Substituted Bicyclic Compounds Useful as T Cell Activators

Abstract

Substituted Bicyclic Compounds Useful as T Cell Activators Formula (I): Disclosed is a compound of formula TIFF2023508052000315.tif45153 (wherein X is CR6 or N; Y is CR3 or N; and R1, R2, R4, R5, R6, R7, and m are defined herein), or a salt thereof. Also disclosed is a method of using the compound, and a pharmaceutical composition comprising the compound, for inhibiting the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ). These compounds are useful in the treatment of viral infections and proliferative diseases (e.g., cancer).

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to Indian Provisional Application No. 201911053552, filed December 23, 2019, which is incorporated herein by reference in its entirety.

[0002] Description of the Invention The present invention generally relates to substituted bicyclic compounds that activate T cells, promote T cell proliferation, and / or exhibit anti-tumor activity. Provided herein are substituted bicyclic compounds, compositions containing the compounds, and methods of using them. The present invention further relates to pharmaceutical compositions containing at least one compound of the present invention that are useful for treating proliferative diseases (e.g., cancer) and viral infections. [Background technology]

[0003] Human cancers contain numerous genetic and epigenetic alterations, producing neoantigens that can potentially be recognized by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has the potential to exert potent anticancer effects, possessing broad capabilities and high specificity to respond to diverse tumor antigens. Furthermore, this immune system possesses considerable plasticity and memory components. Harnessing all these properties of the adaptive immune system makes immunotherapy unique among all cancer treatment approaches. However, although endogenous immune responses to cancer have been observed in preclinical models and patients, these responses are ineffective, and established cancers are considered "self" and tolerated by the immune system. This tolerance allows tumors to actively subvert antitumor immunity using multiple distinct mechanisms. These mechanisms include dysfunctional T cell signaling (Mizoguchi et al., (1992) Science 258:1795-98), suppressive regulatory cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and the utilization of endogenous "immune checkpoints," which act to reduce the strength of the adaptive immune response and protect normal tissues from collateral tumor damage, allowing them to escape immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-489).

[0004] Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby halting T cell function via the TCR signaling pathway. Therefore, DGK functions as an intracellular checkpoint, and its inhibition is expected to promote T cell signaling and activation. Supporting evidence is that mouse models lacking either DGKα or DGKζ exhibit hyperreactive T cell phenotypes and improved antitumor immune activity (Riese MJ et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock BA et al., (2006) 11: 1174-81). Furthermore, tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients have been shown to overexpress DGKα and inhibit T cell function (Prinz, PU et al., J Immunology (2012) 12:5990-6000). Therefore, DGKα and DGKζ are considered as targets for cancer immunotherapy (Riese MJ et al., Front Cell Dev Biol. (2016) 4: 108; Chen, SS et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686).

[0005] There is a need for compounds useful as inhibitors of DGKα and / or DGKζ. Additionally, there is a need for compounds useful as inhibitors of DGKα and / or DGKζ that have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases.

[0006] Therefore, safe and effective agents to restore T cell activity, lower the antigen threshold, enhance antitumor function, and / or overcome the suppressive effects of one or more endogenous immune checkpoints (e.g., PD-1, LAG-3, and TGFβ) would be an important addition to the treatment of patients with proliferative diseases (e.g., cancer), as well as viral infections. Summary of the Invention

[0007] Applicant has discovered compounds that have inhibitory activity against one or both of DGKα and DGKζ. Furthermore, Applicant has discovered compounds that have inhibitory activity against one or both of DGKα and DGKζ and that have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases. These compounds provide useful pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values ​​important for their druggability.

[0008] The present invention provides substituted bicyclic compounds of formula (I), including salts and prodrugs thereof, that are useful as inhibitors of DGKα, DGKζ, or both DGKα and DGKζ.

[0009] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The present invention also provides a method for treating a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ, which method comprises administering to a mammalian patient a compound of formula (I) and / or a pharmaceutically acceptable salt thereof.

[0011] The present invention also provides procedures and intermediates for preparing compounds of formula (I) and / or salts thereof.

[0012] The present invention also provides compounds of formula (I) and / or pharmaceutically acceptable salts thereof for use in therapy.

[0013] The present invention also provides the use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of proliferative diseases (e.g., cancer) and viral infections.

[0014] 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 diseases (e.g., cancer). Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or inhibiting the progression of diseases or disorders in various therapeutic areas (e.g., viral infections and cancer). These and other features of the present invention are set forth in the broader disclosure that follows. DETAILED DESCRIPTION OF THE INVENTION

[0015] A first aspect of the present invention is a compound of formula (I): [ka] [In the formula, X is CR6 or N; Y is CR3 or N; L is -O-, -S-, -S(O)2-, -NR 4c -, or -NR 4d C(O)-; R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1-3Alkyl, 0 to 4 R 1a C replaced with 3-4 Cycloalkyl, 0 to 4 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1-3 is alkyl; Each R e independently, C 3-4 Cycloalkyl or 0 to 4 R 1a C replaced with 1-3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1-3 Alkyl, 0 to 4 R 2a C replaced with 2-3 Alkenyl, or 0 to 4 R 2a C replaced with 3-4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), C 3-4 Cycloalkyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, C 3-4 Fluorocycloalkyl, -NO2, or 0 to 2 R 3a is pyridinyl substituted with; Each R 3a is halogen, -CN, C1-3 Alkyl, or C 1-3 is alkoxy; R4 is R 4a , -CH2R 4a , or -CH2CH2R 4a and; R 4a is C 3-6 Cycloalkyl, C 5-14 Heterocyclyl, C 6-10 Aryl, or C 5-14 Heteroaryl, each of which has 0 to 4 R 4b is replaced by; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-2 O(C 1-3 alkyl), C 1-4 Alkoxy, -O(C 1-4 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-3 Fluoroalkoxy, -O(CH) 1-3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -NR c R c , -NR a S(O)2(C 1-3 alkyl), -NR a C(O)(C 1-3 alkyl), -NR a C(O)O(C 1-4 alkyl), -P(O)(C 1-3 alkyl)2, -S(O)2(C 1-3 alkyl), -O(CH2) 1-2 (C 3-6 cycloalkyl), -O(CH2)1-2 (morpholinyl), C 3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CR c R c (phenyl); Each R c are independently H or C 1-2 is alkyl; R 4c is H, C 1-6 Alkyl, or R 4a and; R 4d is H or C 1-6 is alkyl; Each R5 is independently selected from F, Cl, -CN, -OH, and 0 to 4 R g C replaced with 1-6 Alkyl, 0 to 4 R g C replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-4 Alkenyl, 0 to 4 R g C replaced with 2-4 Alkynyl, -(CH2) 1-2 (0 to 4 R g C replaced with 3-4 cycloalkyl), 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -O(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c S(O)2(C1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl) or two R5 attached to the same carbon atom form =O; Each R g are independently F, Cl, -CN, -OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy, -O(CH2) 1-2 O(C 1-2 alkyl), C 3-5 cycloalkyl, or -NR c R c and; each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; R7 is H or -CH3; m is 0, 1, 2, or 3; and n is 0, 1, or 2] or a salt thereof.

[0016] A second aspect of the present invention is a compound of formula (I): [ka] [In the formula, X is CR6 or N; Y is CR3 or N; L is -O-, -S-, -S(O)2-, -NR 4c -, or -NR 4d C(O)-; R1 is H, F, Cl, Br, -CN, or 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 4 R 1a C replaced with 3-4 Cycloalkyl, 0 to 4 R1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; Each R a are independently H or C 1-3 is alkyl; Each R e independently, C 3-4 Cycloalkyl or 0 to 4 R 1a C replaced with 1-3 is alkyl; R2 is H, 0 to 4 R 2a C replaced with 1-3 Alkyl, 0 to 4 R 2a C replaced with 2-3 Alkenyl, or 0 to 4 R 2a C replaced with 3-4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), C 3-4 Cycloalkyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, C 3-4 Fluorocycloalkyl, -NO2, or 0 to 2 R 3a is pyridinyl substituted with; Each R 3a is halogen, -CN, C 1-3 Alkyl, or C 1-3 is alkoxy; R4 is R4a , -CH2R 4a , or -CH2CH2R 4a and; R 4a But C 3-6 Cycloalkyl, C 5-14 Heterocyclyl, C 6-10 Aryl, or C 5-14 Heteroaryl, each of which has 0 to 4 R 4b is replaced by; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-2 O(C 1-3 alkyl), C 1-4 Alkoxy, -O(C 1-4 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-3 Fluoroalkoxy, -O(CH) 1-3 NR c R c , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -NR c R c , -NR a S(O)2(C 1-3 alkyl), -NR a C(O)(C 1-3 alkyl), -NR a C(O)O(C 1-4 alkyl), -P(O)(C 1-3 alkyl)2, -S(O)2(C 1-3 alkyl), -O(CH2) 1-2 (C 3-6 cycloalkyl), -O(CH2) 1-2 (morpholinyl), C 3-6cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CR c R c (phenyl); Each R c are independently H or C 1-2 is alkyl; R 4c is H, C 1-6 Alkyl, or R 4a and; R 4d is H or C 1-6 is alkyl; Each R5 is independently selected from F, Cl, -CN, -OH, and 0 to 4 R g C replaced with 1-6 Alkyl, 0 to 4 R g C replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-4 Alkenyl, 0 to 4 R g C replaced with 2-4 Alkynyl, 0 to 4 R g C replaced with 3-4 Cycloalkyl, 0 to 4 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH2) 1-2 NR c S(O)2(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NRa R a , or -C(O)NR a (C 3-4 cycloalkyl); Each R g are independently F, Cl, -CN, -OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy, -O(CH2) 1-2 O(C 1-2 alkyl), C 3-5 cycloalkyl, or -NR c R c and; each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; R7 is H or -CH3; m is 0, 1, 2, or 3; and n is 0, 1, or 2] or a salt thereof.

[0017] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is CR6 and Y is CR3 or N. The compound of this embodiment has formula (II): [ka] It has the following structure.

[0018] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is CR6 or N, and Y is CR3. The compound of this embodiment has formula (III): [ka] It has the following structure.

[0019] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 and Y is CR3. The compound of this embodiment has formula (IV): [ka] It has the following structure. Included within this embodiment are compounds where L is O. Also included within this embodiment are compounds where X is CH. Additionally included within this embodiment are compounds where each R6 is H.

[0020] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is N and Y is CR3. The compound of this embodiment has the formula (V): [ka] It has the following structure. Included within this embodiment are compounds wherein L is O. Also included within this embodiment are compounds wherein each R6 is H.

[0021] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 and Y is N. The compound of this embodiment has the formula (VI): [ka] It has the following structure. Included within this embodiment are compounds where L is O. Also included within this embodiment are compounds where X is CH. Additionally included within this embodiment are compounds where each R6 is H.

[0022] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is N and Y is N. The compound of this embodiment has the formula (VII): [ka] It has the following structure. Included within this embodiment are compounds wherein L is O. Also included within this embodiment are compounds wherein each R6 is H.

[0023] In one embodiment, the compound of formula R1 is H, F, Cl, Br, -CN, 0 to 4 R1a C replaced with 1-3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n CH3, or -P(O)(CH3)2; Each R 1a are independently F, Cl, or -CN; Each R a are independently H or C 1-3 is alkyl; R2 is H, 0 to 2 R 2a C replaced with 1-2 Alkyl or 0 to 2 R 2a C replaced with 2-3 is alkenyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -NO2, or 0 to 1 R 3a is pyridinyl substituted with; R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b is replaced by; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 1-2 O(C 1-3 alkyl), C 1-4 Alkoxy, -O(C 1-3 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-2 Fluoroalkoxy, -O(CH) 1-2 NR c R c , -C(O)(C 1-3 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl)2, -NR c R c , -S(O)2(C 1-2 alkyl), C 3-6 Cycloalkyl, or -CR c R c (phenyl); R 4c But H, C 1-4 Alkyl, or R 4a and; R 4d But H or C 1-4is alkyl; Each R5 is independently selected from F, -CN, -OH, and 0 to 4 R g C replaced with 1-5 Alkyl, 0 to 3 R g C replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-3 Alkenyl, 0 to 4 R g C replaced with 2-3 Alkynyl, -(CH2) 1-2 (0 to 4 R g C replaced with 3-4 cycloalkyl), 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -O(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH2) 1-2 NR c S(O)2(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl); each R6 is H, F, or -CH3; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H or -CH3. Included in this embodiment are compounds in which R7 is H, D, -CH3, or -CD3.

[0024] In one embodiment, the compound of formula R1 is H, F, Cl, Br, -CN, 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n CH3, or -P(O)(CH3)2; Each R 1a are independently F, Cl, or -CN; Each R a are independently H or C 1-3 is alkyl; R2 is H, 0 to 2 R 2a C replaced with 1-2 Alkyl or 0 to 2 R 2a C replaced with 2-3 is alkenyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R3 is H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 3-4 cycloalkyl, -NO2, methylpyridinyl, or methoxypyridinyl; R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b is replaced by; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 1-2 O(C 1-3 alkyl), C 1-4 Alkoxy, -O(C 1-3 hydroxyalkyl), -O(CH) 1-3 O(C 1-3 alkyl), C 1-2 Fluoroalkoxy, -O(CH) 1-2 NR c R c , -C(O)(C 1-3 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NH2, -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl)2, -NR c R c , -S(O)2(C 1-2 alkyl), C 3-6 Cycloalkyl, or -CR c R c (phenyl); R 4c But H, C 1-4 Alkyl, or R 4a and; R 4d But H or C 1-4 is alkyl; Each R5 is independently selected from F, -CN, -OH, and 0 to 4 R g C replaced with 1-5 Alkyl, 0 to 3 R g C replaced with 1-2 Alkoxy, 0 to 4 R g C replaced with 2-3 Alkenyl, 0 to 4 R g C replaced with 2-3 Alkynyl, 0 to 4 R g C replaced with 3-4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH2) 1-2 NR c S(O)2(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl); and each R6 is H, F, or -CH3; Provided is a compound of formula (I) or a salt thereof: Included in this embodiment are compounds in which R7 is H, D, -CH3, or -CD3.

[0025] In one embodiment, the compound of formula 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)-; 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 R 4a or -CH2R 4a and; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, C 1-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and The present invention provides a compound of formula (I) or a salt thereof, wherein each R6 is H.

[0026] In one embodiment, the compound of formula 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- or -NH-; R1 is F, Cl, Br, -CN, -OCH3, or -C(O)NH2; R2 is -CH3; R3 is H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -NO2, or 0 to 1 R 3a is pyridinyl substituted with; R4 is R 4a or -CH2R 4a and; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, or C 1-2 is alkoxy; each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

[0027] In one embodiment, the compound of formula 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-; 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 R 4a or -CH2R 4a and; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, C 1-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H or -CH3. Included in this embodiment are compounds in which R7 is H, D, -CH3, or -CD3.

[0028] In one embodiment, the compound of formula 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-; 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 R 4a or -CH2R 4a and; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, or C 1-2 is alkoxy; each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

[0029] In one embodiment, the compound of formula X is CH and Y is CR3; 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 R 4a or -CH2R 4a and; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, C 1-3 alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl); and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

[0030] In one embodiment, the compound of formula X is CH and Y is CR3; 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 R 4a or -CH2R 4a and; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, or C 1-2 is alkoxy; each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

[0031] In one embodiment, the compound of formula X is N and Y is CR3; 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 R 4a or -CH2R 4a and; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, or C 1-2 is alkoxy; each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

[0032] In one embodiment, the compound of formula 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 R 4a or -CH2R 4a and; R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b is replaced by; Each R 4b are 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, C 1-2 Alkyl, or C 1-2 is alkoxy; each R6 is H; and The present invention provides a compound of formula (I) or a salt thereof, wherein R7 is H. Within this embodiment are compounds wherein R7 is D.

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

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

[0035] One embodiment provides a compound of formula (I) or a salt thereof, wherein L is -S-.

[0036] One embodiment provides a compound of formula (I) or a salt thereof, wherein L is -S(O)2-.

[0037] In some embodiments, L is -NR 4c -or-NR4d The present invention provides a compound of formula (I) or a salt thereof, wherein the compound is C(O)-.

[0038] In some embodiments, L is -NR 4c or a salt thereof. This embodiment provides a compound of formula (I) wherein R 4c But H or C 1-4 Also included in this embodiment are compounds in which R 4c But R 4a The compounds include those in which:

[0039] In some embodiments, L is -NR 4d C(O)—, or a salt thereof. This embodiment includes compounds of formula (I) wherein R 4d But H or C 1-2 Included are compounds in which the aryl group is alkyl.

[0040] In some embodiments, R is H, F, Cl, Br, —CN, 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 4 R 1a C replaced with 3-4 Cycloalkyl, 0 to 4 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e In this embodiment, the compound of formula (I) or a salt thereof is provided, wherein R is H, F, Cl, Br, —CN, 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O)n Also included in this embodiment are compounds where R is H, F, Cl, Br, —CN, 0-4 R 1a C replaced with 1-2 Alkyl, 0 to 1 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n Included within this embodiment are compounds where R is F, Cl, Br, -CN, -OCH, or -C(O)NH.

[0041] In some embodiments, in the formula, each R 1a is independently F, Cl, —CN, —OH, or —OCH. This embodiment includes a compound of formula (I) or a salt thereof, wherein each R 1a is independently F, Cl, —CN, or —OCH. This embodiment also includes compounds where each R 1a are independently F, Cl, or —CN.

[0042] In some embodiments, in the formula, each R a are independently H or C 1-2 The present invention provides compounds of formula (I) or salts thereof, wherein each R a are independently H or -CH3.

[0043] In one embodiment, R2 is H, 0 to 3 R 2a C replaced with 1-3 Alkyl or 0 to 2 R 2a C replaced with 3-4 The present invention provides a compound of formula (I) or a salt thereof, wherein R2 is H or 0 to 2 R 2a C replaced with1-2 Also included within this embodiment are compounds where R2 is H or -CH3. Further included within this embodiment are compounds where R2 is -CH3.

[0044] In some embodiments, in the formula, each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), cyclopropyl, C 3-4 Alkenyl, or C 3-4 The present invention provides a compound of formula (I) or a salt thereof, wherein each R 2a are independently F, Cl, —CN, —OH, —OCH 3 , or cyclopropyl.

[0045] In some embodiments, R3 is H, F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -NO2, or 0 to 2 R 3a The present invention provides a compound of formula (I) or a salt thereof, wherein R is pyridinyl substituted with H, F, Cl, Br, —CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -NO2, or 0 to 1 R 3a Also included within this embodiment are compounds where R is H, F, Cl, Br, -CN, -CH, -NO, methylpyridinyl, or methoxypyridinyl. Further included within this embodiment are compounds where R is H, F, Cl, Br, -CN, -CH, or -NO.

[0046] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is Cl; and R3 is -CN. This embodiment includes compounds wherein X is CR6 and Y is CR3. This embodiment also includes compounds wherein X is N and Y is CR3.

[0047] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is Br; and R3 is -CN. This embodiment includes compounds wherein X is CR6 and Y is CR3. This embodiment also includes compounds wherein X is N and Y is CR3.

[0048] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is H. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0049] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is F; and R3 is -NO2. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0050] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -OCH3; and R3 is -CN. This embodiment includes compounds wherein X is CR6 and Y is CR3. This embodiment also includes compounds wherein X is N and Y is CR3.

[0051] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is -CN. This embodiment includes compounds wherein X is CR6 and Y is CR3. This embodiment also includes compounds wherein X is N and Y is CR3.

[0052] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is -NO2. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0053] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -C(O)NH2; and R3 is H. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0054] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is -CH3. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0055] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is F. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0056] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is Cl. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0057] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is -CN; and R3 is Br. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3. Also included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0058] One embodiment provides a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3; R1 is Cl; and R3 is H. Included in this embodiment are compounds wherein X is CR6 and Y is CR3. Also included in this embodiment are compounds wherein X is N and Y is CR3.

[0059] In one embodiment, R4 is R 4a or -CH2R 4a In this embodiment, the compound of formula (I) is 4a Also included in this embodiment are compounds in which R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b Also included are compounds substituted with:

[0060] In one embodiment, R4 is R 4a or -CH2R 4a In this embodiment, the compound of formula (I) is 4a Also included in this embodiment are compounds wherein R4 is -CH2R 4a Further included in this embodiment are compounds in which R 4a But C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthalenyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, indolyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b Included are compounds substituted with:

[0061] In one embodiment, R4 is R 4a and R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b In this embodiment, the compound of formula (I) or a salt thereof is provided, wherein R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b and each R 4b are independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH2CH3, -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.

[0062] In one embodiment, R4 is R 4a and R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b In this embodiment, the compound of formula (I) or a salt thereof is provided, wherein R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b and each R 4b are independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH2CH3, -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.

[0063] In one embodiment, R4 is R 4a , -CH2R 4a , or -CH2CH2R 4a and R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b In this embodiment, the compound of formula (I) or a salt thereof is provided, wherein R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b and each R 4b are independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH2CH3, -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.

[0064] In one embodiment, R4 is R 4a , -CH2R 4a , or -CH2CH2R 4a and R 4a But C 3-6cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 3 R 4b In this embodiment, the compound of formula (I) or a salt thereof is provided, wherein R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b and each R 4b are independently F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH2CH3, -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.

[0065] In some embodiments, R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is 0 to 3 R 4b and each R 4bare 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.

[0066] In some embodiments, R 4a is phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has 0 to 2 R 4b and each R 4b are 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.

[0067] One embodiment provides a compound of formula (I) or a salt thereof, wherein m is 1, 2, or 3. Within this embodiment, there are included compounds wherein m is 0, 1, or 2. Also within this embodiment, there are included compounds wherein m is 1 or 2.

[0068] In some embodiments, m is 1, 2, or 3; and each R is independently selected from F, —CN, —OH, 0 to 4 R g C replaced with 1-5 Alkyl, 0 to 3 R gC replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-3 Alkenyl, 0 to 4 R g C replaced with 2-3 Alkynyl, -(CH2) 1-2 (0 to 4 R g C replaced with 3-4 cycloalkyl), 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -O(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH2) 1-2 NR c S(O)2(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl). This embodiment also provides a compound of formula (I) or a salt thereof, wherein each R is independently hydrogen, F, —OH, C 1-2 Alkyl, C 1-3 Included are compounds that are alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl).

