Tertiary amine-substituted bicyclic compounds useful as T cell activators

Abstract

What is disclosed is TIFF2025528157000071.tif36139 [wherein X, Y, R1, R2, R4, R5 and R6 are as defined herein] or a salt thereof. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ), and pharmaceutical compositions containing such compounds. These compounds are useful in the treatment of proliferative disorders such as viral infections and cancer.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 370,833, filed August 9, 2022, which is incorporated herein by reference in its entirety.

[0002] Description of the invention The present invention generally relates to tertiary amine-substituted bicyclic compounds that activate T cells, promote T cell proliferation, and / or exhibit anti-tumor activity. Provided herein are tertiary amine-substituted bicyclic compounds, compositions containing such compounds, and methods of their use. The present invention further relates to pharmaceutical compositions containing at least one compound of the present invention that are useful in the treatment of proliferative disorders, such as cancer, and viral infections.

[0003] Reference to sequence listings submitted electronically via EFS-WEB Incorporated herein by reference in its entirety is the Sequence Listing entitled "14192WOPCT," including SEQ ID NOs:1 through 6, which contains the nucleic acid and / or amino acid sequences disclosed herein. The Sequence Listing has been submitted via the Patent Center in XML format and thus comprises both a paper copy and a computer-readable version thereof. The Sequence Listing was first generated using WIPO Sequence on July 25, 2023, and is 16.0 KB in size. [Background technology]

[0004] Background of the Invention Human cancers harbor numerous genetic and epigenetic alterations that generate novel antigens that can be recognized by the immune system (Sjoblom et al., (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses potent anticancer potential, with broad capabilities and exquisite specificity to respond to diverse tumor antigens. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all these properties of the adaptive immune system would make immunotherapy unique among all cancer treatments. However, although an endogenous immune response to cancer is observed in preclinical experiments and in patients, this response is ineffective, and established cancers are considered "self" and tolerated by the immune system. This tolerance state may be due in part to tumors using several different mechanisms to actively subvert antitumor immunity. These mechanisms include dysfunction of T cell signaling (Mizoguchi et al., (1992) Science 258:1795-98), suppression of regulatory cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and co-opting by tumors of endogenous "immune checkpoints" that serve to down-modulate the strength of the adaptive immune response and protect normal tissues from collateral damage to evade immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al., (2011) Nature 480:480-489).

[0005] Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby halting T cell function propagated through the TCR signaling pathway. Thus, DGK serves as an intracellular checkpoint, and inhibition of DGK is expected to enhance the T cell signaling pathway and activate T cells. Supporting evidence includes mouse models lacking either DGKα or DGKζ, which display a hyperresponsive T cell phenotype 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 were observed to overexpress DGKα, which resulted in the inhibition of T cell function (Prinz, PU et al., J Immunology (2012) 12:5990-6000). Thus, DGKα and DGKζ are attracting attention 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).

[0006] There remains a need for compounds useful as inhibitors of either or both of DGKα and DGKζ. In addition, there remains a need for compounds useful as inhibitors of either or both of DGKα and DGKζ that have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases. Thus, agents that are safe and effective in restoring T cell activation, lowering the antigen threshold, enhancing antitumor function, and / or overcoming the suppressive effects of one or more endogenous immune checkpoints, such as PD-1, LAG-3, and TGFβ, would be an important addition to treating patients with proliferative disorders such as cancer, as well as viral infections. Summary of the Invention

[0007] The present applicants have discovered compounds that have activity as inhibitors of one or both of DGKα and DGKζ. Furthermore, the present applicants have discovered compounds that have activity as inhibitors of one or both of DGKα and DGKζ and that have selectivity over other diacylglycerol kinases, protein kinases, and / or other lipid kinases. These compounds are provided as useful pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values, which are important for their efficacy.

[0008] The present invention provides tertiary amine-substituted bicyclic compounds of formula (I), or salts and prodrugs thereof, that are useful as inhibitors of DGKα, DGKζ, or both DGKα and DGKζ. 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. 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, comprising administering to a mammalian patient a compound of formula (I) and / or a pharmaceutically acceptable salt thereof.

