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2yl)oxi)piperidin-l-yl)-5-metil-6-oxo-5,6-dihydro-l,5naphthiridina-2-carbonitrilo (267-268); ( + )-trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3methoxypiperidin-l-yl)-5-metil-6-oxo-5,6-dihydro-l,5naphthiridina-2-carbonitrile (269-270); (±)-trans-6-chloro-4-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2d]pyrimidin-2(1H)-one (271—272);(±)-trans-4-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2 555 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[3,2d]pyrimidin-2(1H)-one (275); (±)-trans-4-(3-hydroxy-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2dihydropyrido[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-((2S,5R)-4-((5-methoxypyridin-2-yl)amino)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (280-281); N-((2S,5R)-1-(6-cyano-l-methyl-2-oxo-1,2-dihydro1,5-naphthyridin-4-yl)-2,5-dimethylpiperidin-4-yl)-4-fluoro-Nmethylbenzamide (282-283) N-(1-(6-cyano-l-methyl-2-oxo-1,2-dihydro-1,5naphthyridin-4-yl)-3-methylpiperidin-4-yl)-4-fluoro-Nmethylbenzamide (284-287);N-(1-(3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5naphthyridin-4-yl)-3-methylpiperidin-4-yl)-N-methyl-4(trifluoromethyl)benzamide (288-293). 8-((2S,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (294); 556 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (295); 8-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (296); 8-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (297); 8-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (298); 8-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (299);6-chloro-4-((2S,4R,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1methylpyrido[3,2-d]pyrimidin-2(1H)-ona (300); 4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxi)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2dihydropyrido[3,2-d]pyrimidine-6-carbonitrilo (301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1methylpyrido[3,2-d]pyrimidin-2(1H)-ona (302); 4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2 557 yl)oxi)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2dihydropyrido[3,2-d]pyrimidine-6-carbonitrilo (303); 6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5isopropoxypyridin-2-yl)oxi)-2-methylpiperidin-l-yl)-1methylpyrido[3,2-d]pyrimidin-2(1H)-one (3 04); 4-((2R, 4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxi)-2-methylpiperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine-6-carbonitrilo (305); 6-chloro-4-((2S,4S,5R)-5-ethyl-4-( (5isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-l-yl)-1methylpyrido[3,2-d]pyrimidin-2 (1H)-one (30 6);4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2dihydropyrido[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-5,6dihydro-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-5,6dihydro-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-5,6dihydro-1,5-naphthyridina-2-carbonitrile (310); 8-((2R,4S,5R)-2,5-dimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6 558 dihydro-1,5-naphthyridina-2-carbonitrile (311); 8-((2S,4R,5S)-2,5-dimethyl-4-(p-tolyloxy)piperidin-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2carbonitrile (312); 8-((2S,4R,5S)-4-(3-chlorophenoxy)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridina-2-carbonitrile (313);8-((2S,4R,5S)-4-(3-cyanophenoxy)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (314); 8-((2S,4R,5S)-4-(4-fluorophenoxy)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (315); 8-((2S,5S)-2,5-dimethyl-4-( (4(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316A); 8-(2,5)-dimethyl-4-(methyl(4(trifluoromethyl)phenyl)amino)piperidin-l-yl)-5-methyl-6-oxo5, 6-dihydro-l, 5-naphthyridine-2-carbonitrile (316-319); 8-((2S,5S)-2,5-dimethyl-4-(methyl(3(trifluoromethyl)phenyl)amino)piperidin-l-yl)-5-methyl-6-oxo5, 6-dihydro-1,5-naphthyridine-2-carbonitrile (320-321) ; 8-(4-( (4-fluorobenzyl) (methyl)amino)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2,7-dicarbonitrile (322-325); 559 8-(4-((4-fluorobenzyl) (methyl)amino)-3methylpiperidin-l-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (326-328);8-(4-((4,4-difluorocyclohexyl) (methyl)amino)-3methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2,7-dicarbonitrile (329-330); 8-((2S,5R)-4-((4-fluorobenzyl) (methyl)amino)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (331-332); 8-((2S,5S)-4-((4-fluorobenzyl) (methyl)amino)-2,5dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (333-334); 8-( (2S,5S)-4-( (5-Isopropoxypyridin-2-yl)oxy)-2,4,5trimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-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-1,5naphthyridine-2-carbonitrile (337-338); 1-methyl-2-oxo-4-((2S,5S)-2,4,5-trimethyl-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydropyrido[3,2d]pyrimidine-6-carbonitrile (339-340); trans-8-(3-ethoxy-4-phenoxypiperidin-l-yl)-5-methyl-6oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (341-342);8-((3S,4S)-3-ethoxy-4- (4(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6 560 dihydro-1,5-naphthyridin-2-carbonitrile (343-344); 8-((3S,4S)-3-ethoxy-4- (2(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridin-2-carbonitrile (345-346); 8-((3S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidinl-yl) -5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-2carbonitrile (347-348); 8-((3S,4S)-3-ethoxy-4-(4(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-metil-6-oxo-5,6dihydro-1,5-naphthiridina-2-carbonitrile (349-350); 8-((3S,4S)-3-ethoxy-4-(3(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-metil-6-oxo-5,6dihydro-1,5-naphthiridina-2-carbonitrilo (351-352); 8-((3S,4S)-3-ethoxy-4-(4(methylsulfonyl)phenoxy)piperidin-1-yl)-5-metil-6-oxo-5,6dihydro-1,5-naphthiridina-2-carbonitrile (353-354); 8-( (3S,4S)-3-ethoxy-4-( (2-metilbenzo[d]oxazol-5yl)oxi)piperidin-l-yl)-5-metil-6-oxo-5,6-dihydro-l,5naphthiridina-2-carbonitrilo (355-356);8-((3S,4S)-4-(4-chloro-3-fluorophenoxy)-3ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (357-358); 8-((3S,4S)-3-ethoxy-4-((2-(trifluoromethyl)pyridin-4yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (359-362); 561 trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (363-364); 8-((3S,4S)-3-ethoxy-4-((4-(trifluoromethyl)pyridin-2yl)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-2yl)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-5,6dihydro-1,5-naphthyridine-2-carbonitrile (369-370); cis-8-(3-ethoxy-4-((5-isopropoxypyridin-2yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (371-372);trans-8-^-(benzo[d]thiazol-2-yloxy)-3ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (373-374); 8-((3S,4S)-3-ethoxy-4-( (6-isopropoxypyridazin-3yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (375-376); 8-( (3S,4S)-3-ethoxy-4-( (5-isopropoxypyrazin-2yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (377-378); 8-( (3S,4S)-3-ethoxy-4-( (5-isopropoxypyrimidin-2 562 yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (379-380); 8-((3S,4S)-3-ethoxy-4-( (3(trifluoromethyl)benzyl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridin-2-carbonitrile (381-382); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyridin-2yl)methoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridin-2-carbonitrile (383-384); 8-((3R,4R)-3-(2-(dimethylamino)ethoxy)-4-(3(trifluorometil)phenoxy)piperidin-l-yl)-5-metil-6-oxo-5,6dihydro-1,5-naphthiridina-2-carbonitrilo (385-386);8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (387-388); 8-((3R,4R)-3-(2-methoxyethoxy)-4- (3(trifluoromethyl)phenoxy)piperidin-l-yl)-5-methyl-6-oxo-5,6dihydro-1,5-naphthyridine-2-carbonitrile (389-390); 5-methyl-8-((3R,4R)-3-(2-morpholinoethoxy)-4- (3(trifluoromethyl)phenoxy)piperidin-l-yl)-6-oxo-5,6-dihydro-1,5naphthyridine-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-1,5naphthyridine-2-carbonitrile (393-394); trans-8-(3-isopropoxy-4-(3(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6563 dihydro-1,5-naphthyridine-2-carbonitrile (395-396); trans-Q-(4-((5-isopropoxypyridin-2-yl)oxy)-3ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5naphthyridine-2-carbonitrile (397-398); (±)-trans-6-chloro-4-(3-ethoxy-4-((5isopropoxypyridin-2-yl)oxy)piperidin-l-yl)-1-methylpyrido[3,2— d]pyrimidin-2(1H)-one (399);trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2yl)oxy)piperidin-l-yl)-1-methyl1-2-oxo-1,2-dihydropyrido[3,2— d]pyrimidine-6-carbonitrile (400-401); trans-4-(3-ethoxy-4-phenoxypiperidin-l-yl)-l-methyl-2oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (402403); or 4-((3S,4S)-3-ethoxy-4- (4(trifluoromethyl)phenoxy)piperidin-l-yl)-l-methyl-2-oxo-l,2dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (404-405).; 12. A pharmaceutical composition, characterized in that it comprises the compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

13. The use of a compound according to any of claims 1-11, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or viral infections. 564 14. Use in accordance with claim 13, wherein the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

15. The use of a compound according to any of claims 1-11 or a pharmaceutically acceptable salt thereof, to inhibit the activity of at least one of the diacylglycerol kinases selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (ϋ6Kζ).