[0069] In some embodiments, m is 1, 2, or 3; and each R is independently selected from F, —CN, —OH, 0 to 4 R g C replaced with 1-5 Alkyl, 0 to 3 R g C replaced with 1-2 Alkoxy, 0 to 4 R g C replaced with 2-3 Alkenyl, 0 to 4 R g C replaced with 2-3 Alkynyl, 0 to 4 R g C replaced with 3-4 Cycloalkyl, 0 to 3 R g phenyl substituted with 0 to 3 R g oxadiazolyl substituted with 0-3 R g Pyridinyl substituted with -(CH2) 1-2 (0 to 4 R g heterocyclyl substituted with -(CH2) 1-2 NR c C(O)(C 1-4 alkyl), -(CH2) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH2) 1-2 NR c S(O)2(C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 cycloalkyl), -C(O)NR a R a , or -C(O)NR a (C 3-4 cycloalkyl). This embodiment also provides a compound of formula (I) or a salt thereof, wherein each R is independently hydrogen, F, —CN, —OH, 0 to 4 R g C replaced with 1-2 Alkyl, or C 1-2 Also included in this embodiment are compounds in which each R is independently hydrogen, F, —OH, C 1-2 Alkyl, or C 1-2 Included are compounds that are alkoxy.

[0070] In some embodiments, m is 1 or 2; and each R is independently hydrogen, F, —OH, C 1-2 Alkyl, C 1-3 The present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently selected from the group consisting of F, —OH, C, —C ... 1-2 Alkyl, C 1-3 Included are compounds that are alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl).

[0071] In one embodiment, m is 1; and R5 is hydrogen, F, —OH, C 1-2 Alkyl, C 1-3 The present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently selected from the group consisting of F, —OH, C, —C ... 1-2 Alkyl, C 1-3 Included are compounds that are alkoxy, -CH2CF3, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCH2(cyclopropyl), or -OCH2CH2(morpholinyl).

[0072] In some embodiments, m is 1 or 2; and each R is independently hydrogen, F, —OH, C 1-2 Alkyl, or C 1-2 The present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently selected from the group consisting of F, —OH, C, and the like. 1-2 Alkyl, or C 1-2 Included are compounds that are alkoxy.

[0073] In one embodiment, m is 1; and R5 is hydrogen, F, —OH, C 1-2 Alkyl, or C 1-2 The present invention provides a compound of formula (I) or a salt thereof, wherein R is alkoxy. In this embodiment, R is F, —OH, C 1-2 Alkyl, or C 1-2 Included are compounds that are alkoxy.

[0074] In one embodiment, [ka] The present invention provides a compound of formula (I) or a salt thereof, having a structure selected from:

[0075] In one embodiment, [ka] The present invention provides a compound of formula (I) or a salt thereof, having a structure selected from:

[0076] In one embodiment, the compound is selected from the group consisting of 6-fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (1); 6-fluoro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (2); 6-fluoro-1-methyl-3-nitro-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)quinolin-2(1H)-one (3); 6-fluoro-1-methyl-3-nitro-4-(4-(m-tolyloxy)piperidin-1-yl)quinolin-2(1H)-one (4); 4-(4-((1H-indazol-4-yl)oxy)piperidin-1-yl)-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (5); 3-((1-(6-fluoro-1-methyl-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl)oxy)benzonitrile (6); 4-(4-(3-chlorophenoxy)piperidin-1-yl)-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (7); 6-fluoro-4-(4-(2-methoxy-5-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (8); The compound of formula (I) or a salt thereof is provided, which is 6-fluoro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (9); or 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile (53).

[0077] In one embodiment, the compound is selected from the group consisting of 4-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (243 and 246); 4-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (251 and 253); 4-((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 4-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (255 and 258);(±)-trans-6-chloro-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (271-272); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (273-274); 6-chloro-4-((3R,4R)-3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (275); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (276-277); 4-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (278-279); 6-chloro-4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (300); 4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (302); 4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (303);6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (304); 4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (305); 6-chloro-4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (306); 4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (307); 1-Methyl-2-oxo-4-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (339-340); (±)-trans-6-chloro-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (399); trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (400-401); The compound of formula (I) or a salt thereof is provided, which is trans-4-(3-ethoxy-4-phenoxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (402-403); or 4-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (404-405).

[0078] In one embodiment, the compound is selected from the group consisting of 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (10); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (11); 6-chloro-4-(4-(3,4-difluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (12); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (13); 6-chloro-4-(4-(4-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (14); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15); 6-chloro-4-(4-(4-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (16); 6-chloro-4-(4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (17); 6-chloro-4-(4-(2-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (18); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (19); 6-chloro-4-(4-(4-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20);6-chloro-1-methyl-2-oxo-4-(4-(p-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (21); 6-chloro-1-methyl-2-oxo-4-(4-(m-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (22); 6-chloro-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (23); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (24); 4-((1-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide (25); 4-(4-(4-bromo-2-methylphenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (26); 6-chloro-4-(4-(3-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (27); 6-chloro-4-(4-(3-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (28); 6-chloro-1-methyl-4-(4-(2-methyl-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (29); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (30); 4-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (31);6-chloro-4-(4-(4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (32); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (33); 6-chloro-4-(4-(3-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (34); 6-chloro-4-(4-(2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (35); 6-chloro-4-(4-(4-fluoro-2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (36); 6-chloro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (37); 6-chloro-4-(4-(3-chloro-4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (38); 6-chloro-4-(4-(4-chloro-3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (39); 6-chloro-4-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (40); 6-chloro-4-(4-(2-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (41); 6-chloro-4-(4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (42);6-chloro-4-(4-(2-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (43); 6-chloro-4-(4-(2-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (44); 6-chloro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (45); 6-chloro-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (46); 6-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (47); 6-Methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (48); 1-Methyl-2,6-dioxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2,5,6-tetrahydro-1,5-naphthyridine-3-carbonitrile (49); 5-Methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (50); 5-methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (51); 5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (52); 5-Methyl-6-oxo-8-(4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (54);8-(4-(4-benzylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (55); 8-(4-(4-butylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (56); 5-methyl-6-oxo-8-(4-(4-propylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (57); 8-(4-(4-cyclopentylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (58); 8-(4-(4-cyclopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (59); 8-(4-(4-isopropyl-3-methylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (60); 5-methyl-6-oxo-8-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (61); 5-Methyl-6-oxo-8-(4-(4-pentylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (62); 8-(4-(4-cyclohexylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (63); 8-(4-(4-(2-cyclohexylpropan-2-yl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (64); 8-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (65); 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (66);8-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-(4-((6-(tert-butyl)pyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (68); 5-methyl-6-oxo-8-(4-(quinoxalin-2-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (69); 8-(4-((2,6-dimethylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70); 5-methyl-6-oxo-8-(4-(quinazolin-4-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71); 5-methyl-8-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (72); 8-(4-((7-chloro-4-methoxyquinolin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (73); 8-(4-((1,7-naphthyridin-8-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (74); 5-methyl-6-oxo-8-(4-(phthalazin-1-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (75); 5-Methyl-6-oxo-8-(4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (76); 5-methyl-6-oxo-8-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (77);8-(4-((2-isopropyl-6-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (78); (+ / -) 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (79); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (80); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (81); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (82-84); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (85-87); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (88-90); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (91-93); 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (94-96); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (97-99);8-((3R,4R)-4-(4-cyclopentylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo; -5,6-Dihydro-1,5-naphthyridine-2-carbonitrile (100-102); 8-((3R,4R)-4-(3,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (103-105); 8-((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (106); 5-Methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107-109); 8-((3R,4R)-4-(4-ethylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110); 8-((3R,4R)-4-(4-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (111); 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((3R,4R)-4-(2,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (113-115); 8-((3R,4R)-4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (116-118); 5-methyl-8-((3R,4R)-3-methyl-4-(p-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (119-121);8-((3R,4R)-4-(3-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (122); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (123); 8-((3R,4R)-4-(2-fluoro-6-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (125-127); 8-((3R,4R)-4-(4-fluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (128-130); 5-methyl-8-((3R,4R)-3-methyl-4-(2,4,6-trifluorophenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (131); 8-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (132); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (133-135); 5-methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (136);8-((3R,4R)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (137-139); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (140-142); 8-((3R,4R)-3-ethyl-4-(4-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (143-145); 8-((3R,4R)-3-ethyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (146-148); 8-((3R,4R)-3-ethyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (149-151); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (152-154); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (155-157); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (158-160); 8-((3R,4R)-3-ethyl-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (161);8-((3R,4R)-3-ethyl-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (162-163); 8-((3R,4S)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (164); 8-((3R,4S)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (165-167); 5-Methyl-8-((3R,4S)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (169-171); 8-((3R,4S)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (172-174); 8-((3R,4S)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (175); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (176-178); 8-((3R,4S)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (179-181); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (182-184);(+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (185); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (186); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (187); 5-Methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (188); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (189-191); 8-((3R,4R)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (192-194); 8-((3R,4R)-3-ethyl-4-(4-fluoro-3-propylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (195); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (196-198); 8-((3R,4R)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (199-201);8-((3R,4S)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (202-204); 8-((3R,4S)-4-((5-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (205-207); 8-((3R,4S)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (208-210); 8-((3R,4S)-4-((4-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (211-213); 8-((3R,4S)-4-((6-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (214-216); 5-methyl-8-((3R,4S)-3-methyl-4-(pyrimidin-2-yloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (217); 8-((3R,4S)-4-((4-methoxypyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (218); 5-Methyl-8-((3R,4S)-3-methyl-4-((5-propylpyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (219); 5-methyl-8-((3R,4S)-3-methyl-4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (220);8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (221); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (222); 8-((3R,4S)-4-((5-cyclopropylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (223); 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (224); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (225-227); (+ / -) 8-((3R,4S)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidine Lysin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (228); (+ / -) 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (229); 5-Methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (230); 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (231);(+ / -) 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (232); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (233); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (234); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (235); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (236); 7-Fluoro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (237); 7-chloro; bromo-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (238); 7-bromo-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (239); 7-(6-methoxypyridin-3-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (240); 7-(2-Methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (241); (+ / -) 6-Bromo-1-methyl-4-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (242); 8-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (243 and 246); 8-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (247 and 250);4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (251 and 253); 4-((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (252 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (256-257); 8-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (255 and 258); (±)-trans-8-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (259-260); (±)-trans-8-(3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (261-262); 8-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (263-264); (±)-cis-8-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (265-266); (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (267-268);(±)-trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-methoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (269-270); 8-((2S,5R)-4-((5-methoxypyridin-2-yl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (280-281); N-((2S,5R)-1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (282-283); N-(1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (284-287); N-(1-(3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-N-methyl-4-(trifluoromethyl)benzamide (288-293); 8-((2S,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (294); 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (295); 8-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (296); 8-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (297);8-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (298); 8-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (299); 8-((2S,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (308); 8-((2R,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (309); 8-((2R,4R,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (310); 8-((2R,4S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (311); 8-((2S,4R,5S)-2,5-dimethyl-4-(p-tolyloxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (312); 8-((2S,4R,5S)-4-(3-chlorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (313); 8-((2S,4R,5S)-4-(3-cyanophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (314);8-((2S,4R,5S)-4-(4-fluorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (315); 8-((2S,5S)-2,5-dimethyl-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316A); 8-(2,5)-dimethyl-4-(methyl(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (316-319); 8-((2S,5S)-2,5-dimethyl-4-(methyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (320-321); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (322-325); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (326-328); 8-(4-((4,4-difluorocyclohexyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (329-330); 8-((2S,5R)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (331-332); 8-((2S,5S)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (333-334);8-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,4,5-trimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (335-336); 5-methyl-6-oxo-8-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (337-338); trans-8-(3-ethoxy-4-phenoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (341-342); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (343-344); 8-((3S,4S)-3-ethoxy-4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (345-346); 8-((3S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (347-348); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (349-350); 8-((3S,4S)-3-ethoxy-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (351-352); 8-((3S,4S)-3-ethoxy-4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (353-354);8-((3S,4S)-3-ethoxy-4-((2-methylbenzo[d]oxazol-5-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (355-356); 8-((3S,4S)-4-(4-chloro-3-fluorophenoxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (357-358); 8-((3S,4S)-3-ethoxy-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (359-362); trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (363-364); 8-((3S,4S)-3-ethoxy-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (365-366); trans-8-(3-ethoxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (367-368); cis-8-(3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (369-370); cis-8-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (371-372); trans-8-4-(benzo[d]thiazol-2-yloxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (373-374);8-((3S,4S)-3-ethoxy-4-((6-isopropoxypyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (375-376); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrazin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (377-378); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrimidin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-; Oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (379-380); 8-((3S,4S)-3-ethoxy-4-((3-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (381-382); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyridin-2-yl)methoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (383-384); 8-((3R,4R)-3-(2-(dimethylamino)ethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (385-386); 8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (387-388); 8-((3R,4R)-3-(2-methoxyethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (389-390); 5-methyl-8-((3R,4R)-3-(2-morpholinoethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (391-392); 5-Methyl-6-oxo-8-((3R,4R)-3-(2,2,2-trifluoroethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (393-394); trans-8-(3-isopropoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (395-396);or trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (397-398), or a salt thereof.

[0079] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes any and all combinations of the aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any and all other embodiments to describe additional embodiments. It is also understood that individual elements of an embodiment are meant to be combined with any and all other elements from any and all embodiments to describe additional embodiments.

[0080] (definition) The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described before or after the context of separate embodiments may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment may also be combined to form subcombinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative, not limiting.

[0081] Unless otherwise stated herein, references made in the singular may also include the plural, for example, "a" and "an" may refer to either "one" or "one or more."

[0082] As used herein, the phrase "compound and / or salt thereof" refers to at least one compound, a salt of at least one compound, or a combination thereof. For example, a compound of formula (I) and / or a salt thereof includes a compound of formula (I); two compounds of formula (I); a salt of a compound of formula (I); a compound of formula (I) and one or more salts of a compound of formula (I); and a salt of two or more compounds of formula (I).

[0083] Unless otherwise specified, any atom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0084] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0085] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification (unless otherwise limited in specific instances) either individually or as part of a larger group.

[0086] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0087] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to the core or backbone structure.

[0088] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0089] The term "cyano" refers to the group --CN.

[0090] The term "amino" refers to the group -NH2.

[0091] The term "oxo" refers to the group =O.

[0092] The term "alkyl" as used herein refers to both branched and straight-chain saturated aliphatic hydrocarbon groups, for example, having 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 a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-4 "Alkyl" means straight and branched chain alkyl groups having from 1 to 4 carbon atoms.

[0093] As used herein, the term "fluoroalkyl" is meant to encompass both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 The term "fluoroalkyl" is meant to include C, C, C, and C alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF and -CHCF.

[0094] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and C 1-4 Hydroxyalkyl is an example.

[0095] The term "alkenyl" refers to a straight or branched chain 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, "C 2-6 "Alkenyl" refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms.

[0096] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Examples of such groups include ethynyl. For example, "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms.

[0097] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic hydrocarbon molecule or a non-aromatic polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms.

[0098] As used herein, the term "fluorocycloalkyl" is meant to include cycloalkyl groups that are substituted with one or more fluorine atoms.

[0099] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, a methoxy group (-OCH). 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms.

[0100] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as described above attached through an oxygen linkage (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to encompass C1, C2, C3, and C4 fluoroalkoxy groups.

[0101] The terms "carbocyclo," "carbocycle," or "carbocyclyl," which may be used interchangeably, refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring in which all atoms of all rings are carbon. A carbocyclyl ring can be unsubstituted or can have one or more substituents up to the valence. Thus, the term includes non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, and cycloalkynyl rings). Examples of bicyclic carbocyclyl groups include indanyl, indenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, bicycloheptanyl, bicyclooctanyl, and bicyclononanyl.

[0102] As used herein, the term "aryl" refers to the group of atoms obtained by removing one hydrogen atom attached to an aromatic carbocyclic ring from a molecule containing the aromatic ring. Representative examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. The aryl ring can be unsubstituted or can have one or more substituents, valence permitting.

[0103] As used herein, the term "benzyl" refers to a methyl group in which one of the hydrogen atoms has been replaced by a phenyl group. The phenyl ring can be unsubstituted or can have one or more substituents, valence permitting.

[0104] The term "heteroatom" refers to oxygen (O), sulfur (S), and nitrogen (N).

[0105] The terms "heterocyclo," "heterocycle," or "heterocyclyl," which may be used interchangeably, refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring, wherein one or more of the rings contains at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably contains 1 to 3 heteroatoms independently selected from O, S, and / or N. The rings of such groups containing heteroatoms may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and the ring further contains at least 1 carbon atom. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may be unsubstituted or may have one or more substituents, valence permitting.

[0106] Examples of single-ring heterocyclyl groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0107] The term "heteroaryl" refers to unsubstituted and substituted aromatic rings containing at least one heteroatom (O, S, or N) in at least one ring, with the heteroatom-containing ring preferably containing 1, 2, or 3 heteroatoms independently selected from O, S, and / or N. Heteroaryl groups in each heteroatom-containing ring may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring contains at least 1 carbon atom. Five- to fourteen-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 forming bicyclic and tricyclic heteroaryl groups are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. Bicyclic and tricyclic heteroaryl groups must contain only aromatic rings. The heteroaryl group may be attached at any available nitrogen or carbon atom. Heteroaryl ring systems can be unsubstituted or can bear one or more substituents.

[0108] Examples of single-ring heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0109] Examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

[0110] Examples of tricyclic heteroaryl groups include acridinyl, benzoquinolinyl, benzoisoquinolinyl, and benzonaphthyridinyl.

[0111] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are, within the scope of ordinary medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and that offer a reasonable benefit / risk ratio.

[0112] Compounds of Formula (I) can form salts, and such salts are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the invention is understood to include reference to one or more salts thereof. The term "salt" refers to acid and / or base salts formed with inorganic and / or organic acids and bases. Furthermore, the term "salt" can include zwitterions (internal salts), for example, when a compound of Formula (I) contains both a basic moiety (e.g., an amine, pyridine, or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may also be useful, for example, in isolation or purification steps that may be used in manufacturing processes, and therefore, other salts are also considered within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with a certain amount of acid or base (e.g., 1 equivalent) and precipitating the salt in a solvent, for example, or by subsequent lyophilization of the aqueous solution.

[0113] Examples of acid addition salts include acetates (e.g., acetates prepared from acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrogen bromide), and the like. salts such as those described herein, tartrates, thiocyanates, toluenesulfonates (e.g., tosylates), undecanoates, and the like.

[0114] Examples of base salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), barium, zinc, and aluminum salts, organic base salts such as organic amines (e.g., trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine), or similar pharmaceutically acceptable amines, and amino acid salts (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups may be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide), and other groups. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0115] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as a solid by lyophilization.

[0116] Additionally, solvates (e.g., hydrates) of compounds of formula (I) are also considered to be within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0117] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0118] Additionally, the compound of formula (I) may be isolated and purified after its preparation to obtain a composition containing the compound of formula (I) in an amount of 99% or greater ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0119] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, nor upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0120] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients, that is effective to act as an inhibitor of DGKα and / or DGKζ, or to treat or prevent viral infections and proliferative diseases (e.g., cancer).

[0121] As used herein, the term "treating" or "treatment" covers the treatment of a condition in a mammal, particularly a human, and includes (a) preventing the mammal from acquiring the condition, particularly where the mammal is susceptible to the condition but has not yet been diagnosed as having the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (c) alleviating the condition, i.e., causing regression of the condition.

[0122] The compounds of the present invention are intended to include all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the unlabeled reagent otherwise used.

[0123] The compounds according to formula (I) and / or pharmaceutically acceptable salts thereof may be administered by any means appropriate to the condition to be treated, which may depend on the need for site-specific treatment or the amount of compound of formula (I) to be delivered.

[0124] The present invention also encompasses a class of pharmaceutical compositions comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof; and one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carriers"), and, optionally, other active ingredients. The compound of formula (I) may be administered by any appropriate route, preferably in the form of a pharmaceutical composition adapted for such a route, and in a dosage effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, transmucosally, or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may include a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may also include additional ingredients, such as lubricants (e.g., magnesium stearate) and disintegrants (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets.The pharmaceutical composition may be administered, for example, as an oral dosage form or by infusion.

[0125] 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 formulated in a dosage unit form containing a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose for administration to humans or other mammals may vary greatly depending on the patient's condition and other factors, but can be determined using conventional methods.

[0126] Any of the pharmaceutical compositions discussed herein can be orally delivered, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. To provide a pharmaceutically easy-to-take formulation, the pharmaceutical compositions described in the present invention can include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0127] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt with at least one non-toxic, pharmaceutically acceptable additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0128] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) and / or at least one salt thereof with at least one inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0129] Soft gelatin capsules can 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 (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0130] Aqueous suspensions can 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 additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and fatty acids and and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0131] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in either vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspensions can also contain at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide an oily suspension that is easy to drink, at least one sweetener and / or at least one flavoring agent as described above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant (e.g., butylhydroxyanisole and α-tocopherol).

[0132] Dispersible powders and granules can 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 agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules can also contain at least one excipient (e.g., but not limited to, sweeteners, flavoring agents, and coloring agents).

[0133] Emulsions of at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be prepared, for example, as oil-in-water emulsions. The oil phase of emulsions containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase can contain only an emulsifier, or a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier, with or without a stabilizer, makes up the so-called emulsifying wax, and the wax, together with the oil and fat, makes up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. The emulsion may also include sweeteners, flavoring agents, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with wax; or other materials known in the art.

[0134] In addition, the compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0135] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more of the carriers or diluents described for use in oral preparations, or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrins (e.g., Captisol), solubilizing cosolvents (e.g., propylene glycol), or solubilizing micelles (e.g., Tween 80).

[0136] Alternatively, a sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used, water, Ringer's solution, and isotonic sodium chloride solution are used. Furthermore, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in injectable preparations.

[0137] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the formula (I) containing oil phase with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0138] Sterile aqueous suspensions or sterile oily suspensions can be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions can be prepared using non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol), and sterile oily suspensions can be prepared using sterile, non-toxic, acceptable solvents or suspension media (e.g., sterile fixed oils (e.g., synthetic monoglycerides or diglycerides), and fatty acids (e.g., oleic acid).