[0009] The present invention also provides processes and intermediates for preparing compounds of formula (I) and / or salts thereof. The present invention also provides compounds of formula (I) and / or pharmaceutically acceptable salts thereof for use in therapy. 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 disorders, such as cancer, and viral infections.

[0010] The compounds of formula (I) and compositions comprising the compounds of formula (I) can be used to treat, prevent, or cure various proliferative disorders, such as viral infections and cancer. Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in various therapeutic areas, such as viral infections and cancer. These and other features of the present invention will be set forth in more expanded form as the present disclosure continues. DETAILED DESCRIPTION OF THE INVENTION

[0011] A first aspect of the present invention is a compound of formula (I): [ka] [In formula: X is CR6 or N; Y is CR3 or N; R1 is H, F, Cl, Br, -CN, -OH, C 1-3 Alkyl (0 to 4 R 1a substituted with), C 3-4 Cycloalkyl (0 to 4 R 1a substituted with), C 1-3 Alkoxy (0 to 4 R 1a substituted with -NR a R a , -S(O) n R e , or -P(O)R e R e and; Each R 1aare independently F, Cl, -CN, -OH, -OCH3, or -NR a R a and; R2 is H, C 1-3 Alkyl (0 to 4 R 2a substituted with), C 3-4 Alkenyl, C 3-4 Alkynyl, or C 3-4 Cycloalkyl (0 to 4 R 2a substituted with ); Each R 2a are independently F, Cl, -CN, -OH, C 1-2 Alkoxy, 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, or -NO2; R4 is R 4a , -CHR 4a R 4b , -CH2CHR 4a R 4b , or -CR 4a R 4b R 4e and; R 4a is C 3-6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is 0 to 4 R 4c is replaced by; R 4b is hydrogen or C 1-6 Alkyl (F, Cl, -CN, -OH, -OCH3, C 1-2 Fluoroalkoxy, -NR a R a , -S(O)2R e , or -NR a S(O)2R e and substituted with 0 to 4 independently selected substituents; Each R 4c are independently F, Cl, Br, -CN, -OH, C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Bromoalkyl, C 1-2 Cyanoalkyl, C 1-2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1-2 O(C 1-2 alkyl), -(CH2) 1-2 NR x C(O)O(C 1-2 alkyl), C 1-4 Alkoxy, -O(C 1-4 hydroxyalkyl), -O(CR x R x ) 1-2 O(C 1-2 alkyl), C 1-3 Fluoroalkoxy, C 1-3 Cyanoalkoxy, -O(CH2) 1-2 NR a R a , -OCH2CH=CH2, -OCH2C≡CH, -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -NR a R a , -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 1-2 alkyl)2, -S(O)2(C 1-3 alkyl), -(CH2) 1-2 (C 3-4 cycloalkyl), or cyclic group (C 3-6 cycloalkyl, furanyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolyl, oxazolyl, thiophenyl, pyridinyl, methoxypyridinyl, and phenyl), each of which is selected from 0 to 2 R 4d is replaced by; Each R4d are independently F, Cl, -OH, C 1-3 Alkyl, -C(O)NR a R a , -CH2NHSO2(C 1-3 alkyl), C 1-3 Alkoxy, C 1-3 Fluoroalkoxy, -NR a R a , -NHSO2(C 1-3 alkyl), -OCH2(C 3-6 cycloalkyl), C 3-6 cycloalkyl, piperidinyl, or morpholinyl; R 4e is C 1-6 Alkyl or C 3-6 cycloalkyl, each of which is F, Cl, —OH, C 1-2 Alkoxy, C 1-2 substituted with 0 to 4 substituents independently selected from fluoroalkoxy, and —CN; R5 is -CN, C 1-4 Alkyl (0 to 4 R g substituted with), C 2-4 Alkenyl (0 to 4 R g substituted with -CH2(C 3-6 cycloalkyl); each R6 is H, F, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, or -OCH3; Each R a are independently H or C 1-3 is alkyl; Each R e independently, C 3-4 Cycloalkyl or C 1-3 Alkyl (0 to 4 R 1a substituted with ); 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), or -NR a R aand; Each R x are independently H or -CH3; n is 0, 1, or 2] The present invention provides at least one compound represented by the formula:

[0012] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein X is CR6 and Y is CR3. The compound of this embodiment has formula (II): [ka] It has the structure shown below.