[0139] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts, or electrolytes (e.g., protamine sulfate, PEG-100, PEG-1000), and the like. Examples of suitable carriers include cellulose acetate, cellulose acetate esters, cellulose acetate esters, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives) may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0140] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may additionally be prepared with enteric coatings. Such compositions may also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and fragrances).

[0141] The amount of compound and dosage regimen administered to treat a condition using the compounds and / or compositions of the present invention depend on various factors, such as age, weight, sex, the patient's condition, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used. Therefore, dosage regimens may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosage regimens include weekly and biday cycles.

[0142] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then be tableted or encapsulated for convenient administration.Such capsules or tablets can also contain controlled-release formulations, and can also be provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0143] Pharmaceutical compositions of the present invention include at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additive selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0144] (usefulness) The compounds of formula (I) are useful in the treatment of cancer.

[0145] In another embodiment, the present invention provides a pharmaceutical combination of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof with another therapeutic agent for simultaneous, separate or sequential use in the treatment and / or prevention of multiple diseases or disorders associated with targeted inhibition of DGK in T cells.

[0146] In another aspect, the present invention provides a method for treating a patient suffering from or susceptible to a condition associated with targeted inhibition of DGK in T cells. Numerous conditions may be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof. For example, the compounds described herein may be used to treat or prevent viral infections and proliferative diseases (e.g., cancer).

[0147] The 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 associated with targeted inhibition of DGK in T cells. Such diseases or conditions include viral and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, urogenital infections, systemic infections), and proliferative diseases (e.g., cancer). The compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) can be administered to animals, preferably mammals (e.g., livestock animals, cats, dogs, mice, rats), and more preferably humans. Any administration method may be used to deliver the compound or pharmaceutical composition to a patient. In some embodiments, the compounds of Formula (I) or pharmaceutical compositions comprising at least a compound of Formula (I) are administered orally. In other embodiments, the compounds of Formula (I) or pharmaceutical compositions comprising at least a compound of Formula (I) are administered parenterally.

[0148] The compound of formula (I) can inhibit the activity of diacylglycerol kinase α and ζ (DGKα / ζ). For example, the compound of formula (I) can be used to inhibit the activity of DGKα and DGKζ in cells or individuals in need of regulation of DGKα and DGKζ by administering an inhibitory amount of the compound of formula (I) or a salt thereof.

[0149] The present invention further provides methods for treating diseases associated with activity or expression (e.g., abnormal activity and / or overexpression of DGKα and DGKζ in an individual (e.g., a patient)) by administering a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof to an individual in need of such treatment. Examples of diseases can include any disease, disorder, or condition directly or indirectly associated with the expression or activity (e.g., overexpression or abnormal activity) of DGKα and DGKζ enzymes. DGKα- and DGKζ-associated diseases can also include any disease, disorder, or condition that can be prevented, improved, or reversed by modulating DGKα and DGKζ enzyme activity. Examples of DGKα- and DGKζ-associated diseases include cancer and viral infections (e.g., HIV infection, hepatitis B, and hepatitis C).

[0150] In some embodiments, the compound of Formula (I) is administered sequentially prior to the administration of the immuno-oncology agent. In other embodiments, the compound of Formula (I) is administered simultaneously with the immuno-oncology agent. In yet other embodiments, the compound of Formula (I) is administered sequentially following the administration of the immuno-oncology agent.

[0151] In another embodiment, the compounds of formula (I) may be formulated together with an immuno-oncology agent.

[0152] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological molecules or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized antibody or a human antibody.

[0153] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory receptor (including costimulatory) or (ii) an antagonist of an inhibitory signal (including co-inhibitory) on a T cell, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0154] Certain stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or costibulatory receptors are the TNF family molecules that bind to 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 / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, and lymphotoxin α. 1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0155] In certain embodiments, T cell responses may be stimulated by a combination of a compound of formula (I) and one or more of the following: (i) protein antagonists that inhibit 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) Agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0156] For cancer treatment, other drugs that can be combined with the compound of formula (I) can include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compound of formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0157] Further agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or CSF-1R antagonist antibodies, including FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0158] In another embodiment, the compounds of formula (I) may be used in conjunction with one or more of agonistic 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 different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Treg cells (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo depletion with anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or T cell exhaustion), and agents that activate innate immunity and / or cause inflammation in the tumor area.

[0159] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab) or tremelimumab.

[0160] In another embodiment, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated AMP-224.

[0161] In another embodiment, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0162] In another embodiment, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0163] In another embodiment, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0164] In another embodiment, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0165] In another embodiment, 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).

[0166] In another embodiment, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0167] In another embodiment, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0168] In another embodiment, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0169] In another embodiment, the immuno-oncology agent is a CD27 agonist, such as an antagonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0170] In another embodiment, the immuno-oncology agent is MGA271 (WO11 / 109400) directed against B7H3.

[0171] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The administration of the above therapeutic agents can also be combined with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) to achieve combination therapy. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the synergistic action of the combined therapeutic and non-drug treatment is achieved, e.g., in suitable cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from the administration of the therapeutic agent.

[0172] As used herein, the term "cell" refers to in vitro, ex vivo, or in vivo cells. In some embodiments, ex vivo cells can be part of a tissue sample removed from an organism (e.g., a mammal). In some embodiments, in vitro cells can be cells in cell culture. In some embodiments, in vivo cells are living cells in an organism (e.g., a mammal).

[0173] As used herein, the term "contacting" refers to the joining of the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a compound of Formula (I) with DGKα and DGKζ enzymes includes administering a compound of the invention to an individual or patient (e.g., a human) with DGKα and DGKζ, as well as introducing a compound of Formula (I) into, for example, a sample containing cells or a purified product containing DGKα and DGKζ enzymes.

[0174] The term "DGKα and DGKζ inhibitors" refers to agents capable of inhibiting the activity of diacylglycerol kinase α and / or diacylglycerol kinase ζ (DGKα and DGKζ) in T cells, resulting in stimulation of T cells. DGKα and DGKζ inhibitors can be reversible or irreversible DGKα and DGKζ inhibitors. "Reversible DGKα and DGKζ inhibitors" are compounds that reversibly inhibit DGKα and DGKζ enzyme activity at either the catalytic or non-catalytic site, and "irreversible DGKα and DGKζ inhibitors" are compounds that irreversibly impair DGKα and DGKζ enzyme activity by forming a covalent bond with the enzyme.

[0175] Cancer types that may be treated with the compounds of formula (I) include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer, and bone cancer. Examples of such cancer types include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain Tumors include glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0176] In treating diseases, disorders, or conditions associated with DGKα and DGKζ, one or more additional pharmaceutical agents or therapeutic methods (e.g., antiviral agents, chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compounds of Formula (I), as appropriate. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially in different dosage forms.

[0177] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0178] In the treatment of melanoma, suitable agents for use in combination with the compounds of formula (I) include dacarbazine (DTIC), optionally with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; cisplatin, vinblastine, and DTIC, temozolomide, or Yervoy. TM The compounds of formula (I) may also be combined with immunotherapeutic agents, such as cytokines (such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF)), in the treatment of melanoma.

[0179] The compounds of formula (I) can also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are similar in some respects to antiviral vaccines used to prevent diseases caused by viruses (e.g., polio, measles, and mumps). Attenuated melanoma cells or parts of melanoma cells called antigens can be injected into patients to stimulate the body's immune system and destroy melanoma cells.

[0180] Melanomas of the arms or legs may also be treated using hyperthermic perfusion therapy with a combination of drugs containing one or more compounds of Formula (I). This treatment protocol involves temporarily isolating the circulatory system of the affected limb from the rest of the body, and then infusing high concentrations of chemotherapy drugs into the arteries of the affected limb, delivering high doses to the tumor site that would otherwise cause serious side effects if exposed to internal organs. This treatment typically involves warming body fluids to 38.9°C to 40°C. Melphalan is the drug most frequently used in this chemotherapy. Another agent called tumor necrosis factor (TNF) inhibitor may also be used.

[0181] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0182] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (especially IFNα), etoposide, and teniposide.

[0183] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.

[0184] Suitable cytotoxic agents also include, for example, epipodophyllotoxins; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes (e.g., cisplatin and carboplatin); biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0185] Other anti-cancer agents include antibody drugs such as trastuzumab (Herceptin®), antibodies against costimulatory molecules (e.g., CTLA-4, 4-1BB, and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0186] Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors (eg, CCR2 and CCR4).

[0187] Other anti-cancer drugs also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0188] Anti-cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines and recombinant viruses.

[0189] The pharmaceutical compositions of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in a signal transduction pathway in the normal function of cancer cells, thereby inducing apoptosis. Suitable STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (Gleevec®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (Iressa®, SSI-774) and antibodies (Imclone: ​​C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors (e.g., farnesyltransferase inhibitors (FTIs) such as L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors (e.g., flavopiridol and UCN-O1 (see, e.g., Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of formula (I) can be formulated in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one compound of formula (I) and at least one STI can be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) can be administered first, at least one STI can be administered first, or at least one compound of formula (I) and at least one STI can be administered simultaneously.Furthermore, when more than one compound of Formula (I) and / or STI is used, the compounds may be administered in any order.

[0190] The present invention further provides pharmaceutical compositions comprising at least one compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent, in a pharmaceutically acceptable carrier for treating a chronic viral infection in a patient.

[0191] Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0192] In certain embodiments of the present invention, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to patients simultaneously or sequentially.In other words, at least one compound of formula (I) can be administered first, or at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one chemotherapeutic agent can be administered simultaneously.In addition, when more than one compound of formula (I) and / or chemotherapeutic agent are used, the compounds can be administered in any order.Similarly, any antiviral drug or STI can be administered at any time compared with the administration of the compound of formula (I).

[0193] Chronic viral infections that may be treated using the present combination therapy 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, coxsackievirus, and human immunodeficiency virus (HIV). In particular, parasitic infections (e.g., malaria) may be treated by the above methods, optionally substituting compounds known for the treatment of parasitic diseases for antiviral agents.

[0194] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0195] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir; BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also called β-L-D4C, which is named β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Representative suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0196] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of DGKα and DGKζ-associated diseases or disorders, and other diseases described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further optionally include one or more of a variety of conventional pharmaceutical kit components (e.g., a container containing one or more pharmaceutically acceptable carriers, a separate container), which will be readily apparent to those of skill in the art. Instructions, either in the form of a package insert or label, indicating the amounts of components to be administered, dosage guidelines, and / or mixing guidelines for the components, can also be included in the kit.

[0197] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. Combination therapy can also include the administration of the above-mentioned therapeutic agents in combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy). If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the synergistic action of the combined therapeutic and non-drug treatment is achieved, e.g., in suitable cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from the administration of the therapeutic agent.

[0198] The present invention also provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more compounds of formula (I), formulated together with one or more pharmaceutically acceptable carriers (excipients) and / or diluents, and optionally one or more additional therapeutic agents as described above.

[0199] The compounds of the present invention, for any of the uses described herein, may be administered by any suitable means (e.g., oral administration (e.g., tablets, capsules (each including sustained or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions)); nasal administration, including administration to the nasal membranes (e.g., inhalation spray); topical administration (e.g., in the form of a cream or ointment); or rectal administration (e.g., in the form of a suppository)). They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0200] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, processing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulant, which is involved in the transport or delivery of a particular compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation (i.e., including adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispensing agents), which vary depending on the method of administration and the nature of the dosage form), and not deleterious to the patient.

[0201] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier.

[0202] Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such additional components are included in the formulation for various reasons, such as stabilization of the active agent, binders, etc., as are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors for selecting them can be found in various readily available sources, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0203] Dosage regimens for the compounds of the present invention will, of course, vary depending on known factors, such as the pharmacodynamic properties of the particular drug and its method and route of administration; the recipient's species, age, sex, health, condition, and weight; the nature and extent of the condition; type of concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect.

[0204] As a general guideline, the daily oral dose of each active ingredient, when used to achieve the intended effect, will range from about 0.001 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. The most preferred dose for intravenous constant rate infusion is in the range of about 0.01 to about 10 mg / kg / min. The compounds of the present invention may be administered in a single daily dose, or in divided doses with the total daily dose being given two, three, or four times a day.

[0205] The compounds are generally selected appropriately for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers), consistent with conventional pharmaceutical practice.

[0206] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 mg to about 2000 mg of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is typically present in an amount of about 0.1 to 95% by weight of the total weight of the composition.

[0207] A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg), which mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

[0208] A typical injectable formulation is prepared by aseptically adding at least one compound of the present invention (250 mg) to a vial, aseptically lyophilizing and sealing the vial, and then mixing the contents of the vial with saline (2 mL) to prepare the injectable formulation.

[0209] The present invention includes within its scope pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient, alone or in combination with a pharmaceutical carrier. The compounds of the 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., anti-cancer agents or other pharmaceutically active substances), as appropriate.

[0210] Regardless of the route of administration selected, the compounds of the present invention and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0211] Actual dosage levels of the active ingredient in the pharmaceutical compositions of the present invention may be varied to contain an amount of the active ingredient that is non-toxic to the patient and effective to produce a therapeutic effect for a particular patient, composition, and mode of administration.

[0212] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention or its ester, salt, or amide employed, the route of administration of the particular compound employed, the time of administration, rate of excretion or metabolism, rate and extent of absorption, duration of treatment, other drugs, compounds, and / or substances used in combination with the particular compound employed, the age, sex, weight, symptoms, health, and medical history of the patient being treated, and factors well known in the medical arts.

[0213] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of the compounds of the present invention used in the pharmaceutical composition at levels lower than required to achieve a therapeutic effect, and gradually increase the dosage until an effect is achieved.

[0214] Generally, a suitable daily dose of a compound of the present invention is the lowest effective dose of the compound to achieve a therapeutic effect. Such an effective dose is generally determined by the factors described above. Generally, the dose of a compound of the present invention administered to a patient is about 0.01 to about 50 mg / kg body weight / day for oral, intravenous, intracerebroventricular, and subcutaneous administration.

[0215] If desired, the effective daily dose of the active compound may be administered in two, three, four, five, six or more divided doses at appropriate intervals throughout the day, conveniently in unit dosage forms. In some embodiments of the invention, dosing is once daily.

[0216] 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).

[0217] The other therapeutic agents described above, when used in combination with the compounds of the invention, may be used, for example, in amounts as set forth in the Pharmaceutical and Medical Devices Manual (PDR) or as otherwise specifically determined by one of ordinary skill in the art. In the methods of the invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of the invention.

[0218] (Manufacturing method) The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry. A general synthetic scheme for preparing the compounds of the present invention is described below. This scheme is illustrative and is not intended to limit the possible techniques that one skilled in the art can use to prepare the compounds described herein. Various 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 prepared by methods described in the general scheme are shown in the Examples section below. 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 separating racemic products or diastereomers by chiral-phase preparative HPLC. Alternatively, the compounds can be prepared by known methods that provide enantiomerically enriched or diastereomerically enriched products.

[0219] The reactions and techniques described in this section are carried out in solvents appropriate to the reagents and materials used and are suitable for the transformations being effected. It is also understood that in describing the synthetic methods set forth below, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and work-up method) have been selected to be standard conditions for the reactions, and should be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that functional groups present on various portions of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternatives may be required if the present substituents are not suitable. The reactions may require the determination to alter the order of synthetic steps or to select a different course of action for certain reactions to obtain the compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the desired compounds described herein. For the experienced experimenter, an authoritative reference describing many protecting group alternatives is Greene's Protective Groups in Organic Synthesis by Wuts and Greene (Fourth Edition, Wiley & Sons, 2007).

[0220] As a further enabling embodiment, the intermediates and examples of the present invention may be prepared using stereoselective methods known to those skilled in the art, and are illustrated in the following schemes.

[0221] [ka] Both enantiomers of these chiral oxazolidinones can be reacted with acyl chlorides at low temperatures to give the N-acyl derivatives. These can be converted to the corresponding boron enolates and condensed with 2-(2-alkyl-1,3-dioxolan-2-yl)acetaldehyde to give 4-benzyl-3-(2-alkyl-3-hydroxy-4-(2-alkyl-1,3-dioxolan-2-yl)butanoyl)oxazolidinones of known configuration. Deprotection of the product dioxolanes, for example with iron(III) chloride / acetone, can give 1-(4-benzyl-2-oxooxazolidin-3-yl)-2-alkyl-3-hydroxyalkyl-1,5-diones. Subsequent reductive amination of benzylamine with, for example, sodium triacetoxyborohydride can provide a diastereomeric mixture of 4-benzyl-3-(5-(benzylamino)-2-alkyl-3-hydroxyalkanoyl)oxazolidinones. The resulting amines can be intramolecularly cyclized by heating in MeOH under microwave conditions to provide chromatographically separable 1-benzyl-3-alkyl-4-hydroxy-6-alkylpiperidin-2-ones. The product piperidinones can then be reduced with, for example, borane or LAH to provide N-benzyl-2-alkyl-4-hydroxy-5-alkylpiperidines. Removal of the benzyl moiety under hydrogenolysis conditions in the presence of di-tert-butyl dicarbonate can provide tert-butyl 4-hydroxy-2,5-dialkylpiperidine-1-carboxylates, useful intermediates for the synthesis of embodiments of the present invention. In a further step, the configuration of the 4-hydroxy moiety in these and related intermediates can be inverted using standard Mitsunobu reaction conditions (using p-nitrobenzoic acid to obtain an ester, followed by base-catalyzed hydrolysis to liberate the desired alcohol). By employing appropriately functionalized oxazolidinones and aldehydes in these methods, intermediates of known configuration can be obtained. Examples of the use of the above compounds leading to other embodiments of the present invention are outlined in the following schemes.

[0222] [ka] In the above example, the N-boc-protected 2,5-dialkyl-4-hydroxypiperidine can be first deprotected using standard conditions and then reacted with the appropriate 1-alkylpyrido[3,2-d]pyrimidin-2(1H)-one or 1-alkyl-1,5-naphthyridin-2(1H)-one derivative to provide the product alcohol. This can then be reacted with either a Mitsunobu reaction or SNAr conditions with a selected heterocycle to provide examples of the present invention. Alternatively, the N-boc-protected 2,5-dialkyl-4-hydroxypiperidine can be first reacted with an appropriately functionalized phenol under Mitsunobu conditions or with a selected heterocycle under SNAr conditions to provide additional intermediates to the compounds shown above. Subsequent reaction with an appropriately functionalized pyrido[3,2-d]pyrimidin-2(1H)-one or naphthyridin-2(1H)-one can provide compounds leading to additional examples. In some cases, 2,5-dialkyl-4-hydroxypiperidines or their related ethers can be reacted with 4,6-dichloro-1-alkylpyrido[3,2-d]pyrimidin-2(1H)-ones or 4,6-dichloro-1-alkyl-1,5-naphthyridin-2(1H)-ones to give the related 4-N-piperidinyl derivatives, which can introduce additional functionality (e.g., a nitrile group) at the 6-position of the bicyclic heterocycle. These are also included within the scope of the present invention.

[0223] (Example) The following examples illustrate specific or preferred embodiments of the invention and are not intended to limit the scope of the invention. Chemical and scientific abbreviations and symbols have their common and accustomed meanings unless otherwise specified. Additional abbreviations used in the examples and elsewhere in this specification are defined below. Common intermediates are generally useful in the preparation of one or more examples and are named sequentially (e.g., Intermediate 1, Intermediate 2, etc.) and abbreviated (e.g., Int. 1 or I1, Int. 2 or I2, etc.). Example compounds are identified by the example and step by which they are prepared (e.g., "1-A" refers to Step A of Example 1), or by example only if the compound is the title compound of the example (e.g., "1" refers to the title compound of Example 1). In some cases, alternative methods for preparing intermediates or examples are described. Chemists skilled in the art of synthesis will frequently devise alternative preparation methods that are desirable based on one or more considerations (e.g., shorter reaction times, cheaper starting materials, ease of manipulation and purification, higher yields, ease of catalysis, avoidance of toxic reagents, availability of specialized equipment, and reduced number of steps). The intent in describing alternative preparation methods is to make the embodiments of the present invention more amenable to manufacture. In some cases, some functional groups in the outlined examples and claims may be replaced by bioisosteric substitutions known to those skilled in the art (e.g., replacing carboxylic acid groups with tetrazole or phosphate moieties). Measured in deuterated dimethyl sulfoxide. 1 H NMR data used water suppression in data processing. The spectra shown are uncorrected to reflect water suppression. Protons adjacent to the water suppression frequency at 3.35 ppm are shown with reduced signal intensity.

[0224] In the examples, dotted wedge bonds indicate relative configuration. The symbol "(+ / -)" preceding the name of a compound indicates a racemic mixture. The symbol "(rel)" indicates any stereochemical designation of a compound that is relative and not absolute. An undashed bond at a chiral center indicates that the relative configuration is unknown. In the tables below, the configuration of the examples is indicated in the column entitled "Configuration," where the symbol "A" indicates "achiral," the symbol "R" indicates a racemic mixture, and the symbol "H" indicates a homochiral compound.

[0225] [Table 1]

[0226] The following schemes illustrate methods that may be used in the synthesis of intermediates useful in the preparation of examples of the present invention.

[0227] Benzoxazine-2,4(1H)-diones can be treated with a strong base and a methylating agent (e.g., methyl iodide) to give 1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-diones. These can be reacted with, for example, ethyl nitroacetate to give 1-methyl-3-nitroquinoline-2,4(1H,3H)-diones. These can then be converted to the related 4-chloro derivatives, which can be reacted with piperidines substituted with various functional groups to give examples of the present invention. Alternatively, picolinic acid can be esterified under standard conditions, followed by treatment with, for example, acetic anhydride, to give ethyl 3-acetamidopicolinate. These can be alkylated under standard conditions, followed by treatment with a mixture of hydrogen peroxide and trifluoroacetic anhydride to give the related N-oxides (e.g., 2-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide). Under conditions known to those skilled in the art, these intermediates can be converted to 6-cyano-3-(N-methylacetamido)picolinic acid, which can be cyclized by treatment with base to give 1,5-naphthyridine-2,4(1H,3H)-diones. Compounds of this type can be derived to a number of useful intermediates in multiple ways. For example, standard nitration conditions can give the related 1-methyl-3-nitro-1,5-naphthyridine-2,4(1H,3H)-diones. This can be converted to a 4-chloro- or 4-trifluoromethanesulfonic acid intermediate under standard conditions and reacted with various functionally substituted piperidines to provide other embodiments of the present invention. Alternatively, treatment under bromination conditions (e.g., N-bromosuccinimide / DMF) affords the related 3-bromo derivatives, which can then be used to introduce a variety of piperidines at the 4-position of the heterocycle and further derivatives at the 3-position of the naphthyridine. For example, aromatic and heteroaromatic moieties can be introduced at this position via coupling reactions. In another method, ethyl 3-amino-6-bromopicolinate, prepared from the related ethyl 3-amino-picolinate, can be treated as described above to give 6-bromo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione. Introduction of various moieties has been carried out at the 6-position of this naphthyridine heterocycle; an example of the introduction of a cyano group at this position is shown in Scheme 1. [ka]

[0228] An alternative method useful for synthesizing intermediates of the present invention is shown in the following scheme. Ethyl 3-amino-6-bromopicolinate can be cyclized with 2-cyanoacetyl chloride to give 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile. These can be alkylated with N1 under standard conditions and then converted to the related 6-bromo-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid, which is useful for the preparation of other examples. Alternatively, sequential treatment with POCl3 and HCl / dioxane provides 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile, which is also a useful intermediate. [ka]

[0229] Another synthetic method useful for introducing a cyano group at the 6-position of examples of the present invention may involve treating a 6-bromo-3-(2-cyanoacetamido)ethyl picolinate intermediate with zinc and zinc cyanide under palladium catalysis to give ethyl 3-(2-cyanoacetamido)-6-cyanopicolinate, which may be converted to 4-chloro-6-isocyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile as described above, which may then be reacted with a variety of functionally substituted piperidines to produce numerous examples of the present invention. Further useful intermediates can be prepared by condensing naphthyridinone and quinolone heterocycles bearing appropriate functional groups with various functionally substituted piperidines as shown in the scheme below. The intermediates can be prepared, for example, by Mitsunobu or SN reactions. Ar The reaction can be used to couple with aromatics or heteroaromatics bearing appropriate functional groups and converted to examples of the present invention. [Table 2]

[0230] Methods for preparing useful piperidine intermediates and additional examples are shown in the following schemes. [ka] In these examples, N-protected cis-4-hydroxy-3-alkylpiperidines can be treated with a carboxylic acid, for example under Mitsunobu reaction conditions, to give trans-4-benzoyloxy-3-alkylpiperidines, which may then be hydrolyzed to give the corresponding trans-4-hydroxy-3-alkylpiperidines. These can then be deprotected in a manner similar to that described above, and the intermediate trans-4-hydroxy-3-alkylpiperidines can be condensed with appropriately functionalized naphthyridinones or quinolones to give trans-4-hydroxy-3-alkylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridines, or the corresponding quinolone intermediates can be subjected to Mitsunobu or SN reactions. Ar Reaction under these conditions can again provide examples of the present invention. In another example, it is preferable to prepare an intermediate piperidine ether and then react it with naphthyridinones and quinolones having appropriate functional groups to obtain other examples. Some examples are shown in the following scheme. In this method, N-protected alkylpiperidin-4-ones as shown are reduced to N-protected 3-alkylpiperidin-4-ols by methods known to those skilled in the art. [ka] The relative configuration of the alkyl and hydroxy groups can be controlled by various methods, and in some examples, as shown above, simultaneous treatment with phosphoric acid and sodium borohydride can give predominantly trans products, while the use of L-selectride / THF can give predominantly cis products. These intermediates can then be further converted to SN AR Under certain conditions, reaction with a strong base and a heterocycle bearing an appropriate functional group can produce N-protected cis- or N-protected trans-3-alkyl-4-(heteroaryloxy)piperidines. These intermediates can be deprotected and reacted with naphthyridinones or quinolones bearing appropriate functional groups to provide various embodiments of the present invention.

[0231] Intermediate 1 (+ / -) trans-1-benzyl-3-methylpiperidin-4-ol To a solution of 1-benzyl-3-methylpiperidin-4-one (7.5 g, 36.9 mmol) in water (50 mL) and methanol (25 mL) was added phosphoric acid (85%, 4.25 g, 36.9 mmol) dropwise at −10° C. Sodium borohydride (2.79 g, 73.8 mmol) was then added portionwise, and the mixture was allowed to warm to room temperature and stirred overnight. The pH of the solution was adjusted to ∼9 by the addition of 5 M sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate (3 × 15 mL), and the combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the product as a viscous yellow oil (4.65 g, 22.65 mmol, 61.4% yield). LCMS(m / z):(M+H) + =206.3, 1 H NMR (500 MHz, chloroform-d) δ 7.52-7.12 (m, 5H), 3.71-3.40 (m, 2H), 3.22-3.10 (m, 1H), 2.93-2.86 (m, 1H), 2.85-2.79 (m, 1H), 2.11-1.99 (m, 1H), 1.97-1.87 (m, 1H), 1.76-1.56 (m, 3H), 1.54-1.39 (m, 1H), 1.05-0.86 (m, 3H).

[0232] Intermediate 2 (+ / -) tert-Butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate [ka] A solution of (+ / -)(trans)-1-benzyl-3-methylpiperidin-4-ol (2.5 g, 12.18 mmol) and Boc anhydride (3.11 mL, 13.39 mmol) in methanol (50 mL) was degassed and flushed with nitrogen (twice). 10% Pd-C (1.2 g, 1.128 mmol) was then added, and the mixture was re-evacuated and flushed with nitrogen (twice). It was then evacuated and filled with hydrogen (balloon) to 1 atm. The mixture was stirred vigorously under a hydrogen atmosphere for 2 days. It was then filtered through Celite, washed with methanol, and the washings were combined with the original filtrate. The combined solution was concentrated under reduced pressure to give the product as a viscous yellow oil (1.71 g, 7.94 mmol, 65.2% yield). LCMS: (m / z) (M-tBu+ACN+H) + =201.2; 1 H NMR (500 MHz, chloroform-d) δ 4.10-3.85 (m, 2H), 3.40-3.24 (m, 1H), 2.93-2.71 (m, 1H), 2.62-2.34 (m, 1H), 1.99-1.87 (m, 1H), 1.50-1.46 (m, 11H), 1.57-1.40 (m, 12H), 1.06-0.99 (m, 3H).

[0233] Intermediate 3 (+ / -) 5-Isopropoxy-2-((trans-3-methylpiperidin-4-yl)oxy)pyridine·TFA [ka] To a solution of (+ / -)tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate (120 mg, 0.557 mmol) in THF (4 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, and then 2-fluoro-5-isopropoxypyridine (0.100 mL, 0.836 mmol) was added. The reaction mixture was then heated at 60 °C overnight. Water was then added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil. The product was purified by preparative reverse-phase HPLC (eluent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The residue was then treated with a mixture of TFA (0.5 mL) and DCM (2 mL) for 3 hours at room temperature, and the resulting mixture was then concentrated under reduced pressure to give the product as a brown oil (40 mg, 0.110 mmol, 19.70% yield).

[0234] Intermediate 4 (+ / -) 2-((trans-3-ethylpiperidin-4-yl)oxy)-5-isopropoxypyridine [ka] To a solution of (+ / -)tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (100 mg, 0.436 mmol) in THF (2 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (1.090 mL, 1.090 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, then 2-fluoro-5-isopropoxypyridine (0.078 mL, 0.654 mmol) in THF (1 mL) was added, and the mixture was heated at 60°C under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, then dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a viscous yellow oil. The product was purified by flash silica chromatography (eluent: 20% ethyl acetate / hexane). The homogeneous fractions were combined and concentrated under reduced pressure to give the product as a viscous colorless oil, which was treated with TFA (1 mL) / DCM (3 mL) at room temperature overnight. The resulting mixture was then concentrated under reduced pressure to give 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

[0235] Intermediate 5 (+ / -) 5-Isopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in THF (2 mL) was added sodium hydride (60% mineral oil, 69.7 mg, 1.742 mmol) in portions. The mixture was stirred at room temperature for 10 minutes, and then 2-chloro-5-isopropylpyridine (163 mg, 1.045 mmol) in THF (1 mL) was added. The reaction mixture was then heated at 60°C overnight. Water was then added to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give a viscous brown oil. The resulting crude product was purified by preparative reverse-phase HPLC (solvent: CH3CN-HO-TFA). Homogeneous fractions were combined and concentrated under reduced pressure, and the resulting residue was treated with TFA (1 mL) in DCM (2 mL) for 3 hours at room temperature. The solution was concentrated under reduced pressure to give 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) +

[0236] Intermediate 6 (+ / -) 5-Isopropoxy-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of cis- and trans-tert-butyl-4-hydroxy-3-methylpiperidine-1-carboxylate (9:1 mixture, 120 mg, 0.557 mmol) in THF (4 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, then 2-fluoro-5-isopropoxypyridine (0.100 mL, 0.836 mmol) was added and heated at 60 °C overnight. Water was then added to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil. The resulting crude product was purified by reverse-phase preparative HPLC (solvent: CHCN-HO-TFA). Homogeneous fractions were combined and concentrated under reduced pressure overnight. The resulting residue was then dissolved in dichloromethane (2 mL) and TFA (0.5 mL) was added. The solution was stirred at room temperature for 3 hours, and the mixture was then concentrated under reduced pressure to give the TFA salt of the title compound as a viscous brown oil (40 mg, 0.110 mmol, 19.70% yield). LCMS: (m / z): (M+H) + =251.3

[0237] Intermediate 7 (+ / -) 2-((3,3-dimethylpiperidin-4-yl)oxy)-5-isopropoxypyridine [ka] To a solution of tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (80 mg, 0.349 mmol) in THF (2 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (0.872 mL, 0.872 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, and then 2-fluoro-5-isopropoxypyridine (0.062 mL, 0.523 mmol) was added. The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a brown oil. The product was purified by reverse-phase preparative HPLC (solvent: CHCN-HO-TFA), and homogeneous fractions were collected and concentrated under reduced pressure. The resulting 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 under reduced pressure to give the TFA salt of the title compound as a viscous brown oil (24 mg, 0.063 mmol, 18.18% yield). (m / z): (M+H) + =251.3

[0238] Intermediate 8 (+ / -) 5-(Difluoromethyl)-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (120 mg, 0.557 mmol) in THF (2 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (1.393 mL, 1.393 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, and then 2-chloro-5-(trifluoromethyl)pyridine (137 mg, 0.836 mmol) in THF (1 mL) was added, and the mixture was heated at 60 °C overnight. Water was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was then purified by reverse-phase preparative HPLC (solvent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The resulting residue was then dissolved in dichloromethane (1 mL) and treated with TFA (0.5 mL) for 3 hours at room temperature. The mixture was then concentrated under reduced pressure to give the TFA salt of the title compound as a viscous brown oil (160 mg, 0.340 mmol, 61.0% yield). LCMS: (m / z): (M+H) + =243.3

[0239] Intermediate 9 (+ / -) 2-Isopropyl-6-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in anhydrous THF (2 mL) was added sodium hydride (69.7 mg, 1.742 mmol, 60% mineral oil) in portions. After the addition, the reaction mixture was stirred at room temperature for 10 minutes. Then, 2-chloro-6-isopropylpyridine (163 mg, 1.045 mmol) in THF (1 mL) was added, and the mixture was heated at 60°C overnight under a nitrogen atmosphere. Water was then added to quench the reaction, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a viscous brown oil. The product was purified by preparative reverse-phase HPLC (solvent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL) and TFA (1 mL) was added, after which the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give the TFA salt of the title compound as a viscous yellow oil (53 mg, 0.115 mmol, 16.45% yield). LCMS: (m / z): (M+H) +. = 235.1

[0240] Intermediate 10 (+ / -) 2-((cis-3-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridine [ka] To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in anhydrous THF (2 mL) was added sodium hydride (69.7 mg, 1.742 mmol, 60% mineral oil). The mixture was stirred at room temperature for 10 minutes, then 2-chloro-5-(trifluoromethyl)pyridine (190 mg, 1.045 mmol) in THF (1 mL) was added, heated at 60 °C for 3 hours, and quenched by the addition of water. The mixture was then extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using reverse-phase preparative HPLC (solvent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The resulting residue was then dissolved in dichloromethane (2 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give the TFA salt of the title compound as a white solid (157 mg, 0.419 mmol, 60.2% yield). LCMS: (m / z): (M+H) + = 260.9

[0241] Intermediate 11 (+ / -) 4-Isopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (150 mg, 0.697 mmol) in THF (2 mL) was added dropwise a 1.0 M solution of potassium bis(trimethylsilyl)amide (1.742 mL, 1.742 mmol) in THF. The mixture was stirred at room temperature for 30 minutes, and then 2-chloro-4-isopropylpyridine (163 mg, 1.045 mmol) in THF (1 mL) was added. The mixture was then heated at 60°C overnight under a nitrogen atmosphere. Water was then added to quench the reaction. The mixture was then extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a viscous brown oil. The product was purified using reverse-phase preparative HPLC (solvent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The resulting 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 and then concentrated under reduced pressure to give the TFA salt of the title compound as a viscous yellow oil (42 mg, 0.091 mmol, 13.04% yield). LCMS: (m / z): (M+H) + =235.0

[0242] Intermediate 12 (+ / -) 5-Cyclopropyl-2-((cis-3-methylpiperidin-4-yl)oxy)pyridine [ka] To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (100 mg, 0.464 mmol) in anhydrous THF (2 mL), potassium bis(trimethylsilyl)amide (1.161 mL, 1.161 mmol) in THF (1.0 M) was added dropwise and stirred at room temperature for 30 minutes. Next, 2-chloro-5-cyclopropylpyridine (107 mg, 0.697 mmol) in THF (1 mL) was added and heated at 60 °C overnight. The reaction was quenched by the addition of water. The resulting mixture was extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product as a viscous yellow oil. The product was purified using reverse-phase preparative HPLC (solvent: CHCN-HO-TFA), and homogenous fractions were combined and concentrated under reduced pressure. The resulting residue was then dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours before being concentrated under reduced pressure to give the TFA salt of the title compound as a viscous yellow oil (10 mg, 0.043 mmol, 9.27% ​​yield). LCMS: (m / z): (M+H) + = 232.55

[0243] Other related intermediates can be prepared by the method described in the scheme below, which involves the reaction of the potassium alkoxide salt of an unprotected hydroxypiperidine with a chloropyrimidine.

[0244] Intermediate 13 (+ / -)2-((cis-3-methylpiperidin-4-yl)oxy)pyrimidine [ka] To a solution of (+ / -)cis-3-methylpiperidin-4-ol (104 mg, 0.901 mmol) in THF (2 mL), potassium bis(trimethylsilyl)amide (0.901 mL, 0.901 mmol) was added and stirred at room temperature for 30 minutes. The amino alcohol did not completely dissolve in THF and remained in suspension even after the addition of the base. A solution of 2-chloropyrimidine (86 mg, 0.751 mmol) in THF (1 mL) was then added, and stirring was continued at 60 °C overnight. The reaction mixture was then concentrated to dryness, and the resulting crude residue was used in the next step. LCMS: Start %B: 0, End %B: 100; Gradient Time: 3.00 min; Stop Time: 3.50 min; Flow Rate: 1.0 mL / min; Wavelength 1: 220 nm; Solvent Pair: AA S174 / S175; Solvent A: A1 = CH3CN:water (5:95, containing 10 mM NH4OAc) S174; Solvent B: B1 = CH3CN:water (95:5, containing 10 mM NH4OAc) S175; Column ID: 3; Name: 3 (AA SCP 3 min) Acquity BEH C18 1.7 μm 2.1 x 50 mm; Retention Time = 1.213 min; (m / z): (M+H) + =194.2

[0245] Using similar procedures, the following intermediates were prepared: [ka]

[0246] [Table 3]

[0247] Intermediate 20 6-Fluoro-1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [ka] To a solution of 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2 g, 11.04 mmol) in DMF (10 mL) was added sodium hydride (0.530 g, 13.25 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at room temperature for 30 minutes, then methyl iodide (0.829 mL, 13.25 mmol) was added dropwise and stirred at room temperature overnight. Water was added to quench the reaction, and the yellow solid was collected by filtration. The solid was suspended in ethyl acetate, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product as a yellow solid (395 mg, 2.024 mmol, 18.33% yield). LCMS: (m / z): (M+H) + = 196; 1 H NMR(400MHz, DMSO-d6)δ 7.83-7.74(m, 2H), 7.55-7.46(m, 1H)

[0248] Intermediate 21 6-Fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione [ka] To a solution of ethyl 2-nitroacetate (293 mg, 2.198 mmol) in NMP (5 mL) in a round-bottom flask at 0 °C, sodium hydride (96 mg, 2.398 mmol, 60% dispersion in mineral oil) was added portionwise and stirred at 0 °C for 5 minutes, then at room temperature for 15 minutes. 6-Fluoro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (390 mg, 1.998 mmol) was then added and heated at 120 °C for 2 hours. LC / MS showed the reaction was complete, and the reaction was quenched by adding ice water. The mixture was acidified with HCl solution (1N). Ethyl ether was added to give 6-fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione (140 mg, 0.588 mmol, 29.4% yield) as a yellow solid. LCMS: (m / z): (M+H) + =239

[0249] Intermediate 22 4-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one [ka] In a sealed tube, 6-fluoro-1-methyl-3-nitroquinoline-2,4(1H,3H)-dione (140 mg, 0.588 mmol) and phosphoryl chloride (3 mL, 32.2 mmol) were added and heated at 95 °C for 4 h. The mixture was added to ice water, neutralized with saturated NaHCO solution, and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried (MgSO) and concentrated to give 4-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (140 mg, 0.546 mmol, 93% yield) as an orange solid. LCMS: (m / z) 257 (MH + )

[0250] Intermediate 23 3-aminopicolinic acid ethyl ester [ka] To a stirred suspension of 3-aminopicolinic acid (150 g, 1086 mmol) in ethanol (1500 mL) was added H2SO4 (463 mL, 8688 mmol) using a dropping funnel (1 L) over 60 min at 0–5 °C. After the addition was complete, the clear brown solution was refluxed at 90 °C for 24 h. The reaction mixture was then cooled to room temperature and then poured onto ice in a 10 L beaker equipped with an overhead stirrer. The mixture was basified to pH ∼9 with NH4OH solution (∼2 L required) and stirred at room temperature for an additional 60 min. A solid material was observed in the beaker, which was filtered through a Buchner funnel, washed with water (1 L), and dried under vacuum to give the product (60 g) as a gray-yellow solid. The filtrate was extracted with DCM (3 x 1000 mL) and the combined extracts were washed with brine (1 x 1.5 L), dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 3-aminopicolinate (116 g, 691 mmol, 63.6% yield). LCMS: m / z=167.2 (m / z):(M+H); RT 0.78 min; Method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water:acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B for 0.6 min (flow rate 1.5 mL / min), followed by a gradient of 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0251] Intermediate 24 Ethyl 3-acetamidopicolinate [ka] To a stirred solution of ethyl 3-aminopicolinate (115 g, 692 mmol) in THF (1000 mL) was added AcO (588 mL, 6228 mmol) at room temperature and heated at 60 °C under a nitrogen atmosphere for 7–8 h. The reaction mixture was cooled to room temperature, and the volatiles were evaporated under vacuum at a water bath temperature of 50 °C. The acetic acid was then removed under high vacuum at 50 °C to give an off-white solid. The solid was triturated with petroleum ether (500 mL), stirred at room temperature for 30 min, and then filtered through a Buchner funnel and washed with petroleum ether (500 mL). The filtrate was dried under vacuum at room temperature for 3 h to give ethyl 3-acetamidopicolinate (139 g, 641 mmol, 93% yield) as an off-white solid. LCMS: m / z=209.3 (m / z):(M+H); rt 0.76 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water:acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0252] Intermediate 25 3-(N-methylacetamido)picolinic acid ethyl ester [ka] 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, resulting in a slight exotherm. A portion of the resulting brown mixture was stirred at room temperature for ∼8 h, and the reaction was quenched with water (1500 mL). After a slight exotherm was observed, the mixture was extracted with DCM (3 × 1000 mL). The combined extracts were washed with water (2 × 1000 mL), and the aqueous layer was re-extracted with DCM (2 × 500 mL). The combined organic solvents were washed with brine (2 × 1000 mL), dried over Na2SO4, filtered, concentrated at ∼50 °C, and then dried under vacuum at ∼60 °C to give a brown solution containing some DMF. The material was then dried under high vacuum at 58 °C for 25 min to remove the DMF and yield a brown solid. This was dissolved in petroleum ether (1000 mL), stirred for 30 min at room temperature, filtered through a Buchner funnel, washed with petroleum ether (500 mL) after filtration, and dried under vacuum for 8 h to give ethyl 3-(N-methylacetamido)picolinate (70 g, 302 mmol, 84% yield) as a brown solid. LCMS: m / z=223.2 (m / z):(M+H); rt 0.64 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water:acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B for 0.6 min (flow rate 1.5 mL / min); followed by gradient 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0253] Intermediate 26 2-(Ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide [ka] To a stirred, brown, clear solution of ethyl 3-(N-methylacetamido)picolinate (70 g, 315 mmol) in DCM (700 mL) was added urea hydrogen peroxide (44.4 g, 472 mmol) at 0–5°C, followed by the slow addition of trifluoroacetic anhydride (66.7 mL, 472 mmol) via a 100 mL addition funnel over 40 min. The mixture solidified during the addition of trifluoroacetic anhydride. After the addition was complete, the reaction mixture was stirred at room temperature for ∼2 h, quenched with 10% NaHCO3 solution (700 mL), and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over Na2SO4, and concentrated to give 2-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide (70 g, 285 mmol, 90% yield) as a pale yellow solid. LCMS: m / z=239.0 (m / z):(M+H); rt 0.48 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0254] Intermediate 27 6-cyano-3-(N-methylacetamido)picolinic acid ethyl ester [ka] To a stirred pale yellow solution of 2-(ethoxycarbonyl)-3-(N-methylacetamido)pyridine 1-oxide (50 g, 210 mmol) in DCM (500 mL) was added trimethylsilyl cyanide (39.4 mL, 294 mmol) at room temperature, 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 min, followed by the slow addition of TEA (41.0 mL, 294 mmol) via a 50 mL addition funnel over 20 min. An exothermic reaction was observed during the addition of TEA. The reaction mixture became a suspension (TEA salt) and was continued to stir at the same temperature for 2.5 h. The reaction was quenched with 10% NaHCO3 solution (500 mL) and extracted with DCM (3 x 300 mL). The combined organic layers were washed with brine (2x250 mL), then dried over NaSO and concentrated to give a pale yellow crude product. The crude material was purified on a normal phase RediSep silica column (ISCO®, eluent: EA / petroleum ether). The product was isolated at 65-70% EA / petroleum ether and the fractions were concentrated to give ethyl 6-cyano-3-(N-methylacetamido)picolinate (43 g, 83% yield) as a pale brown liquid. LCMS: m / z=248.0 (m / z):(M+H); rt 1.26 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0255] Intermediate 28 8-Hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a stirred solution of ethyl 6-cyano-3-(N-methylacetamido)picolinate (0.9 g, 3.64 mmol) in tetrahydrofuran (10 mL) was added KHMDS (4.80 mL, 4.37 mmol) over 10 min at -78 °C and stirred for 15 min. The reaction mixture was slowly warmed to room temperature over 30 min and then stirred for an additional 90 min. The reaction mixture was cooled to 0 °C and quenched with saturated sodium bicarbonate solution (70 mL). The mixture was diluted with ethyl acetate (2 × 100 mL), and the aqueous layer was collected and acidified with HCl (1.5 N) to pH 3.0. After stirring the mixture for 15 min, a solid formed, which was filtered through a Buchner funnel to give 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (550 mg, 75% yield) as a brown solid. LCMS: m / z=202.0 (m / z):(M+H); rt 0.36 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0256] Intermediate 29 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.55 g, 2.73 mmol) in acetonitrile (10 mL) was added POCl (1.53 mL, 16.4 mmol) and heated to 85 °C for 5 minutes, then stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The reaction mixture was cooled to 0 °C and quenched by the addition of saturated sodium bicarbonate solution (50 mL). The resulting mixture was extracted with DCM (3 × 100 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.25 g, 29.1% yield) as a brown solid. LCMS: m / z=220.2 (m / z):(M+H); rt 1.53 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0257] Intermediate 30 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid [ka] To a mixture of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.3 g, 1.49 mmol), DMAP (0.018 g, 0.15 mmol), and TEA (0.312 mL, 2.24 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (0.269 mL, 1.640 mmol) in DCM (3 mL) dropwise at 0° C. and stirred for 3 h. The reaction mixture was diluted with DCM and washed with water, and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (0.45 g, 81% yield) as a pale yellow solid. LCMS: m / z=334.2 (m / z):(M+H); rt 1.40 min; LCMS Method: Column: AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: Buffer:Acetonitrile (95:5); Mobile Phase B: Buffer:Acetonitrile (5:95), Buffer: 10 mM Ammonium Acetate; Gradient: 20-100% B over 2.0 min, followed by 100% B for 0.2 min (Flow Rate 0.7 mL / min).