[0013] In one embodiment, there is provided 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 (III): [ka] It has the structure shown below.

[0014] In one embodiment, there is provided 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 (IV): [ka] It has the structure shown below.

[0015] In one embodiment, there is provided 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 (V): [ka] It has the structure shown below.

[0016] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein X is CR6 or N; Y is CR3 or N; and at least one of X and Y is N. This embodiment includes compounds of formula (III), compounds of formula (IV); and compounds of formula (V). In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein X is N; and Y is CR3 or N. This embodiment includes compounds of formula (III) and compounds of formula (V). In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein X is CR6 or N; and Y is N. This embodiment includes compounds of formula (IV) and compounds of formula (V).

[0017] In one embodiment, the compound of formula (I) or a salt thereof, wherein R is H, F, Cl, Br, —CN, —OH, C 1-3 Alkyl (0 to 4 R 1a substituted with cyclopropyl (0 to 3 R 1a substituted with), C 1-3 Alkoxy (0 to 3 R 1a substituted with -NR a R a and R2 is H, C 1-2 alkyl (0 to 2 R 2a substituted with ), or C 3-4 alkynyl; each R 2a are independently F, Cl, -CN, -OH, -O(C 1-2 alkyl), or cyclopropyl; R3 is H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 cycloalkyl; R4 is R 4a , -CHR 4a R 4b , or -CHCHR 4a R 4b and;R 4a C3-6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is selected from 0 to 3 R 4c is substituted with;R 4b is hydrogen or C 1-3 Alkyl (F, Cl, -CN, -OH, -OCH3, C 1-2 Fluoroalkoxy, or -NR a R a and each R 4c are independently F, Cl, Br, -CN, -OH, C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Bromoalkyl, C 1-2 Cyanoalkyl, C 1-2 Hydroxyalkyl, -CHNR a R a , -(CH2) 1-2 O(C 1-2 alkyl), -(CH2) 1-2 NR x C(O)O(C 1-2 alkyl), C 1-4 Alkoxy, -O(C 1-4 hydroxyalkyl), -O(CR x R x ) 1-2 O(C 1-2 alkyl), C 1-2 Fluoroalkoxy, C 1-2 Cyanoalkoxy, -O(CH2) 1-2 NR a R a , -C(O)(C 1-4 alkyl), -C(O)OH, -C(O)O(C 1-3 alkyl), -NR a R a , -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), -S(O)2(C 1-3 alkyl), -(CH2) 1-2(C 3-4 cycloalkyl), or cyclic group (C 3-6 cycloalkyl, furanyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolyl, oxazolyl, thiophenyl, pyridinyl, methoxypyridinyl, and phenyl), each of which is selected from 0 to 2 R 4d and each R 4d are independently F, Cl, -OH, C 1-3 Alkyl, -C(O)NR a R a , -CH2NHSO2(C 1-2 alkyl), C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, -NR a R a , -NHSO2(C 1-2 alkyl), -OCH2(C 3-6 cycloalkyl), C 3-6 cycloalkyl, piperidinyl, or morpholinyl; R 4e But C 1-3 Alkyl or C 3-6 cycloalkyl, each of which is selected from F, Cl, —OH, C 1-2 Alkoxy, C 1-2 substituted with 0 to 4 substituents independently selected from -fluoroalkoxy, -CN; 1-3 alkyl, —CHOH, —CHOCH, —CHOCHCH, —CHNH, or —CH(cyclopropyl); each R is H, F, or —CH; each R a is independently H or —CH 3 , or a salt thereof.

[0018] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein R1 is H, Cl, Br, -CN, -CH3, -CH2CN, or -OCH3; R2 is -CH3 is -CH2C≡CH; R3 is H or -CN; and R4 is R 4a or -CHR 4a R 4b and;R 4ais cyclopropyl, cyclohexyl, phenyl, pyridinyl, benzo[d][1,3]dioxolyl, benzofuranyl, or dihydrobenzo[b][1,4]dioxinyl, each of which is 0 to 2 R 4c is substituted with;R 4b is hydrogen or -CH3; each R 4c are independently F, Cl, Br, -CN, -CH3, -CF3, -CH2OCH3, -OCH3, -OCHF2, -OCH2CF3, -OCF3, -C(O)OCH3, -N(CH3)2, -N(CH3)C(O)CH3, cyclopropyl, cyclobutyl, cyclohexyl, pyrrolyl, oxazolyl, pyridinyl, methoxypyridinyl, or phenyl (wherein 0 to 1 R 4d substituted with ;R 4d is F, Cl, -OH, -CH3, -C(O)NH2, -C(O)N(CH3)2, -CH2NHSO2CH3, -OCH3, -OCF3, -N(CH3)2, -NHSO2CH3, -OCH2(cyclopropyl), cyclopropyl, or morpholinyl; R5 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH2(cyclopropyl); and each R6 is H, or a salt thereof.

[0019] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein R is H, F, Cl, Br, —CN, —OH, C 1-3 Alkyl (0 to 4 R 1a substituted with), C 3-4 Cycloalkyl (0 to 4 R 1a substituted with), C 1-3 Alkoxy (0 to 4 R 1a substituted with -NR a R a , -S(O)2(C 1-3 alkyl), or -P(O)R e R e In this embodiment, there is provided a compound or a salt thereof, wherein R is H, F, Cl, Br, —CN, —OH, C 1-3 Alkyl (0 to 4 R 1a substituted with cyclopropyl (0 to 3 R1a substituted with), C 1-3 Alkoxy (0 to 3 R 1a substituted with -NR a R a Also included within this embodiment are compounds where R1 is H, Cl, Br, -CN, -CH3, -CH2CN, or -OCH3. Additionally, included within this embodiment are compounds where R1 is Cl, Br, -CN, or -CH3.

[0020] In one embodiment, the compound of formula (I) or a salt thereof, wherein R2 is H, C 1-3 Alkyl (0 to 3 R 2a substituted with), C 3-4 Alkenyl, C 3-4 Alkynyl, or C 3-4 Cycloalkyl (0 to 3 R 2a In this embodiment, the compound or salt thereof is provided, wherein R is H, C 1-2 alkyl (0 to 2 R 2a substituted with ), or C 3-4 Included within this embodiment are compounds where R2 is -CH3 or -CH2C≡CH. Additionally, included within this embodiment are compounds where R2 is -CH3.

[0021] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R1 is H, Cl, Br, -CN, -CH3, -CH2CN, or -OCH3; and R2 is -CH3 or -CH2C≡CH. This embodiment includes compounds where R1 is Cl, Br, -CN, or -CH3; and R2 is -CH3. In one embodiment, the compound of formula (I) or a salt thereof, wherein Y is CR3 and R3 is H, F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 3-4In some embodiments, Y is CR3, and R3 is H, F, Cl, Br, -CN, C, or a salt thereof. 1-2 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 Also included within this embodiment are compounds where Y is CR3 and R3 is H or -CN.