[0258] Intermediate 31 8-Hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (1 g, 4.97 mmol) in acetic acid (10 mL) was added nitric acid (0.666 mL, 14.91 mmol) and heated for 1 hour at 80° C. The reaction mixture was cooled to room temperature, diluted with water, stirred for 10 minutes, and the solid was filtered to give 8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.805 g, 65.1% yield) as a pale yellow solid. LCMS: m / z=247.2 (M+H); rt 1.19 min; LCMS method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water:acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water:acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B for 0.6 min (flow rate 1.5 mL / min); Gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0259] Intermediate 32 8-chloro-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] 8-Hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (192 mg, 0.780 mmol) was dissolved in a mixture of acetonitrile (3.1 mL) and DIEA (0.272 mL, 1.560 mmol) to give a yellow solution. POCl3 (0.131 mL, 1.404 mmol) was then added and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Benzyltriethylammonium chloride (200 mg, 0.878 mmol) was added and the mixture was heated at 65 °C for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The resulting solution was poured onto ice. After allowing to stand for approximately 1 hour, the mixture was transferred to a separatory funnel. The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed sequentially with K2HPO4 solution (1.5 M), saturated NaHCO3 solution, and then brine. The mixture was then dried over MgSO4, filtered and concentrated in vacuo to give a brown crystalline solid (204 mg, 90% yield). LCMS: (m / z): (M+H) + =264.9; 1 H NMR (chloroform-d) δ 8.03 (d, J=8.8Hz, 1H), 7.89-7.97 (m, 1H), 3.82 (s, 3H)

[0260] Intermediate 33 6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid [ka] To a suspension of 8-hydroxy-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.25 g, 1.016 mmol) in dry DCM (10 mL) was added TEA (0.212 mL, 1.523 mmol) followed by trifluoromethanesulfonic anhydride (0.183 mL, 1.117 mmol) under a nitrogen atmosphere at 0° C. and stirred for 3 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 6-cyano-1-methyl-3-nitro-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (0.25 g, 48.8% yield) as a light brown solid. LCMS: m / z=379.2 (m / z):(M+H); rt 1.66 min; LCMS Method: Column: AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: Buffer:acetonitrile (95:5); Mobile Phase B: Buffer:acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B over 2.0 min, followed by 100% B for 0.2 min (flow rate 0.7 mL / min).

[0261] Intermediate 34 7-Bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a stirred solution of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (1000 mg, 4.97 mmol) in dry DMF (10 mL) was added NBS (973 mg, 5.47 mmol) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give a residue. The resulting residue was dissolved in water and stirred for 10 minutes. The solid was filtered and washed with petroleum ether to give 7-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.8 g, 56.9% yield) as an off-white solid. LCMS: m / z=282 (M+H); rt 1.60 min; Method: Column: KINETEX-XB-C18 (75x3 mm; 2.6 μm); Mobile phase A: 10 mM ammonium formate in water: acetonitrile (98:2); Mobile phase B: 10 mM ammonium formate in water: acetonitrile (2:98); Gradient: 20-100% B over 4 min (flow rate 1.0 mL / min), followed by 100% B over 0.6 min (flow rate 1.5 mL / min); followed by gradient: 100-20% B over 0.1 min (flow rate 1.5 mL / min).

[0262] Intermediate 35 3-Bromo-6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid [ka] To a stirred solution of 7-bromo-8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (0.175 g, 0.625 mmol) and TEA (0.131 mL, 0.937 mmol) in dry DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.137 mL, 0.812 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with water followed by brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-bromo-6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (190 mg, 53.9% yield) as a pale yellow solid. LCMS: m / z=414 (m / z):(M+H); rt 1.61 min; Method: Column: AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile phase A: Buffer:acetonitrile (95:5); Mobile phase B: Buffer:acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B over 2.0 min, followed by 100% B for 0.3 min (flow rate 0.7 mL / min).

[0263] Intermediate 36 Ethyl 3-amino-6-bromopicolinate [ka] Ethyl 3-aminopicolinate (8.0 g, 48.1 mmol) was suspended in water (66 mL) in a three-neck flask (250 mL) equipped with a mechanical stirrer, an addition funnel, and a thermocouple temperature probe. The flask was immersed in a room-temperature water bath to control the temperature, and sulfuric acid (1.7 mL, 31.9 mmol) and acetic acid (3.31 mL, 57.8 mmol) were slowly added. A solution of bromine (2.5 mL, 48.5 mmol) in acetic acid (17.5 mL, 306 mmol) was added to the reaction mixture over 15 minutes at ambient temperature with vigorous stirring, maintaining the reaction mixture temperature below 23°C. The water bath was removed, and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction suspension was filtered, rinsed with a small amount of water, and then dried under vacuum at room temperature to give ethyl 3-amino-6-bromopicolinate (9.305 g) as a yellow solid. LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 100% water (containing 0.05% trifluoroacetic acid); Mobile phase B: 100% acetonitrile (containing 0.05% trifluoroacetic acid); Temperature: 40 °C; Gradient: 2 to 98% B for 1.5 min, followed by 98% B for 0.5 min; Flow rate: 0.8 mL / min; Detection: UV (220 nm); Retention time: 0.94 min; Observed adduct: [M+H]; Observed molecular weight: 245.0; 1 H NMR(DMSO-d6)δ 7.44 (d, J=8.8Hz, 1H), 7.21 (d, J=8.7Hz, 1H), 6.88 (br. s., 2H), 4.29 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H)

[0264] Intermediate 37 Ethyl 3-acetamido-6-bromopicolinate [ka] Ethyl 3-amino-6-bromopicolinate (1.31 g, 5.35 mmol) was dissolved in THF (6 mL), followed by the addition of acetic anhydride (1.6 mL, 16.96 mmol) to form a suspension (partial solution). This mixture was heated to reflux under a nitrogen atmosphere and became a homogeneous solution within 15 minutes. This mixture was refluxed for 4 hours, and the volatiles were removed using a vacuum rotary evaporator. A small amount of ethyl acetate was added to the residue, and the nearly colorless solid was filtered and dried under vacuum to give ethyl 3-acetamido-6-bromopicolinate (787 mg). LCMS: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 100% water (containing 0.05% trifluoroacetic acid); Mobile phase B: 100% acetonitrile (containing 0.05% trifluoroacetic acid); Temperature: 40 °C; Gradient: 2 to 98% B for 1.5 min, followed by 98% B for 0.5 min; Flow rate: 0.8 mL / min; Detection: UV (220 nm); Retention time: 0.98 min; Observed adduct: [M+H]; Observed molecular weight: 287.0; 1 H 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=7.1 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); removal of the solvent from the filtrate gave an additional 695 mg of product (87% pure).

[0265] Intermediate 38 6-Bromo-3-(N-methylacetamido)picolinic acid ethyl ester [ka] Ethyl 3-acetamido-6-bromopicolinate (5 g, 17.41 mmol) was dissolved in DMF (100 mL), followed by the addition of cesium carbonate (8.15 g, 25.01 mmol) and methyl iodide (1.75 mL, 28.0 mmol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours and 40 minutes. The solvent was removed under reduced pressure using a rotary evaporator / vacuum pump combination, and ethyl acetate and DCM, as well as chloroform and toluene, were added to the residue. The mixture was filtered through Celite to remove salts. The solvent was again removed under reduced pressure on the rotary evaporator, and the reaction residue was again dissolved in chloroform and toluene and filtered through Celite to remove any remaining traces of insoluble material. The solvent was removed under reduced pressure to give the product (5.35 g) as an orange oil. LCMS; Column: Waters Acquity BEH 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: 10:90 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 90:10 acetonitrile:water (containing 0.1% TFA); Temperature: 40 °C; Gradient elution from 0% B to 100% B over 2 min, followed by 100% B for 1 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection volume: 1 μL; Retention time: 1.07 min; Observed adduct: [M+H]; Observed molecular weight: 301.1; Proton NMR shows characteristics of hindered rotation (rotamer). 1 H NMR (500MHz, chloroform-d) δ 7.72 (d, J=8.4Hz, 0.8H), 7.66 (d, J=8.4Hz, 0.2H), 7.51 (d, J=8.4Hz, 0.8H), 7.45 (d, J=8.4Hz, 0.2H), 4.50-4.36(m, 2.0H), 3.37 (s, 0.6H), 3.19 (s, 2.4H), 2.24 (s, 0.6H), 1.82 (s, 2.5H), 1.43-1.36(m, 3.1H)

[0266] Intermediate 39 6-Bromo-4-hydroxy-1-methyl-1,5-naphthyridin-2(1H)-one [ka] A round-bottom flask (25 mL) was charged with KHMDS (4.3 mL, 2.150 mmol, 0.5 M toluene solution) and cooled to -78 °C under a nitrogen atmosphere. A solution of ethyl 6-bromo-3-(N-methylacetamido)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 allowed to warm to room temperature, transferred to a separatory funnel (60 mL), and a 1:1 mixture of ethyl acetate and water was added. After layer separation, the aqueous layer was acidified with 1 N hydrochloric acid (2.5 mL) and concentrated on a rotary evaporator using a vacuum pump. The resulting crude residue was stirred in an Erlenmeyer flask with water (7 mL). The yellow solid was collected and dried under vacuum to give the title compound (130.2 mg, 72%). LCMS; Column: Waters Acquity UPLC BEH C18 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: 100% water (containing 0.05% TFA); Mobile phase B: 100% acetonitrile (containing 0.05% TFA); Temperature: 40°C; Gradient: 2% B to 98% B over 1.5 min, followed by 100% B for 1 min; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm); Injection volume: 3 μL; Retention time: 0.8 min; Observed adducts: [M+H]; Observed molecular weights: 254.9, 256.9

[0267] Intermediate 40 6-Bromo-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid [ka] In a round-bottom flask, 6-bromo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione (200 mg, 0.784 mmol) was combined with DMAP (9.58 mg, 0.078 mmol), DIPEA (0.205 mL, 1.176 mmol), and DCM (20 mL), and 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 h, and LC / MS analysis indicated the reaction was complete. The solvent was removed under reduced pressure, and the resulting crude material was purified by chromatography (hexane:ethyl acetate (1:1), 24 g silica gel column) to give the product as a white solid (260 mg, 86%). Analytical LC / MS conditions: injection volume = 1 μL, initial %B: 0, final %B: 100, gradient time: 2 min, flow rate 1 mL / min, wavelength 220 nm, solvent: acetonitrile / water / TFA, solvent A: 10% acetonitrile / 90% water / 0.1% TFA, solvent B: 90% acetonitrile / 10% water / 0.1% TFA, column: Acquity BEH C18 21x50 mm 1.7 μm, column oven temperature = 40 °C; LC / MS results: retention time 1.5 min, observed masses 386.7, 388.7 (M + )

[0268] Intermediate 41 2-Cyanoacetyl chloride [ka] To a solution of 2-cyanoacetic acid (500 mg, 5.88 mmol) in CHCl (5 mL) was added a few drops of DMF, followed by the dropwise addition of a 2 M solution of oxalyl chloride (3.23 mL, 6.47 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 2 h and concentrated.

[0269] Intermediate 42 6-Bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of ethyl 3-amino-6-bromopicolinate (1.3 g, 5.30 mmol) in 10 mL of DCM was added DIPEA (2.78 mL, 15.91 mmol). 2-Cyanoacetyl chloride (0.609 g, 5.88 mmol) in 10 mL of DCM was then slowly added and stirred at room temperature for 10 minutes. LC / MS indicated the formation of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate (MS: 312). The reaction was quenched with water, and the resulting mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried (MgSO), and concentrated to give a thick brownish oil as the crude product. The crude product was triturated with ethyl acetate / hexanes to give a yellow solid. 1 H NMR confirmed the structure of the cyclic product and DIPEA. The product was washed with HCl solution (1N) to give 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (650 mg, 2.443 mmol, 46.1% yield) as an off-white solid. 1 H NMR(DMSO-d6); LCMS:(m / z): 266, 268(MH + ), >90% pure

[0270] Intermediate 43 6-Bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 6-bromo-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (250 mg, 0.940 mmol) in DMF (5 mL) was added sodium hydride (113 mg, 2.82 mmol, 60% mineral oil) in portions and stirred at room temperature for 30 minutes. Iodomethane (0.176 mL, 2.82 mmol) was added, and the reaction mixture was stirred at room temperature overnight.

[0271] Intermediate 44 6-Bromo-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid [ka] To a stirred solution of 6-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (0.6 g, 2.14 mmol) in DCM (8 mL) was added TEA (0.896 mL, 6.43 mmol) and DMAP (0.026 g, 0.214 mmol) at 0 °C, followed by trifluoromethanesulfonic anhydride (0.724 mL, 4.28 mmol). The mixture was slowly warmed to room temperature and stirred for 3 h. The reaction was quenched with water (50 mL) and diluted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid. The crude compound was triturated with DCM and hexane (1:4) to give 6-bromo-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (700 mg, 79% yield) as a brown solid. LCMS: m / z = 414.1 (m / z): (M+H); rt 0.65 min; LCMS Method: Column: AQUITY UPLC BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: Buffer:acetonitrile (95:5); Mobile Phase B: Buffer:acetonitrile (5:95), Buffer: 10 mM ammonium acetate; Gradient: 20-100% B over 2.0 min, followed by 100% B for 0.3 min (flow rate 0.7 mL / min).

[0272] Intermediate 45 6-Bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a round-bottom flask (500 mL) containing 6-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (2.50 g, 8.93 mmol) in acetonitrile (89 mL) was added DIEA (9.4 mL, 53.8 mmol), and the mixture was stirred for 2 minutes to form a homogeneous solution. POCl (3.3 mL, 35.4 mmol) was then added, followed by benzyltriethylammonium chloride (2.68 g, 11.77 mmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was first concentrated under reduced pressure and then concentrated under high vacuum. The resulting residue was then poured into ice-cold 1.5 M KHPO solution, and after 30 minutes, the mixture was extracted three times with chloroform. The combined extracts were washed sequentially with KHPO solution, 1 N HCl solution, and then brine. The organic solvent was then dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a brown solid (3.1 g). The product was purified by flash silica gel chromatography (eluent: 2% ethyl acetate / DCM) and homogenous fractions were combined and concentrated in vacuo to give the product as a yellow solid (1.922 g, 72% yield). LCMS: (m / z): (M+H) + =298.05; 1 H NMR (500 MHz, chloroform-d) δ 7.83 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H)

[0273] Intermediate 46 4,6-Dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] In a dry glass pressure tube, HCl / dioxane solution (4 M, 20 mL, 80 mmol) was added to 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (1 g, 3.35 mmol). The reaction mixture was sealed and heated at 85° C. for 4 days. The mixture was then cooled and concentrated under reduced pressure. The resulting residue was triturated with methanol, and the solid was collected by filtration and dried under reduced pressure to give the hydrochloride salt of the title compound as a brown solid (0.78 g, 2.68 mmol, 80% yield). (LCMS: (m / z): (M+H) + =254.15, 1 H NMR(400MHz, DMSO-d6)δ 8.29 (d, J=9.0Hz, 1H), 8.00 (d, J=9.0Hz, 1H), 3.66 (s, 3H)

[0274] Intermediate 47 6-Bromo-3-(2-cyanoacetamido)picolinic acid ethyl ester [ka] 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 1-propanephosphonic anhydride (10.78 mL, 17.95 mmol). The mixture was stirred at room temperature for 16 hours and then carefully quenched with water (100 mL). The resulting mixture was stirred for 15 minutes, during which time a solid separated and was collected by filtration to give the product as a yellow solid (2.45 g, 7.85 mmol, 96% yield).

[0275] Intermediate 48 6-cyano-3-(2-cyanoacetamido)picolinic acid ethyl ester [ka] To a stirred solution of ethyl 6-bromo-3-(2-cyanoacetamido)picolinate (200 mg, 0.641 mmol) in NMP (8 mL) under a nitrogen atmosphere, zinc (8.38 mg, 0.128 mmol) and zinc cyanide (150 mg, 1.282 mmol) were added and purged with nitrogen for 3 minutes. Then, dppf (21.31 mg, 0.038 mmol) and Pd2(dba)3 (58.7 mg, 0.064 mmol) were added and purged with nitrogen for an additional 3 minutes. The mixture was then heated to 80 °C for 5 minutes, stirred for an additional 1 hour, and cooled to room temperature. Water was then added to quench the reaction, and the resulting mixture was filtered through Celite. The filtrate was extracted with ethyl acetate (3 × 100 mL), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash silica gel chromatography (eluent: 34%-39% ethyl acetate / petroleum ether). Homogeneous fractions were combined and concentrated under reduced pressure 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); Details: Method: %B: 0 min 5%: 1.1 min 95%: 1.7 min 95%; Column: Acquity BEH C18 (2.1 x 50 mm) 1.7 μm; Method: C: / MassLynx / BMS_2013; Flow Rate: 0.8 mL / min; LCMS RT = 1.10 min (MH). - =257.2

[0276] Intermediate 49 6,8-Dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] To a stirred solution of ethyl 6-cyano-3-(2-cyanoacetamido)picolinate (70 mg, 0.271 mmol) in DCM (5 mL) was added triethylamine (0.113 mL, 0.813 mmol), warmed to 45° C., and stirred for 3 h. The mixture was concentrated under reduced pressure, and the resulting residue was triturated with ethyl acetate for 15 min. The suspension was filtered, and the collected material was dried under reduced pressure to give the product as a brown solid (54 mg, 0.255 mmol, 94% yield). LCMS: (m / z): (M+H) + =213.2

[0277] Intermediate 50 5-Methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] To a stirred solution of 6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile (50 mg, 0.236 mmol) in DMF (3 mL) was added NaH (28.3 mg, 0.707 mmol) at 0 °C. The stirred mixture was then warmed to room temperature, and methyl iodide (0.044 mL, 0.707 mmol) was added, followed by stirring for 3 h under a nitrogen atmosphere. Water (10 mL) was added to quench the reaction, and the pH of the mixture was adjusted to ~6 with 1.5 N HCl. The resulting mixture was stirred for 15 min, during which time a solid separated out and was collected by filtration and then dried under vacuum to give the product as a brown solid (20 mg, 0.088 mmol, 37.5% yield). LCMS method: Column: Ascentis Express C8 (50X2.1mm; 2.7μm), Mobile phase A: (2%ACN / 98%H2O / 10mM NH4COOH), Mobile phase B: (98%ACN / 2%H2O / 10mM NH4COOH), Flow rate = 1mL / min, Time %B (0.0 0.0), (1.5 100.0), (3.2 100.0); LCMS RT=1.301 min; (m / z):(M+H) + =225.0

[0278] Intermediate 51 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] Starting material: 5-methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile hydrochloride, dried overnight under vacuum at 90 °C and used in the reaction. To a stirred suspension of 5-methyl-6,8-dioxo-5,6,7,8-tetrahydro-1,5-naphthyridine-2,7-dicarbonitrile hydrochloride (10 g, 38.1 mmol) in acetonitrile (100 mL) was added DIPEA (19.95 mL, 114 mmol). The resulting opaque brown solution was cooled to 0–5 °C, and POCl (40.8 mL, 438 mmol) was added slowly over ∼20 min. The mixture was then heated at 90 °C for ∼1 h. The reaction mixture was cooled to room temperature and then concentrated under high vacuum to give a light brown residue. Ice pellets were added, and the slurry was stirred for ∼15 min, during which time a free solid formed. The mixture was neutralized by the addition of saturated NaHCO3 solution, and the product was extracted with DCM (4 x 500 mL). The combined extracts were washed with brine (1 x 500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a brown solid. This was triturated with acetone (50 mL), and the product was collected by filtration and dried under reduced pressure to give a solid (6 g). The filtrate was concentrated, and the resulting residue was again triturated with acetone to give an additional solid (2.4 g). The above solids were combined to give the title compound as a brown solid (8.4 g, 33.8 mmol, 89% yield).