[0022] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein Y is CR3; R1 is H, Cl, Br, -CN, -CH3, -CH2CN or -OCH3; R2 is -CH3 or -CH2C≡CH; and R3 is H, F, Cl, Br, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, or C 3-4 cycloalkyl, or a salt thereof. In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein Y is CR3; R1 is H, Cl, Br, -CN, -CH3, -CH2CN or -OCH3; R2 is -CH3 or -CH2C≡CH; and R3 is H or -CN. In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is R 4a , -CHR 4a R 4b or -CHCHR 4a R 4b In this embodiment, a compound or salt thereof is provided, wherein R4 is R 4a or -CHR 4a R 4b Compounds are included in which:

[0023] In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is R 4a or a salt thereof. In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is -CHR 4a R 4b, -CH2CHR 4a R 4b or -CR 4a R 4b R 4e In some embodiments, R4 is -CHR 4a R 4b or -CHCHR 4a R 4b This embodiment also includes compounds where R4 is -CHR 4a R 4b Also included are compounds in which:

[0024] In one embodiment, a compound of formula (I) or a salt thereof, wherein R 4a C 3-6 cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is selected from 0 to 3 R 4c In this embodiment, compounds or salts thereof are provided, wherein R is substituted with 4a C 3-6 cycloalkyl, phenyl, pyridinyl, pyrimidinyl, triazinyl, benzo[d][1,3]dioxolyl, benzofuranyl, or dihydrobenzo[b][1,4]dioxinyl, each of which is 0 to 2 R 4c In this embodiment, compounds are included in which R is substituted with 4a is cyclopropyl, cyclohexyl, phenyl, pyridinyl, benzo[d][1,3]dioxolyl, benzofuranyl, or dihydrobenzo[b][1,4]dioxinyl, each of which contains 0 to 2 R 4c Additionally, this embodiment also includes compounds in which R is substituted with 4a is cyclohexyl or phenyl, each of which contains 0 to 2 R 4c The compounds include compounds in which the compound is substituted with

[0025] In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is -CHR 4a R 4b , -CH2CHR 4a R 4b or -CR4a R 4b R 4e And;R 4b is hydrogen or C 1-3 Alkyl (F, Cl, -CN, -OH, -OCH3, C 1-2 Fluoroalkoxy, or -NR a R a and R is -CHR (substituted with 0 to 4 independently selected from the group consisting of -CHR, ... 4a R 4b , -CH2CHR 4a R 4b or -CR 4a R 4b R 4e And;R 4b is hydrogen or -CH3. This embodiment also includes compounds where R 4e C 1-3 Alkyl or C 3-6 cycloalkyl, each of which is F, Cl, —OH, C 1-2 Alkoxy, C 1-2 Also included are compounds substituted with 0 to 4 substituents independently selected from fluoroalkoxy, and -CN.

[0026] In one embodiment, a compound of formula (I) or a salt thereof, wherein R 4a is cyclopropyl, cyclohexyl, phenyl, pyridinyl, benzo[d][1,3]dioxolyl, benzofuranyl, or dihydrobenzo[b][1,4]dioxinyl, each of which contains 0 to 2 R 4c is substituted with;R 4b is hydrogen or -CH3; each R 4c are independently F, Cl, Br, -CN, -CH3, -CF3, -CH2OCH3, -OCH3, -OCHF2, -OCH2CF3, -OCF3, -C(O)OCH3, -N(CH3)2, -N(CH3)C(O)CH3, cyclopropyl, cyclobutyl, cyclohexyl, pyrrolyl, oxazolyl, pyridinyl, methoxypyridinyl, or phenyl (wherein 0 to 1 R 4d substituted with R 4dis F, Cl, —OH, —CH3, —C(O)NH2, —C(O)N(CH3)2, —CH2NHSO2CH3, —OCH3, —OCF3, —N(CH3)2, —NHSO2CH3, —OCH2(cyclopropyl), cyclopropyl, or morpholinyl, or a salt thereof.