[0279] Intermediate 52 6-chloro-4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile hydrochloride (300 mg, 1.033 mmol) and triethylamine (0.720 mL, 5.16 mmol) in DMF (5 mL), piperidin-4-ol (110 mg, 1.084 mmol) was added, stirred overnight at room temperature, and quenched with water. After stirring, a yellow solid separated, which was collected by filtration and dried under reduced pressure to give the title compound as a yellow solid (325 mg, 1.020 mmol, 99% yield). LCMS: (m / z): (M+H) + =319.08, 1 H NMR(500MHz, DMSO-d6)δ 8.04 (d, J=9.2Hz, 1H), 7.77 (d, J=9.2Hz, 1H), 4.72 (d, J=4.4Hz, 1H), 4.14-3.99(m, 2H), 3.87 (br dd, J=8.1, 4.0Hz, 1H), 3.59 (ddd, J=13.0, 9.4, 3.3Hz, 2H), 3.53 (s, 3H), 1.98 (ddd, J=9.4, 5.7, 2.9Hz, 2H), 1.70 (td, J=8.4, 4.4Hz, 2H)

[0280] Intermediate 53 (+ / -) 6-Bromo-4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (1.0 g, 3.35 mmol) in DMF (8 mL) was added (+ / -)cis-3-methylpiperidin-4-ol (0.405 g, 3.52 mmol) and triethylamine (1.167 mL, 8.37 mmol) and stirred at room temperature for 2 hours. Water was then added, and an orange solid separated and collected by filtration. The crude product was triturated with methanol / dichloromethane and filtered to give the final product as a yellow solid (0.82 g, 2.174 mmol, 64.9% yield). LCMS: (m / z): (M+H) + =376.9; 1 H NMR (400MHz, DMSO-d6) δ 7.97-7.87(m, 1H), 8.02-7.79(m, 1H), 4.79-4.64(m, 1H), 3.91-3.71(m, 4H), 3.51 (s, 3H), 3.45 (br dd, J=12.3, 10.1Hz, 1H), 2.06 (ddd, J=9.7, 6.5, 3.2Hz, 1H), 1.87 (br d, J=3.9Hz, 2H), 0.91 (d, J=6.8Hz, 3H)

[0281] Example 49 (+ / -) 6-Bromo-1-methyl-4-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 4-(tert-pentyl)phenol (65.3 mg, 0.398 mmol) in THF (8 mL), solid-state triphenylphosphine (194 mg, 0.583 mmol) was added and stirred at room temperature for 5 minutes. Di-tert-butyl (E)-diazene-1,2-dicarboxylate (98 mg, 0.424 mmol) and (+ / -) 6-bromo-4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (100 mg, 0.265 mmol) were then added and stirred at room temperature for 6 days. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The product was purified using a reverse-phase preparative HPLC column (eluent: CHCN-HO-TFA). Homogeneous fractions were collected and concentrated under reduced pressure to give the TFA salt of the title compound as a pale yellow solid (31 mg, 0.049 mmol, 18.34% yield). LCMS: (m / z): (M+H) + =523.0; 1 H NMR (400MHz, acetone) δ 7.98 (d, J=9.0Hz, 1H), 7.86 (d, J=9.0Hz, 1H), 7.30 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 4.40-4.32(m, 2H), 4.31-4.23(m, 1H), 3.77 (ddd, J=13.4, 10.9, 2.8Hz, 1H), 3.63 (s, 3H), 3.35 (dd, J=13.2, 9.8Hz, 1H), 2.54-2.42(m, 1H), 2.37 (ddd, J=12.6, 6.2, 2.9Hz, 1H), 1.97-1.78(m, 1H), 1.15 (d, J=6.6Hz, 3H), 0.69 (t, J=7.5Hz, 3H) The solvent impurity peaks obscure some of the compounds, and not all peaks can be identified.

[0282] Intermediate 55 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] To a stirred suspension of 8-hydroxy-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile hydrochloride (10 g, 38.1 mmol) in acetonitrile (100 mL) was added DIPEA (19.95 mL, 114 mmol). The opaque brown solution was cooled to 0–5°C. POCl3 (40.8 mL, 438 mmol) was then added slowly via addition funnel over ~20 min. The mixture was heated at 90°C for 1 min and then cooled to room temperature. The mixture was concentrated under high vacuum to give a light brown residue. Ice pellets were added, and the resulting mixture was stirred for ~15 min, during which time a free solid formed. The mixture was neutralized with saturated NaHCO3 solution and then extracted with DCM (4 x 500 mL). The combined extracts were washed with brine (1 x 500 mL), dried over Na2SO4, filtered, and concentrated to give a brown material. The product was triturated with acetone (50 mL) and the solid collected by filtration. It was dried under vacuum to give the title compound as a brown solid (6 g). The filtrate was concentrated and the resulting residue was triturated again with acetone to give more product. The combined filtrate was dried under vacuum to give the title compound as a brown solid (8.4 g, 33.8 mmol, 89% yield). LCMS: (M+H+ HO) + =262.0; 1 H NMR(300MHz, DMSO-d6)δ 8.49-8.37(m, 2H), 3.72-3.61(m, 3H)

[0283] Intermediate 56 8-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a mixture of acetonitrile (18.00 mL) and N-ethyl-N-isopropylpropan-2-amine (0.95 mL, 5.45 mmol) in a round-bottom flask (50 mL) was added 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (0.600 g, 1.800 mmol) and 4-hydroxypiperidine (0.266 g, 2.63 mmol) and heated at 80° C. for 1 hour. The heterogeneous mixture was then cooled in an ice bath at 0° C. and the resulting yellow precipitate was collected by filtration and then dried under vacuum to give the product as a yellow solid (473 mg, 92%). 1 H NMR (500MHz, chloroform-d)δ 7.80 (d, J=8.7Hz, 0.9H), 7.70 (d, J=8.7Hz, 0.9H), 6.23 (s, 0.9H), 4.02 (br s, 1.0H), 3.94-3.85(m, 2.0H), 3.64 (s, 3.0H), 3.27 (ddd, J=12.5, 9.1, 3.3Hz, 2.0H), 2.15-2.07(m, 1.9H), 1.87-1.76(m, 2.0H)

[0284] Intermediate 57 (+ / -) 4-(cis-4-hydroxy-3-methylpiperidin-1-yl)-6-cyano-1-methyl-1,5-naphthyridin-2(1H)-one [ka] To a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (100 mg, 0.300 mmol) and Hunig's base (0.105 mL, 0.600 mmol) in DMF (4 mL) was added cis-3-methylpiperidin-4-ol (34.6 mg, 0.300 mmol) and heated at 85° C. overnight. The solvent was removed under high vacuum, the residue was dissolved in EtOAc, and the resulting solution was washed with water (twice) and brine (once). The mixture was then dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow solid (89 mg, 100%). LCMS: R T=1.01(m / z):(M+H) + =299.03; 1 H NMR(400MHz,)δ 8.02 (d, J=7.8Hz, 1H), 7.85 (d, J=7.8Hz, 1H), 5.88 (s, 1H), 3.72 (dddd, J=4.5, 4.2, 3.5, 3.4Hz, 1H), 3.65 (s, 3H), 3.36 (dd, J=3.1, -12.2Hz, 1H), 3.35 (ddd, J=12.1, 3.1, -12.2Hz, 1H), 2.88 (dd, J=12.2, 4.5Hz, 1H), 2.88 (dd, J=12.2, 11.8Hz, 1H), 2.12 (dqt, J=11.8, 6.6, 4.5Hz, 1H), 1.78 (dddd, J=12.1, 3.4, 3.1, -13.5Hz, 1H), 1.72 (ddd, J=3.5, 3.1, -13.5Hz, 1H), 0.98 (d, J=6.6Hz, 3H)

[0285] Intermediate 58 (+ / -)tert-Butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate [ka] 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) was added Boc anhydride (2.419 mL, 10.42 mmol) and stirred at room temperature overnight. The mixture was then diluted with DCM and acidified to pH ∼6 with 1N HCl solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvent was concentrated under reduced pressure to give a yellowish oil. The crude product was then purified by flash chromatography (eluent: 10-40% ethyl acetate / hexane). Homogeneous fractions were collected and concentrated under reduced pressure to give the product as a colorless viscous oil (1.35 g, 6.27 mmol, 72.2% yield). LCMS: 216 (m / z): (M+H) + =216; 1H NMR (500 MHz, chloroform-d) δ 3.98-3.81 (m, 1H), 3.69-3.52 (m, 2H), 3.42-3.25 (m, 1H), 3.16-2.96 (m, 1H), 1.86-1.64 (m, 3H), 1.48 (s, 9H), 0.96 (d, J=7.0 Hz, 3H).

[0286] Intermediate 59 (+ / -) tert-Butyl trans-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate To a solution of (+ / -)tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (0.982 g, 4.56 mmol) in THF (8 mL) was added triphenylphosphine (1.675 g, 6.39 mmol) and benzoic acid (0.780 g, 6.39 mmol). Di-tert-butyl (E)-diazene-1,2-dicarboxylate (1.470 g, 6.39 mmol) in THF was then added dropwise at 0 °C. The mixture was warmed and stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (eluent: ethyl acetate / hexane (10-30%)). Homogeneous fractions were combined and concentrated in vacuo to give the product as a viscous colorless oil (0.77 g, 2.411 mmol, 52.9% yield). 1 H NMR(500MHz, chloroform-d)δ 8.07 (d, J=7.6Hz, 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=6.6Hz, 3H)

[0287] Intermediate 60 (+ / -) tert-Butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate [ka] To a solution of (+ / -)tert-butyl trans-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate (0.761 g, 2.383 mmol) in MeOH (10 mL) was added sodium hydroxide (0.476 g, 11.91 mmol) and stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was then separated and washed successively with water and brine, then dried over MgSO4, filtered, and concentrated under reduced pressure to give the product as a viscous colorless oil (446 mg, 2.072 mmol, 87% yield). 1 H NMR (500 MHz, chloroform-d) δ 4.16-3.88 (m, 2H), 3.37-3.19 (m, 1H), 2.93-2.75 (m, 1H), 2.67-2.34 (m, br, 1H), 2.00-1.84 (m, 1H), 1.55-1.40 (m, 11H), 1.02 (d, J=6.6 Hz, 3H).

[0288] Intermediate 61 (+ / -) trans-3-methylpiperidin-4-ol [ka] To a solution of (+ / -)tert-butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate (440 mg, 2.044 mmol) in DCM (3 mL) was added TFA (1 mL, 12.98 mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure to give the TFA salt of the title compound as a colorless viscous oil.

[0289] Intermediate 62 (+ / -) 8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonate (487 mg, 1.460 mmol) and Hunig's base (1.275 mL, 7.30 mmol) in DMF (5 mL) was added (+ / -) trans-3-methylpiperidin-4-ol trifluoroacetic acid (468 mg, 2.044 mmol) and heated at 85 °C overnight. The mixture was diluted with water, and a yellow solid separated. This was collected by filtration and dried under vacuum to give the product as a solid (385 mg, 1.290 mmol, 88% yield). LCMS: (m / z): (M+H) + =299; 1 H NMR (500MHz, DMSO-d6) δ 8.16 (d, J=8.9Hz, 1H), 8.07 (d, J=8.9Hz, 1H), 6.07 (s, 1H), 4.72 (d, J=5.5Hz, 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=6.6Hz, 3H)

[0290] Intermediate 63 6-cyano-1-methyl-4-(5-methyl-3,6-dihydropyridin-1(2H)-yl)-1,5-naphthyridin-2(1H)-one [ka] Triphenylphosphine (polymer-bound, 3 mmol / g, 2.212 mL, 0.664 mmol) was added to a dry scintillation vial (20 mL) fitted with a septum, followed by evacuation and flushing with nitrogen. THF (2 mL) was then added, followed after ∼1 min by the addition of 4-(trifluoromethoxy)phenol (0.039 mL, 0.302 mmol). The 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 in one portion via syringe. The mixture was shaken on a shaker for 3 minutes, after which a solution of 8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90 mg, 0.302 mmol) in THF (2 mL) was added in one portion, and the vial was then shaken at room temperature overnight. The reaction mixture was then filtered and concentrated to dryness. The resulting residue was dissolved in DMF (2 mL), and this solution was fractionated by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 31% B at 0 min, followed by 31–71% B at 25 min, then 100% B at 5 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by UV signal, and the product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 32.9 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 100.0%; Observed mass: 281.11; Retention time: 1.69 minutes. 1 H NMR(500MHz, 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)

[0291] Intermediate 64 (+ / -)tert-Butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate [ka] To a solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (2.5 g, 11.00 mmol) in THF (10 mL) was added dropwise L-Selectride / THF solution (1 M, 16.50 mL, 16.50 mmol) at -78 °C. Under a nitrogen atmosphere, the mixture was stirred for 2 h, followed by the addition of EtOH (2 mL), water (5 mL), and NaOH solution (1 M, 5 mL) successively at the same temperature. The mixture was then warmed to 0 °C, and 30% aqueous HO (5 mL) was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 2 h and then diluted with EtOAc. An insoluble white solid precipitated and was removed by filtration. The filtrate was collected, washed successively with saturated NaHCO solution and brine, then dried over MgSO, filtered, and concentrated under reduced pressure to give a colorless viscous oil. The mixture was fractionated using flash silica gel chromatography (eluent: 10-30% EtOAc / hexanes). Homogeneous fractions were collected and concentrated in vacuo to give the product as a colorless oil (1.6 g, 6.98 mmol, 63.4% yield). LCMS: (M-(t-Bu)+ACN+H). + =215.35; 1 H NMR (500 MHz, chloroform-d): All peaks were very broad.

[0292] Intermediate 65 (+ / -)cis-3-Ethylpiperidin-4-ol TFA salt [ka] To a solution of tert-butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate (1.6 g, 6.98 mmol) in DCM (5 mL) was added TFA (2 mL, 26.0 mmol), stirred at room temperature overnight, and then concentrated under reduced pressure to give the TFA salt of the product as a viscous pale yellow oil (1.65 g, 6.78 mmol, 97% yield). 1H NMR (500 MHz, chloroform-d) δ 9.03-8.82 (m, 1H), 8.82-8.60 (m, 1H), 4.19-4.02 (m, 1H), 3.38-3.20 (m, 2H), 3.17-2.99 (m, 2H), 2.08-1.97 (m, 2H), 1.90-1.80 (m, 1H), 1.52-1.40 (m, 1H), 1.40-1.29 (m, 1H), 1.02-0.94 (m, 3H).

[0293] Intermediate 66 (+ / -) tert-Butyl trans-4-(benzoyloxy)-3-ethylpiperidine-1-carboxylate [ka] To a solution of (+ / -)tert-butyl cis-3-ethyl-4-hydroxypiperidine-1-carboxylate (1.5 g, 6.54 mmol) in THF (10 mL) was added triphenylphosphine (2.402 g, 9.16 mmol) and benzoic acid (1.118 g, 9.16 mmol), and di-tert-butyl (E)-diazene-1,2-dicarboxylate (2.109 g, 9.16 mmol) was added portionwise at 0 °C. The mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (eluent: 0-20% ethyl acetate in hexanes). Homogeneous fractions were combined and concentrated under reduced pressure to give the product as a viscous, colorless oil (1.70 g, 5.10 mmol, 78% yield).

[0294] Intermediate 67 (+ / -) tert-Butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate [ka] To a solution of (+ / -)tert-butyl trans-4-(benzoyloxy)-3-ethylpiperidine-1-carboxylate (1.7 g, 5.10 mmol) in MeOH (15 mL) was added sodium hydroxide (1.020 g, 25.5 mmol) and stirred at room temperature for 3 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was then separated and washed successively with water and brine, then dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a viscous oil. The mixture was fractionated by flash silica gel chromatography (eluent: 10–30% ethyl acetate / hexanes). Homogeneous fractions were combined and concentrated under reduced pressure to give tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (0.68 g, 2.97 mmol, 58.2% yield) as a viscous colorless oil. 1 H NMR (500 MHz, chloroform-d) δ 3.95 (br d, J = 12.6 Hz, 1H), 3.46 (br d, J = 0.9 Hz, 1H), 3.05-2.87 (m, 1H), 1.97-1.87 (m, 1H), 1.75 (br d, J = 1.6 Hz, 1H), 1.51-1.40 (m, 11H), 1.40-1.30 (m, 1H), 1.25-1.15 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H); the spectrum is broad and cannot be fully identified.

[0295] Intermediate 68 (+ / -) trans-3-Ethylpiperidin-4-ol·TFA [ka] To a solution of (+ / -)tert-butyl trans-3-ethyl-4-hydroxypiperidine-1-carboxylate (0.3 g, 1.308 mmol) in dichloromethane (3 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure.

[0296] Intermediate 69 (+ / -) 8-(cis-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (1.370 g, 4.11 mmol) and Hunig's base (2.87 mL, 16.45 mmol) in DMF (8 mL) was added (+ / -)cis-3-ethylpiperidin-4-ol·TFA salt (1.2 g, 4.93 mmol) and heated at 85°C overnight under a nitrogen atmosphere. The resulting mixture was diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over MgSO4, filtered, and concentrated in vacuo to give 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 give the product as a pale yellow solid (520 mg, 1.665 mmol, 40.5% yield). A portion of the filtrate was then purified (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 10% B for 0 min, followed by 10–50% B over 22 min, then 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The product-containing fractions were combined and dried in a centrifugal evaporator. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes. 1 H NMR(500MHz, DMSO-d6)δ 8.17-8.10(m, 1H), 8.10-8.02(m, 1H), 6.11-6.01(m, 1H), 4.70-4.62(m, 1H), 3.91-3.84(m, 1H), 3.75-3.66(m, 1H), 3.31-3.22(m, 1H), 3.14-3.05(m, 1H), 1.87-1.71(m, 2H), 1.71-1.60(m, 1H), 1.49-1.36(m, 1H), 1.34-1.21(m, 1H), 1.00-0.86(m, 3H) The peaks cannot be completely identified because the water suppression function was used.

[0297] Intermediate 70 4-(3-chlorophenoxy)piperidine [ka] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (100 mg, 0.497 mmol) and 3-chlorophenol (63.9 mg, 0.497 mmol) in THF (5 mL) was added triphenylphosphine (156 mg, 0.596 mmol) and stirred at 0 °C for 15 minutes, after which DIAD (0.116 mL, 0.596 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and stirred overnight under a nitrogen atmosphere. Water was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. This material was dissolved in DCM (5 mL), and TFA (3 mL) 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 by reverse-phase preparative HPLC (CHOH-HO-TFA buffer system), and homogenous fractions were combined and concentrated under reduced pressure to give the TFA salt of the title compound as a white solid (101.5 mg, 0.312 mmol, 62.7% yield). LCMS: (m / z): (M+H). + =212.0; 1 H NMR (400MHz, methanol-d4) δ 7.30 (t, J=8.2Hz, 1H), 7.08-7.06(m, 1H), 7.03-6.99(m, 1H), 6.98-6.94(m, 1H), 4.96-4.87(m, 1H), 4.79-4.66(m, 1H), 3.48-3.37(m, 2H), 3.28-3.15(m, 2H), 2.25-2.11(m, 2H), 2.11-1.96(m, 2H)

[0298] Intermediate 71 4-(3-fluoro-5-methylphenoxy)piperidine [ka] Solid-bound triphenylphosphine (3 mmol / g) (289 mg, 1.1 mmol) was placed in a dry scintillation vial (20 mL), which was then capped and flushed with nitrogen. The resin was suspended in DCM (3 mL), and the reaction vial was shaken on a shaker for 2 minutes. 3-Fluoro-5-methylphenol (0.081 mL, 0.745 mmol) was then added in one portion, and the mixture was further stirred briefly, followed by the addition of di-tert-butyl (E)-diazene-1,2-dicarboxylate (183 mg, 0.795 mmol). The mixture was then shaken for an additional 3 minutes, and tert-butyl 4-hydroxypiperidine-1-carboxylate (100 mg, 0.497 mmol) was then added, and the resulting mixture was stirred overnight at room temperature. The suspension was filtered, the resin washed with DCM, and the combined wash solution and filtrate were concentrated under reduced pressure. The resulting residue was treated with a mixed solvent of DCM and TFA (1:1, 6 mL) for 30 minutes, and then the mixture was concentrated to dryness. The resulting residue was dissolved in DCM, and NaOH solution (5N) was added, followed by extraction with DCM. The combined extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the product as a colorless oil (63 mg, 61%). LCMS: (m / z): (M+H) + =210.10

[0299] Intermediate 72 (+ / -)cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidine·TFA [ka] To a solution of tert-butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (100 mg, 0.464 mmol) in THF (2 mL) was added potassium bis(trimethylsilyl)amide (1.0 M, 1.161 mL, 1.161 mmol, in THF) and stirred at room temperature for 30 minutes, followed by the addition of 1-fluoro-4-(trifluoromethyl)benzene (114 mg, 0.697 mmol) in THF (1 mL). The reaction mixture was then heated at 60° C. for 4 hours, and the reaction was then quenched with water. The resulting mixture was extracted with ethyl acetate, and the organic layer was separated, washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure to give an oil. The product was fractionated by preparative HPLC (solvent: CHCN-HO-TFA), and the homogeneous fractions were combined and concentrated under reduced pressure for 24 hours. The resulting residue was dissolved in DCM (3 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure to give the TFA salt of the title compound as a white solid (120 mg, 0.321 mmol, 69.2% yield). LCMS: (m / z): (M+H) + =260; 1 H NMR (CD3OD): 1 H NMR (500MHz, methanol-d4)δ 7.63 (br d, J=8.5Hz, 2H), 7.19 (d, J=8.5Hz, 2H), 4.77-4.73(m, 1H), 3.28-3.12(m, 4H), 2.33-2.18(m, 2H), 2.08-1.93(m, 1H), 1.11 (d, J=6.9Hz, 3H)

[0300] The following method (Method A) was used to prepare many of the examples of the present invention described below.