[0027] In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is R 4a or -CHR 4a R 4b and;R 4a is cyclopropyl, cyclohexyl, or phenyl, each of which contains 0 to 2 R 4c is substituted with;R 4b is hydrogen or -CH3; each R 4c are independently F, Cl, Br, -CN, -CH3, -CF3, -CH2OCH3, -OCH3, -OCHF2, -OCH2CF3, -OCF3, -C(O)OCH3, -N(CH3)2, -N(CH3)C(O)CH3, cyclopropyl, cyclobutyl, cyclohexyl, or phenyl (wherein 0 to 1 R 4d substituted with R 4d is F, Cl, —OH, —CH3, —C(O)NH2, —C(O)N(CH3)2, —CH2NHSO2CH3, —OCH3, —OCF3, —N(CH3)2, —NHSO2CH3, or cyclopropyl, or a salt thereof.

[0028] In one embodiment, the compound of formula (I) or a salt thereof, wherein R5 is -CN, C 1-4 Alkyl (0 to 4 R g substituted with) or -CH2(C 3-6 cycloalkyl). In this embodiment, compounds or salts thereof are provided in which R5 is C 1-3 Included in this embodiment are compounds where R5 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH2(cyclopropyl). Also included in this embodiment are compounds where R5 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH2(cyclopropyl).

[0029] In one embodiment, the compound of formula (I) or a salt thereof, wherein R5 is C 1-3 alkyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2 or -CH2(cyclopropyl); R4 is R 4a , -CHR 4a R 4b or -CHCHR 4a R 4b In this embodiment, a compound or salt thereof is provided, wherein R4 is R 4a or -CHR 4a R 4b Compounds are included in which: In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R5 is -CH3, -CH2CH3 or -CH2CH2CH3.

[0030] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R5 is -CH3. In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R5 is -CH2 (cyclopropyl). In one embodiment, the compound of formula (I) or a salt thereof, wherein R4 is R 4a or -CHR 4a R 4b and R5 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH2(cyclopropyl). Within this embodiment are compounds where R5 is -CH3, -CH2CH3, -CH2CH2CH3, or -CH2(cyclopropyl), or a salt thereof.

[0031] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein each R6 is H, F, Cl, -CN, -CH3, or -OCH3. Included in this embodiment are compounds where each R6 is H, F, or -CH3. Also included in this embodiment are compounds where each R6 is H. In one embodiment, there is provided a compound of formula (II) or a salt thereof, wherein each R6 is H. In one embodiment, there is provided a compound of formula (III) or a salt thereof, wherein each R6 is H.

[0032] In one embodiment, there is provided a compound of formula (IV) or a salt thereof, wherein each R6 is H. In one embodiment, there is provided a compound of formula (V) or a salt thereof, wherein each R6 is H. In one embodiment, a compound of formula (I) or a salt thereof, wherein each R a is independently H or —CH 3 , or a salt thereof.

[0033] In one embodiment, the compound of formula (I) or a salt thereof is selected from the group consisting of: 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (4); 8-((4'-methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (5); 5-methyl-8-(methyl(4'-(trifluoromethoxy)-[1 ,1'-biphenyl]-3-yl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (6); 6-Bromo-4-[cyclohexyl(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (7); 6-Bromo-1-methyl-4-(methyl(4-methylcyclohexyl)amino)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (8); 6-Bromo-4-((1-cyclopropylethyl)(methyl)amino)-1-methyl 2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (9); 8-[cyclohexyl(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (10); 8-[(1-cyclopropylethyl)(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (11); 4-[cyclohexyl(methyl)amino]-6-methoxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine 4-[cyclohexyl(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (13); 4-[(1-cyclopropylethyl)(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (14); 6-(cyanomethyl)-4-[(1-cyclopropylethyl)(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15);6-Bromo-4-[cyclohexyl(methyl)amino]-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (16); 8-[cyclohexyl(methyl)amino]-6-oxo-5-(prop-2-yn-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (17); 8-[(4-bromophenyl)(cyclopropylmethyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (18); 8-(cyclohexyl) 5-Methyl-8-(methyl(p-tolyl)amino)-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (19); 5-Methyl-8-(methyl(p-tolyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (20); 8-((3-cyanophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (21); 5-Methyl-8-(methyl(m-tolyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile 22;8-((4-fluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (23);8-((4-methoxyphenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (24);8-((3-fluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (25);5-methyl-8-(methyl(o-tolyl)amino)-6-oxo -5,6-Dihydro-1,5-naphthyridine-2-carbonitrile (26); 8-((3-methoxyphenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (27); 8-((3,4-difluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (28); 8-((4-chlorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (29);