[0301] Example 1 6-Fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one [ka] To a solution of 4-chloro-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (20.44 mg, 0.080 mmol) and Hunig's base (0.028 mL, 0.159 mmol) in DMF, 4-(3-fluoro-5-methylphenoxy)piperidine (20 mg, 0.096 mmol) was added and stirred at room temperature overnight. The resulting crude reaction mixture was then filtered and subsequently purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5µm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 41-81% B over 25 min, followed by 100% B for 6 min; flow rate: 20mL / min). The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 22.1mg, and its purity was estimated to be 100% by LCMS analysis. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 100.0%; Observed mass: 429.95; Retention time: 2.33 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 7.76-7.57 (m, 3H), 6.75-6.62 (m, 2H), 6.64-6.55 (m, 1H), 4.68 (dt, J=7.7, 3.9 Hz, 1H), 3.66 (s, 3H), 3.45-3.31 (m, 2H), 2.30 (s, 3H), 2.22-2.10 (m, 2H), 1.97-1.81 (m, 2H); not all peaks in the spectrum could be identified due to water suppression in the NMR.

[0302] The following examples were prepared according to Method B.

[0303] Example 2 6-Fluoro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one [ka] Solid-bound triphenylphosphine (3 mmol / g, 82.0 mg, 0.313 mmol) was placed in a dry scintillation vial (20 mL), and the resin was suspended in anhydrous DCM (3 mL) under a nitrogen atmosphere for 2 minutes. 4-Isopropylphenol (12.72 mg, 0.093 mmol) was added, followed 5 minutes later by the addition of di-tert-butyl (E)-diazene-1,2-dicarboxylate (22.93 mg, 0.100 mmol). The resulting suspension was agitated on a shaker for 3 minutes, and then 6-fluoro-4-(4-hydroxypiperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (20 mg, 0.062 mmol) was added in one portion. Shaking was continued overnight at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was triturated with DMF (2 mL). The suspension was then filtered, and the resulting crude product was fractionated by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5µm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 53-93% B over 20 min, followed by 100% B over 6 min; flow rate: 20mL / min). The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 8.8mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile Phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, followed by 100% B for 0.75 min; 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 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes. 1 H NMR (600 MHz, DMSO-d6) 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 of the piperazine ring were obscured by water suppression during the spectrum acquisition.

[0304] The following examples were prepared in a similar manner. [ka] [ka] [Table 4]

[0305] Many of the examples below were prepared using Method A.

[0306] Example 10 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile hydrochloride (15 mg, 0.052 mmol) in DMF (1.5 mL), 4-(3-methoxyphenoxy)piperidine hydrochloride (13.84 mg, 0.057 mmol) and triethylamine (0.036 mL, 0.258 mmol) were added and stirred at room temperature for 2 hours. This was then diluted with methanol (2 mL), filtered, and the resulting crude mixture was purified by preparative LC / MS (conditions: column: XBridge C18, 19 x 200 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 38–78% B over 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min). The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 16.5 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, followed by 100% B for 0.75 min; 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 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 100.0%; Observed mass: 425.1; Retention time: 2.09 minutes. 1 H NMR (600 MHz, DMSO-d6) δ 8.07 (br d, J = 8.8 Hz, 1H), 7.81 (br d, J = 8.8 Hz, 1H), 7.20 (t, J = 8.3 Hz, 1H), 6.65-6.49 (m, 3H), 4.78 (dt, J = 7.4, 3.8 Hz, 1H), 4.09-3.97 (m, 2H), 3.77-3.69 (m, 4H), 2.19 (td, J = 6.1, 2.9 Hz, 2H), 1.99-1.79 (m, 2H); not all peaks were identified due to water suppression used during spectral acquisition.

[0307] The following method (Method B) was used to prepare many of the examples of the present invention described below.

[0308] Example 11 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 2-(trifluoromethyl)phenol (30.5 mg, 0.188 mmol) in DCM (2 mL) was added triphenylphosphine (49.4 mg, 0.188 mmol) and stirred at room temperature for 5 minutes. 6-Chloro-4-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15 mg, 0.047 mmol) was added. After stirring for 15 minutes, DIAD (0.037 mL, 0.188 mmol) was added in one portion. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in a 1:1 mixture of CHCl and DMF (1.8 mL). This crude mixture was then purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5µm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 41-81% B over 20 min, followed by 100% B for 5 min; flow rate: 20mL / min), and the product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 8.0mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 100.0%; Observed Mass: 463.02; Retention Time: 2.20 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes. 1 H NMR(500MHz, DMSO-d6)δ 8.08 (d, J=8.8Hz, 1H), 7.82 (d, J=8.9Hz, 1H), 7.65 (br d, J=7.0Hz, 2H), 7.42 (br d, J=8.5Hz, 1H), 7.11 (t, J=7.6Hz, 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=12.2Hz, 2H), 1.96 (br d, J=6.4Hz, 2H)

[0309] Similar to the above two methods, the following examples can be prepared. [ka] [ka] [Table 5] [Table 6] [Table 7]

[0310] Example 47 6-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] To a solution of 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.167 mmol) in DMF (4 mL), 4-(4-(trifluoromethoxy)phenoxy)piperidine (48.1 mg, 0.184 mmol) and triethylamine (0.093 mL, 0.670 mmol) were added and stirred at room temperature for 2 hours. The mixture was then quenched with water. A white solid separated and was collected by filtration (85 mg). This material (20 mg) was dissolved in a 1:1 mixture of DMF and methanol and purified by preparative LC / MS (conditions: column: XBridge C18, 19 x 200 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 41–81% B over 15 min, followed by 100% B for 5 min; flow rate: 20 mL / min). The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 9.5 mg, and its estimated purity by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes. 1 H 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); not all peaks were identified due to water suppression used during spectral acquisition.

[0311] Example 48 6-Methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka] 6-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (30 mg, 0.057 mmol), 5-[di(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'h-[1,4']bipyrazole (3.80 mg, 5.73 μmol), cesium carbonate (18.68 mg, 0.057 mmol), and Pd(OAc) (0.644 mg, 2.87 μmol) were placed in a dry vial, which was then sealed, evacuated, and flushed with nitrogen. Acetonitrile (2 mL) and methanol (0.1 mL) were then added and heated at 80 °C overnight. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 41% B at 0 min, followed by 41–81% B over 25 min, then 100% B at 4 min; flow rate: 20 mL / min; column temperature: 25 °C), and fractions were collected as determined by MS and UV signals. The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 14.4 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile Phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes. 1 H NMR(500MHz, DMSO-d6)δ 8.02 (br d, J=9.2Hz, 1H), 7.31 (br d, J=8.5Hz, 2H), 7.25 (d, J=9.2Hz, 1H), 7.15 (br d, J=8.9Hz, 2H), 4.78 (br s, 1H), 4.14 (br d, J=12.5Hz, 2H), 3.92 (s, 3H), 3.79 (br t, J=9.6Hz, 2H), 2.22 (br s, 2H), 1.91 (br d, J=8.2Hz, 2H)

[0312] Example 50 5-Methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] 6-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (50 mg, 0.096 mmol), zinc (1.249 mg, 0.019 mmol), zinc cyanide (6.73 mg, 0.057 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (7.80 mg, 9.55 μmol) were placed in a dry microwave vial, sealed, evacuated, and then flushed with nitrogen. NMP (4 mL) was added, and the resulting mixture was irradiated in a 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 by reverse-phase preparative HPLC (solvent: CHCN-H2O-TFA), and the homogenous fractions were combined, neutralized with saturated NaHCO3 solution, and then concentrated under reduced pressure to give the product as a yellow solid (22.5 mg, 0.048 mmol, 50.2% yield). LCMS: (m / z) (Method 2) RT = 4.39 min; (m / z): (M+H). + =470.1; 1 H NMR (400MHz, DMSO-d6) δ 8.28 (d, J=8.8Hz, 1H), 8.17 (d, J=8.8Hz, 1H), 7.31 (br d, J=8.8Hz, 2H), 7.16 (d, J=9.0Hz, 2H), 4.83 (dt, J=7.4, 4.0Hz, 1H), 4.18-4.02(m, 2H), 3.78 (br t, J=9.5Hz, 2H), 3.55 (s, 3H), 2.29-2.16(m, 2H), 2.02-1.84(m, 2H)

[0313] Example 51 5-Methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a solution of 8-chloro-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (15 mg, 0.057 mmol) in DMF (1.5 mL) was added 4-(4-(trifluoromethoxy)phenoxy)piperidine (16.29 mg, 0.062 mmol) and triethylamine (0.024 mL, 0.170 mmol) and stirred at room temperature over the weekend. The resulting solution was purified by preparative HPLC (conditions: column: XBridge C18, 19 x 200 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 38–78% B over 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min). The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 19.1 mg, and its estimated purity by LCMS analysis was 99%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile Phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; 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 minutes. 1 H NMR (500 MHz, DMSO-d6) 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); not all peaks were identified due to water suppression used during spectral acquisition.

[0314] The following method (Method A) was used to prepare many of the examples of the present invention described below. Example 52 5-Methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] In a 1-dram pressure vial, 8-chloro-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (22 mg, 0.100 mmol) was dissolved in DMF (1 mL). 4-[4-trifluoromethoxy)phenoxy]piperidine (32 mg, 0.122 mmol) was added along with potassium carbonate (40 mg, 0.289 mmol), and the reaction vessel was evacuated, flushed with nitrogen, sealed, and heated in an oil bath at 90° C. for 5 hours. The reaction mixture was cooled and then diluted to a volume of 2 mL with acetonitrile and 2 drops of water. The mixture was filtered, and the resulting crude solution was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 33% B for 0 min, followed by 33–73% B over 25 min, then 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 26.1 mg, and its estimated purity by LC / MS analysis was 100%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 100.0%; Observed Mass: 445.12; Retention Time: 2.19 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 100.0%; Observed mass: 445.14; Retention time: 2.12 minutes. 1 H 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, 2.0H), 6.12 (s, 0.9H), 4.65 (br s, 0.9H), 3.75 (br d, J = 7.6 Hz, 1.2H), 3.51 (s, 2.6H), 3.33 (br t, J = 9.2 Hz, 1.9H), 2.09 (br s, 2.1H), 1.83–1.68 (m, 2.0H); chemical shifts are uncorrected after water suppression.

[0315] The following method (Method B) was used to prepare many of the examples of the present invention described below.

[0316] Example 53 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile [ka] Triphenylphosphine resin (56.6 mg, 0.217 mmol (70 mg, approximately 3 mmol / g)) was placed in a vacuum-cooled, oven-dried 1-dram vial and suspended in NMP (0.5 mL) under a nitrogen atmosphere for 2 minutes. 4-tert-butylphenol (23.0 mg, 0.153 mmol) and di-tert-butyl azodicarboxylate (43 mg, 0.187 mmol) were then added, and the mixture was shaken for an additional 5 minutes. A solution of 8-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile / N-methyl-2-pyrrolidinone (1.0 mL, 28 mg, 0.098 mmol) was added, and the resulting suspension was placed under a nitrogen atmosphere and stirred overnight at room temperature. The mixture was then filtered, and the volume of the filtrate was adjusted to 2 mL with additional NMP. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 42% B for 0 min, followed by 42–82% B over 20 min, then 100% B for 7 min; flow rate: 20 mL / min; column temperature: 25 °C), and fractions were collected as determined by MS and UV signals. The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 0.6 mg, and its estimated purity by LCMS analysis was 96%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 96.4%; Observed mass: 417.06; Retention time: 2.27 minutes. 1 H NMR(500MHz, DMSO-d6)δ 8.16 (d, J=8.9Hz, 1.0H), 8.08 (d, J=8.9Hz, 1.0H), 7.29 (br d, J=8.5Hz, 1.9H), 6.92 (br d, J=8.5Hz, 1.9H), 6.14 (s, 1.0H), 4.66-4.55(m, 1.0H), 3.82-3.71(m, 2.0H), 3.54 (s, 1.8H), 2.16-2.02(m, 2.0H), 1.88-1.73(m, 1.9H), 1.25 (s, 9.0H)

[0317] In a similar manner the following examples can be prepared: [ka] [ka] [Table 8]

[0318] The following method (Method A) was used to prepare many of the examples of the present invention described below.

[0319] Example 66 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] In a dry 1-dram vial, 8-(4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (29 mg, 0.102 mmol) was dissolved in NMP (1.0 mL) under a nitrogen atmosphere. Sodium hydride (10.6 mg, 0.265 mmol) was then added, and the mixture was stirred for 3 minutes. 2-Fluoro-5-isopropoxypyridine (17 μL, 0.142 mmol) was then added. Stirring was continued overnight at room temperature, and the reaction was quenched by the addition of acetic acid. The volume was adjusted to 1.8 mL with NMP, and the mixture was filtered and then purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 30% B for 0 min, 30–70% B over 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected based on MS signal, and the product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 9.3 mg, and its estimated purity by LC / MS analysis was 97%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes. 1 H NMR(500MHz, DMSO-d6)δ 8.11 (s, 1.0H), 8.07-8.00(m, 1.0H), 7.79 (d, J=3.1Hz, 1.0H), 7.36 (dd, J=8.9, 3.1Hz, 1.0H), 6.74 (d, J=9.2Hz, 1.0H), 6.13 (s, 1.0H), 5.18-5.04(m, 1.0H), 4.49 (dt, J=12.1, 6.0Hz, 1.0H), 3.85-3.71(m, 1.7H), 3.30 (br t, J=9.6Hz, 1.8H), 2.18-2.04(m, 2.0H), 1.87-1.71 (m, 2.0H), 1.23 (d, J=5.8Hz, 6.0H); water suppression at 3.57 ppm reduces the intensity of the adjacent peak.

[0320] In a similar manner the following examples can be prepared: [ka] [Table 9] [Table 10]

[0321] Example 79 (+ / -) 6-Cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one [ka] Triphenylphosphine (polymer-bound) (3 mmol / g, 2.212 mL, 0.664 mmol) was added to a dry scintillation vial (20 mL) fitted with a septum, followed by evacuation and flushing with nitrogen. THF (2 mL) was then added, followed approximately 1 minute later by the addition of 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 in one portion via syringe. After the mixture was shaken on a shaker for 3 minutes, a solution of 8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90 mg, 0.302 mmol) in THF (2 mL) was added in one portion. The vial was then shaken overnight at room temperature, after which the reaction mixture was filtered and concentrated to dryness. The resulting residue was dissolved in DMF (2 mL), and the resulting solution was fractionated by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 31% B at 0 min, followed by 31–71% B at 25 min, then 100% B at 5 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by UV signal. The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 13.3 mg, and its estimated purity by LCMS analysis was 100%. Analytical LC / MS was used to determine purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 results: Purity: 100.0%; Observed mass: 459.08; Retention time: 2.28 minutes. 1 H NMR(500MHz, 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=3.7Hz, 1H), 4.04-3.87(m, 2H), 3.59-3.51(m, 3H), 3.39 (br d, J=4.9Hz, 1H), 3.23-3.12(m, 1H), 3.00 (br t, J=11.3Hz, 1H), 2.24-1.99(m, 2H), 1.73-1.58(m, 1H), 1.07 (br d, J=6.4Hz, 3H)

[0322] The above racemic mixture was resolved by chiral SFC separation. Approximately 10.1 mg of the racemate was resolved into two peaks and collected in IPA (containing 0.1% DEA). The chiral purity of the isolate was estimated based on the preparative chromatogram below. [Table 11] Preparative chromatogram conditions Equipment:Waters 100 Prep SFC Column: Chiral AD, 30x250mm, 5μ Mobile phase: 75%CO2 / 25%IPA (contains 0.1%DEA) Flow rate conditions: 100mL / min Detection wavelength: 220 nm Injection details: 1500 μL of 10.1 mg dissolved in MeOH (4 mL) Analytical chromatogram conditions (before fractionation) Equipment: Shimadzu Nexera UC SFC Column: Chiralpak AD, 4.6x100mm, 5μ Mobile phase: 75%CO2 / 25%IPA (contains 0.1%DEA) Flow rate conditions: 2mL / min Detection wavelength: 220 nm Example 80: Isolate 1 (first eluting peak) Example 81: Isolate 2 (second eluting peak)

[0323] Example 80 6-Cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one(rel) [ka] Analytical LC / MS was used to determine purity. Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 98.7%; Observed Mass: 458.95; Retention Time: 2.2 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; 1 H NMR (500MHz, 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)

[0324] Example 81 6-Cyano-1-methyl-4-(trans-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one(rel) [ka] Analytical LC / MS was used to determine purity. Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 99.3%; Observed Mass: 459.08; Retention Time: 2.2 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; 1 H NMR (500MHz, 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)

[0325] Similar manufacturing and purification methods were used to prepare the following examples. [ka] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0326] Using the above scheme and related methods shown in the tables, the following examples can be prepared by using (+ / -)8-(cis-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile as the coupling compound for an appropriately functionalized phenol in the Mitsunobu reaction. Isolation of the specific enantiomer can be achieved using the preparative HPLC method described above. [ka] [Table 17]

[0327] Using a related method, the following examples can be prepared by using (+ / -)8-(cis-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as the coupling compound for an appropriately functionalized phenol in a Mitsunobu reaction. Isolation of the specific enantiomer can be achieved using the preparative HPLC method described above. [ka] [Table 18] TIFF0007653440000127.tif244130 TIFF0007653440000128.tif56130

[0328] Using the relevant methods shown in the table above, the following examples can be prepared by using (+ / -)8-(trans-3-ethyl-4-hydroxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as the coupling compound for an appropriately functionalized phenol in the Mitsunobu reaction. Isolation of the specific enantiomers is achieved using the preparative HPLC method described above. [ka] [Table 19]

[0329] Using the relevant methods shown in the table above, the following examples can be prepared by using (+ / -)8-(trans-4-hydroxy-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as the coupling compound for an appropriately functionalized phenol in the Mitsunobu reaction. Isolation of the specific enantiomers is achieved using the preparative HPLC method described above. [ka] [Table 20] [Table 21]

[0330] Example 185 (+ / -) 5-Methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide

change

[0331] Example 186 (+ / -) 5-Methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka] To a solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid (30 mg, 0.090 mmol) and Hunig's base (0.047 mL, 0.270 mmol) in DMF (1.5 mL) was added (+ / -)cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidine TFA salt (40.3 mg, 0.108 mmol), and the mixture was heated at 85° C. overnight. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 40% B for 0 min, 40–80% B over 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C), and fractions were collected as determined by MS signal. Product-containing fractions were combined and dried on a centrifugal evaporator. Analytical LC / MS was used to determine final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.20-8.11 (m, 1H), 8.11-8.02 (m, 1H), 7.72-7.57 (m, 2H), 7.32-7.12 (m, 2H), 6.21-6.06 (m, 1H), 4.84-4.63 (m, 1H), 2.36-2.21 (m, 1H), 2.10-1.90 (m, 2H), 1.12-0.91 (m, 3H); not all peaks were identified due to the water suppression used.

[0332] The racemic product was further fractionated using SFC chiral chromatography to obtain and identify the following two enantiomers:

[0333] Example 187 5-Methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile(rel) [ka] Analytical LC / MS was used to determine the final purity. Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 97.5%; Observed Mass: 442.84; Retention Time: 2.25 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; 1 H NMR (500 MHz, DMSO-d) 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); not all peaks were identified due to the water suppression used.

[0334] Example 188 5-Methyl-8-(cis-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile(rel) [ka] Analytical LC / MS was used to determine the final purity. Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 1 Results: Purity: 96.4%; Observed Mass: 443.09; Retention Time: 2.26 minutes; Injection 2 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 Acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0% B to 100% B over 3 minutes, followed by 100% B for 0.50 minutes; 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 minutes; 1 H 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), 1.06-0.92 (m, 3H); not all peaks were identified due to the water suppression used.

[0335] The following examples were prepared using the relevant methods shown in the table above, by using 3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid as the coupling compound for the appropriately functionalized (+ / -)cis-3-methyl-4-aryloxypiperidine intermediate. Isolation of the specific enantiomers is achieved using the preparative HPLC method described above. [ka] [Table 22]

[0336] Using the relevant method shown in the table above, the following examples were prepared by using 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid as a coupling compound for the appropriately functionalized (+ / -) trans-3-ethyl-4-aryloxypiperidine intermediate. Isolation of the specific enantiomer can be achieved using the preparative HPLC method described above. [ka] [Table 23]

[0337] Using the relevant method shown in the table above, the following examples were prepared by using 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid as a coupling compound for the appropriately functionalized (+ / -) trans-3-methyl-4-aryloxypiperidine intermediate. Isolation of the specific enantiomer can be achieved using the preparative HPLC method described above. [ka] [Table 24]

[0338] Using the relevant methods shown in the table above, and SN Ar By using 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid as a coupling compound for the appropriately functionalized (+ / -)cis-3-ethyl-4-aryloxypiperidine intermediate in the reaction, the following examples can be prepared. Isolation of the specific enantiomers can be carried out using the preparative HPLC method described above. [ka] [Table 25]

[0339] The following examples were prepared using the relevant methods shown in the table above, using 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yltrifluoromethanesulfonic acid as the coupling compound for the appropriately functionalized (+ / -)cis-3-methyl-4-aryloxypiperidine intermediate. Isolation of the specific enantiomers can be achieved using the preparative HPLC method described above. [ka] [Table 26] [Table 27]

[0340] Example 228 (+ / -) 8-(cis-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile

change

[0341] Example 229 (+ / -) 5-Methyl-8-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka] In a microwave tube, (+ / -)6-bromo-1-methyl-4-(trans-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile TFA salt (31 mg, 0.049 mmol), zinc (0.636 mg, 9.73 μmol), zinc cyanide (3.43 mg, 0.029 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.97 mg, 4.86 μmol) were added. The tube was sealed, evacuated, and then flushed with nitrogen. NMP (1.5 mL) was then added and heated at 80°C for 4 hours. The mixture was then cooled, diluted to 2 mL with acetonitrile, and the mixture was filtered. The resulting crude solution was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 52% B for 0 min, followed by 52–92% B over 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The product-containing fractions were combined and dried in a centrifugal evaporator. The product yield was 10.2 mg, and its estimated purity by LC / MS analysis was 98%. Analytical LC / MS was used to determine the final purity.Injection 1 Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, Particle Size: 1.7 μm; Mobile Phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile Phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); T...

Claims

1. Formula (I): [In the formula, X is CR 6 or N; Y is CR 3 or N; L is -O-, -S-, -S(O) 2 -, -NR 4c -, or -NR 4d C(O)-; R 1 is F, Cl, Br, -CN, 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 4 R 1a C replaced with 3-4 Cycloalkyl, 0 to 4 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n R e , or -P(O)R e R e and; Each R 1a are independently F, Cl, -CN, -OH, -OCH 3 , or -NR a R a and; Each R a are independently H or C 1-3 is alkyl; Each R e is independently 3-4 Cycloalkyl or 0 to 4 R 1a C replaced with 1-3 is alkyl; R 2 is H, 0 to 4 R 2a C replaced with 1-3 Alkyl, 0 to 4 R 2a C replaced with 2-3 alkenyl, or 0 to 4 R 2a C replaced with 3-4 is cycloalkyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 Alkyl), C 3-4 Cycloalkyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R 3 are H, F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, C 3-4 Fluorocycloalkyl, -NO 2 , or 0 to 2 R 3a is pyridinyl substituted with; Each R 3a is halogen, -CN, C 1-3 Alkyl, or C 1-3 is alkoxy; R 4 is R 4a , -CH 2 R 4a , or -CH 2 CH 2 R 4a and; R 4a is C 3-6 Cycloalkyl, C 5-14 Heterocyclyl, C 6-10 Aryl, or C 5-14 heteroaryl, each of which is 0 to 4 R 4b Replaced with; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 Alkyl), C 1-4 Alkoxy, -O(C 1-4 Hydroxyalkyl), -O(CH) 1-3 O(C 1-3 Alkyl), C 1-3 Fluoroalkoxy, -O(CH) 1-3 NR c R c , -OCH 2 CH=CH 2 , -OCH 2 C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 Alkyl) 2 , -NR c R c , -NR a S(O) 2 (C 1-3 alkyl), -NR a C(O)(C 1-3 alkyl), -NR a C(O)O(C 1-4 alkyl), -P(O)(C 1-3 Alkyl) 2 , -S(O) 2 (C 1-3 alkyl), -O(CH 2 ) 1-2 (C 3-6 Cycloalkyl), -O(CH 2 ) 1-2 (morpholinyl), C 3-6 Cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or -CR c R c (phenyl); Each R c are independently H or C 1-2 is alkyl; R 4c , H, C 1-6 Alkyl, or R 4a and; R 4d is H or C 1-6 is alkyl; Each R 5 are independently F, Cl, -CN, -OH, 0 to 4 R g C replaced with 1-6 Alkyl, 0 to 4 R g C replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-4 Alkenyl, 0-4 R g C replaced with 2-4 Alkynyl, -(CH 2 ) 1-2 (0 to 4 R g C replaced with 3-4 cycloalkyl), 0 to 4 R g phenyl substituted with 0-3 R g oxadiazolyl substituted with 0 to 4 R g Pyridinyl substituted with -(CH 2 ) 1-2 (0 to 4 R g -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -O(CH 2 ) 1-2 (0 to 4 R g -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 Cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3-4 cycloalkyl) or two R 5 forms =O; Each R g are independently F, Cl, -CN, -OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy, -O(CH 2 ) 1-2 O(C 1-2 Alkyl), C 3-5 Cycloalkyl, or -NR c R c and; Each R 6 are H, F, Cl, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -OCH 3 and; R 7 is H or -CH 3 and; m is 0, 1, 2, or 3; and n is 0, 1, or 2. or a salt thereof.

2. During the ceremony, R 1 is F, Cl, Br, -CN, 0 to 4 R 1a C replaced with 1-3 Alkyl, 0 to 3 R 1a cyclopropyl substituted with 0-3 R 1a C replaced with 1-3 Alkoxy, -C(O)NR a R a , -NR a R a , -S(O) n CH 3 , or -P(O)(CH 3 ) 2 and; Each R 1a is independently F, Cl, or -CN; Each R a are independently H or C 1-3 is alkyl; R 2 H, 0 to 2 R 2a C replaced with 1-2 Alkyl or 0 to 2 R 2a C replaced with 2-3 alkenyl; Each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 Alkyl), cyclopropyl, C 3-4 Alkenyl, or C 3-4 is alkynyl; R 3 H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 3-4 Cycloalkyl, -NO 2 , or 0 to 1 R 3a is pyridinyl substituted with; R 4a But, C 3-6 cycloalkyl, 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, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which has zero to three R 4b Replaced with; Each R 4b are independently F, Cl, Br, -CN, -OH, C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH 2 ) 1-2 O(C 1-3 Alkyl), C 1-4 Alkoxy, -O(C 1-3 Hydroxyalkyl), -O(CH) 1-3 O(C 1-3 Alkyl), C 1-2 Fluoroalkoxy, -O(CH) 1-2 NR c R c , -C(O)(C 1-3 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl) 2 , -NR c R c , -S(O) 2 (C 1-2 Alkyl), C 3-6 Cycloalkyl, or -CR c R c (phenyl); R 4c But, H, C 1-4 Alkyl, or R 4a and; R 4d But H or C 1-4 is alkyl; Each R 5 are independently selected from F, -CN, -OH, and 0 to 4 R g C replaced with 1-5 Alkyl, 0 to 3 R g C replaced with 1-3 Alkoxy, 0 to 4 R g C replaced with 2-3 Alkenyl, 0-4 R g C replaced with 2-3 Alkynyl, -(CH 2 ) 1-2 (0 to 4 R g C replaced with 3-4 cycloalkyl), 0 to 3 R g phenyl substituted with 0-3 R g oxadiazolyl substituted with 0 to 3 R g Pyridinyl substituted with -(CH 2 ) 1-2 (0 to 4 R g -O(CH 2 ) 1-2 (0 to 4 R g -(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), -(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), -(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-4 alkyl), -C(O)O(C 3-4 Cycloalkyl), -C(O)NR a R a or -C(O)NR a (C 3-4 cycloalkyl); and Each R 6 is H, F, or -CH 3 2. The compound according to claim 1, wherein:

3. During the ceremony, X is CH, Y is CR 3 X is N and Y is CR 3 or X is N and Y is N; L is -O-, -NH-, -N(CH 3 )- or -N(CH 3 )C(O)-; R 1 F, Cl, Br, -CN, -OCH 3 , or -C(O)NH 2 and; R 2 But -CH 3 and; R 3 H, F, Cl, Br, -CN, -CH 3 , -NO 2 , methylpyridinyl, or methoxypyridinyl; R 4 But R 4a or -CH 2 R 4a and; R 4a is cyclohexyl, phenyl, indazolyl, phthalazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 1,7-naphthyridinyl, or dihydrobenzo[b][1,4]dioxepinyl, each of which is selected from 0 to 3 R 4b Replaced with; Each R 4b are independently F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 2 CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCF 3 , -C(O)N(CH 3 ) 2 , -S(O) 2 CH 3 , -CH 2 (phenyl), -C(CH 3 ) 2 (phenyl), cyclopropyl, cyclopentyl, or cyclohexyl; Each R 5 are independently F, -OH, and C 1-2 Alkyl, C 1-3 Alkoxy, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 (cyclopropyl), or -OCH 2 CH 2 (morpholinyl); and Each R 6 is H, or a salt thereof.

4. wherein X is N; and Y is CR 3 2. The compound according to claim 1, wherein:

5. In the formula, X is CR 6 and Y is CR 3 2. The compound according to claim 1, wherein:

6. 2. The compound according to claim 1, or a salt thereof, wherein X is N; and Y is N.

7. 2. The compound according to claim 1, wherein L is -O-, or a salt thereof.

8. In the formula, L is -NR 4c 2. The compound according to claim 1, wherein:

9. In the formula, L is -NR 4d 2. The compound according to claim 1, wherein the compound is C(O)-, or a salt thereof.

10. below 【Chemistry 1】 2. The compound of claim 1, or a salt thereof, having a structure selected from: Claim 11. 6-Fluoro-4-(4-(3-fluoro-5-methylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (Example 1); 6-Fluoro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (Example 2); 6-Fluoro-1-methyl-3-nitro-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)quinolin-2(1H)-one (Example 3); 6-Fluoro-1-methyl-3-nitro-4-(4-(m-tolyloxy)piperidin-1-yl)quinolin-2(1H)-one (Example 4); 4-(4-((1H-indazol-4-yl)oxy)piperidin-1-yl)-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (Example 5); 3-((1-(6-fluoro-1-methyl-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)piperidin-4-yl)oxy)benzonitrile (Example 6); 4-(4-(3-chlorophenoxy)piperidin-1-yl)-6-fluoro-1-methyl-3-nitroquinolin-2(1H)-one (Example 7); 6-Fluoro-4-(4-(2-methoxy-5-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (Example 8); 6-Fluoro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-3-nitroquinolin-2(1H)-one (Example 9); 6-chloro-4-(4-(3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 10); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 11); 6-chloro-4-(4-(3,4-difluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 12); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 13); 6-chloro-4-(4-(4-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 14); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 15); 6-chloro-4-(4-(4-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 16); 6-chloro-4-(4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 17); 6-chloro-4-(4-(2-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 18); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 19); 6-chloro-4-(4-(4-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 20); 6-chloro-1-methyl-2-oxo-4-(4-(p-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 21); 6-chloro-1-methyl-2-oxo-4-(4-(m-tolyloxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 22); 6-chloro-4-(4-(2-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 23); 6-chloro-1-methyl-2-oxo-4-(4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 24); 4-((1-(6-chloro-3-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)piperidin-4-yl)oxy)-N,N-dimethylbenzamide (Example 25); 4-(4-(4-bromo-2-methylphenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 26); 6-chloro-4-(4-(3-chlorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 27); 6-chloro-4-(4-(3-chloro-5-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 28); 6-chloro-1-methyl-4-(4-(2-methyl-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 29); 6-chloro-1-methyl-2-oxo-4-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 30); 4-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-6-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 31); 6-chloro-4-(4-(4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 32); 6-chloro-1-methyl-2-oxo-4-(4-(2-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 33); 6-chloro-4-(4-(3-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 34); 6-chloro-4-(4-(2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 35); 6-chloro-4-(4-(4-fluoro-2-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 36); 6-chloro-4-(4-(4-isopropylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 37); 6-chloro-4-(4-(3-chloro-4-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 38); 6-chloro-4-(4-(4-chloro-3-methoxyphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 39); 6-chloro-4-(4-(3-chloro-4-methylphenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 40); 6-chloro-4-(4-(2-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 41); 6-chloro-4-(4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 42); 6-chloro-4-(4-(2-cyanophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 43); 6-chloro-4-(4-(2-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 44); 6-chloro-4-(4-(3-fluorophenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 45); 6-chloro-1-methyl-2-oxo-4-(4-phenoxypiperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 46); 6-Bromo-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 47); 6-Methoxy-1-methyl-2-oxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 48); 1-Methyl-2,6-dioxo-4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,2,5,6-tetrahydro-1,5-naphthyridine-3-carbonitrile (Example 49); 5-Methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Example 50); 5-Methyl-7-nitro-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 51); 5-Methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 52); 4-(4-(4-(tert-butyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile (Example 53); 5-Methyl-6-oxo-8-(4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 54); 8-(4-(4-benzylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 55); 8-(4-(4-butylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 56); 5-Methyl-6-oxo-8-(4-(4-propylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 57); 8-(4-(4-cyclopentylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 58); 8-(4-(4-cyclopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 59); 8-(4-(4-isopropyl-3-methylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 60); 5-Methyl-6-oxo-8-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 61); 5-Methyl-6-oxo-8-(4-(4-pentylphenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 62); 8-(4-(4-cyclohexylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 63); 8-(4-(4-(2-cyclohexylpropan-2-yl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 64); 8-(4-(4-(tert-butoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 65); 8-(4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 66); 8-(4-((5-chloropyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 67); 8-(4-((6-(tert-butyl)pyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 68); 5-Methyl-6-oxo-8-(4-(quinoxalin-2-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 69); 8-(4-((2,6-dimethylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 70); 5-Methyl-6-oxo-8-(4-(quinazolin-4-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 71); 5-methyl-8-(4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 72); 8-(4-((7-chloro-4-methoxyquinolin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 73); 8-(4-((1,7-naphthyridin-8-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 74); 5-Methyl-6-oxo-8-(4-(phthalazin-1-yloxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 75); 5-Methyl-6-oxo-8-(4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 76); 5-Methyl-6-oxo-8-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 77); 8-(4-((2-isopropyl-6-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 78); (+ / -) 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (Example 79); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (Example 80); 6-cyano-1-methyl-4-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,5-naphthyridin-2(1H)-one (Example 81); 5-Methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 82-84); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 85-87); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 88-90); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 91-93); 8-((3R,4R)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 94-96); 5-Methyl-8-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 97-99); 8-((3R,4R)-4-(4-cyclopentylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 100-102); 8-((3R,4R)-4-(3,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 103-105); 8-((3R,4R)-4-(4-cyclohexylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 106); 5-Methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 107-109); 8-((3R,4R)-4-(4-ethylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 110); 8-((3R,4R)-4-(4-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 111); 8-((3R,4R)-4-(2-fluoro-4-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 112); 8-((3R,4R)-4-(2,4-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 113-115); 8-((3R,4R)-4-(4-fluoro-2-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 116-118); 5-Methyl-8-((3R,4R)-3-methyl-4-(p-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 119-121); 8-((3R,4R)-4-(3-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 122); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 123); 8-((3R,4R)-4-(2-fluoro-6-(trifluoromethyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 124); 8-((3R,4R)-4-(2,6-difluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 125-127); 8-((3R,4R)-4-(4-fluorophenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 128-130); 5-Methyl-8-((3R,4R)-3-methyl-4-(2,4,6-trifluorophenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 131); 8-((3R,4R)-4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 132); 5-Methyl-8-((3R,4R)-3-methyl-4-(m-tolyloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Example 136); 8-((3R,4R)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 137-139); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 140-142); 8-((3R,4R)-3-ethyl-4-(4-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 143-145); 8-((3R,4R)-3-ethyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 146-148); 8-((3R,4R)-3-ethyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 149-151); 8-((3R,4R)-4-(4-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 152-154); 8-((3R,4R)-4-(3-cyclopropylphenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 155-157); 8-((3R,4R)-4-(4-(tert-butoxy)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 158-160); 8-((3R,4R)-3-ethyl-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 161); 8-((3R,4R)-3-ethyl-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 162-163); 8-((3R,4S)-3-ethyl-4-(3-isopropylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 164); 8-((3R,4S)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 165-167); 5-Methyl-8-((3R,4S)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 169-171); 8-((3R,4S)-4-(4-(tert-butoxy)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 172-174); 8-((3R,4S)-4-(4-(tert-butyl)phenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 175); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 176-178); 8-((3R,4S)-4-(3-cyclopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 179-181); 8-((3R,4S)-4-(4-isopropylphenoxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 182-184); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (Example 185); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 186); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 187); 5-methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 188); 5-Methyl-8-((3R,4S)-3-methyl-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Examples 189-191); 8-((3R,4R)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 192-194); 8-((3R,4R)-3-ethyl-4-(4-fluoro-3-propylphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 195); 8-((3R,4R)-4-(3-(tert-butyl)phenoxy)-3-ethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 196-198); 8-((3R,4R)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 199-201); 8-((3R,4S)-3-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 202-204); 8-((3R,4S)-4-((5-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 205-207); 8-((3R,4S)-4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 208-210); 8-((3R,4S)-4-((4-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 211-213); 8-((3R,4S)-4-((6-isopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 214-216); 5-Methyl-8-((3R,4S)-3-methyl-4-(pyrimidin-2-yloxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 217); 8-((3R,4S)-4-((4-methoxypyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 218); 5-Methyl-8-((3R,4S)-3-methyl-4-((5-propylpyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 219); 5-methyl-8-((3R,4S)-3-methyl-4-((2-methylpyrimidin-4-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 220); 8-((3R,4S)-4-((5-ethylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 221); 5-methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 222); 8-((3R,4S)-4-((5-cyclopropylpyrimidin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 223); 8-((3R,4S)-4-((5-cyclopropylpyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 224); 5-Methyl-8-((3R,4S)-3-methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 225-227); (+ / -) 8-((3R,4S)-4-((5-isopropoxypyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 228); (+ / -) 5-methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Example 229); 5-Methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Example 230); 5-Methyl-8-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Example 231); (+ / -) 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 232); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 233); 8-(4-((5-isopropoxypyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 234); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 235); (+ / -) 5-methyl-8-((3R,4S)-3-methyl-4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carboxamide (Example 236); 7-Fluoro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 237); 7-chloro-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 238); 7-Bromo-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 239); 7-(6-methoxypyridin-3-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 240); 7-(2-methoxypyridin-4-yl)-5-methyl-6-oxo-8-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 241); (+ / -) 6-bromo-1-methyl-4-((3R,4R)-3-methyl-4-(4-(tert-pentyl)phenoxy)piperidin-1-yl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (Example 242); 8-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 243 and 246); 8-((2R,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 244-245); 4-((2R,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 248-249); 4-((2S,5R)-4-((5-isopropoxypyridin-2-yl)oxy)-2,5-dimethylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 247 and 250); 4-((2R,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 252 and 253); 4-((2S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 251 and 254); 4-((2R,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 256-257); 8-((2S,5S)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 255 and 258); (±)-trans-8-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 259-260); (±)-trans-8-(3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 261-262); 8-((3R,4R)-3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 263-264); (±)-cis-8-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 265-266); (±)-trans-8-(3-hydroxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 267-268); (±)-trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-methoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 269-270); (±)-trans-6-chloro-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Examples 271-272); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 273-274); 6-chloro-4-((3R,4R)-3-methoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 275); (±)-trans-4-(3-hydroxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 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 (Examples 278-279); 8-((2S,5R)-4-((5-methoxypyridin-2-yl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 280-281); N-((2S,5R)-1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-2,5-dimethylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (Examples 282-283) N-(1-(6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-4-fluoro-N-methylbenzamide (Examples 284-287); N-(1-(3,6-dicyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)-3-methylpiperidin-4-yl)-N-methyl-4-(trifluoromethyl)benzamide (Examples 288-293); 8-((2S,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 294); 8-((2R,4S,5S)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 295); 8-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 296); 8-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 297); 8-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 298); 8-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 299); 6-chloro-4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 300); 4-((2S,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Example 301); 6-chloro-4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 302); 4-((2R,4R,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Example 303); 6-chloro-4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 304); 4-((2R,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Example 305); 6-chloro-4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 306); 4-((2S,4S,5R)-5-ethyl-4-((5-isopropoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Example 307); 8-((2S,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 308); 8-((2R,4S,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 309); 8-((2R,4R,5R)-5-ethyl-2-methyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 310); 8-((2R,4S,5R)-2,5-dimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 311); 8-((2S,4R,5S)-2,5-dimethyl-4-(p-tolyloxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 312); 8-((2S,4R,5S)-4-(3-chlorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 313); 8-((2S,4R,5S)-4-(3-cyanophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 314); 8-((2S,4R,5S)-4-(4-fluorophenoxy)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 315); 8-((2S,5S)-2,5-dimethyl-4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Example 316A); 8-(2,5)-dimethyl-4-(methyl(4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 316-319); 8-((2S,5S)-2,5-dimethyl-4-(methyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 320-321); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Examples 322-325); 8-(4-((4-fluorobenzyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 326-328); 8-(4-((4,4-difluorocyclohexyl)(methyl)amino)-3-methylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (Examples 329-330); 8-((2S,5R)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 331-332); 8-((2S,5S)-4-((4-fluorobenzyl)(methyl)amino)-2,5-dimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 333-334); 8-((2S,5S)-4-((5-isopropoxypyridin-2-yl)oxy)-2,4,5-trimethylpiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 335-336); 5-Methyl-6-oxo-8-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 337-338); 1-Methyl-2-oxo-4-((2S,5S)-2,4,5-trimethyl-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 339-340); trans-8-(3-ethoxy-4-phenoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 341-342); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 343-344); 8-((3S,4S)-3-ethoxy-4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 345-346); 8-((3S,4S)-3-ethoxy-4-(4-isopropoxyphenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 347-348); 8-((3S,4S)-3-ethoxy-4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 349-350); 8-((3S,4S)-3-ethoxy-4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 351-352); 8-((3S,4S)-3-ethoxy-4-(4-(methylsulfonyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 353-354); 8-((3S,4S)-3-ethoxy-4-((2-methylbenzo[d]oxazol-5-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 355-356); 8-((3S,4S)-4-(4-chloro-3-fluorophenoxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 357-358); 8-((3S,4S)-3-ethoxy-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 359-362); trans-8-(3-ethoxy-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 363-364); 8-((3S,4S)-3-ethoxy-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 365-366); trans-8-(3-ethoxy-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 367-368); cis-8-(3-ethoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 369-370); cis-8-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 371-372); trans-8-4-(benzo[d]thiazol-2-yloxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 373-374); 8-((3S,4S)-3-ethoxy-4-((6-isopropoxypyridazin-3-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 375-376); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrazin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 377-378); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyrimidin-2-yl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 379-380); 8-((3S,4S)-3-ethoxy-4-((3-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 381-382); 8-((3S,4S)-3-ethoxy-4-((5-isopropoxypyridin-2-yl)methoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 383-384); 8-((3R,4R)-3-(2-(dimethylamino)ethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 385-386); 8-((3R,4R)-3-(cyclopropylmethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 387-388); 8-((3R,4R)-3-(2-methoxyethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 389-390); 5-Methyl-8-((3R,4R)-3-(2-morpholinoethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 391-392); 5-Methyl-6-oxo-8-((3R,4R)-3-(2,2,2-trifluoroethoxy)-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 393-394); trans-8-(3-isopropoxy-4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 395-396); trans-8-(4-((5-isopropoxypyridin-2-yl)oxy)-3-ethoxypiperidin-1-yl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (Examples 397-398); (±)-trans-6-chloro-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (Example 399); trans-4-(3-ethoxy-4-((5-isopropoxypyridin-2-yl)oxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 400-401); trans-4-(3-ethoxy-4-phenoxypiperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 402-403); or 4-((3S,4S)-3-ethoxy-4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (Examples 404-405) or a salt thereof.

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a salt thereof; and a pharma- ceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1 to 11 for the treatment of cancer or a viral infection.

14. 14. The pharmaceutical composition of claim 13, wherein the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia and melanoma.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a salt thereof for inhibiting the activity of at least one diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ).

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