[0034] 8-((1-cyclopropylethyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (32); 5-methyl-8-(methyl(4-(trifluoromethyl)phenyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (33); 8-(ethyl(4-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (34); 8-((cyclopropylmethyl)(4-fluoromethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile 8-((cyclopropylmethyl)(4-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (35); 8-((cyclopropylmethyl)(4-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (36); 8-((cyclopropylmethyl)(4-(2,2,2-trifluoroethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (37); 8-((cyclopropylmethyl)(3 -methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (38); 8-((cyclopropylmethyl)(4-(difluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (39); 8-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (40); 8-((cyclopropylmethyl) (4-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (41); 8-((cyclopropylmethyl)(4-(trifluoromethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (42); 8-((cyclopropylmethyl)(3-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (43);8-((3-Bromophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (44); Methyl 4-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)benzoate (45); 8-((cyclopropylmethyl)(5-cyclopropylpyridin-2-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (46); 8-((cyclopropylmethyl)(3-(trifluoromethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine 8-((5-Bromopyridin-2-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (48); 8-((cyclopropylmethyl)(o-tolyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (49); 8-((2-chloro-4-(trifluoromethoxy)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo -5,6-Dihydro-1,5-naphthyridine-2-carbonitrile (50); 8-((cyclopropylmethyl)(3-methyl-4-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (51); 8-(benzyl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (52); 8-((cyclopropylmethyl)(4-(oxazol-5-yl) 8-((4-(1H-pyrrol-1-yl)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (53); 8-((4-(1H-pyrrol-1-yl)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (54); 8-((cyclopropylmethyl)(4-fluoro-3-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (55);8-((3-chlorophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (56); 8-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (59); 4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (60);

[0035] 8-((cyclopropylmethyl)(4-(difluoromethoxy)-3-fluorophenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (61); 8-((cyclopropylmethyl)(p-tolyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (62); 8-((3-cyano-4-(difluoromethoxy)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1 ,5-Naphthyridine-2-carbonitrile (63);8-((cyclopropylmethyl)(6-fluoropyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (64);8-(benzofuran-5-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (65);8-((6-cyanopyridin-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5 ,6-Dihydro-1,5-naphthyridine-2-carbonitrile (66); 8-((cyclopropylmethyl)(2-(methoxymethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-([1,1'-biphenyl]-4-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (68); 8-((cyclopropylmethyl)(4'-methyl-[1,1'-biphenyl ]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (69); 8-([1,1'-biphenyl]-3-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70); 8-((4'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71);8-((cyclopropylmethyl)(4'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (72); 8-((cyclopropylmethyl)(4'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (73); 8-((cyclopropylmethyl)(3'-methyl-[1,1'-biphenyl]-4-yl)amino)- 5-Methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (74); 8-((cyclopropylmethyl)(2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (75); 8-((3'-chloro-[1,1'-biphenyl]-4-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (76); 8- ((Cyclopropylmethyl)(3'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (77); 8-((Cyclopropylmethyl)(2'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (78); 8-((2'-chloro-[1,1'-biphenyl]-4-yl)(cyclopropylmethyl)amino)-5- Methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (79); 8-((cyclopropylmethyl)(2'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (80); 8-((cyclopropylmethyl)(3'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (81);4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (82); N-((4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-yl)methyl)methanesulfonamide (83); 4'-((6-cyano-1 -Methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-carboxamide (84); N-((4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)methyl)methanesulfonamide (85); 8-((cyclopropylmethyl)(4-(pyridin-3-yl)phenyl) )amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (86); 8-((cyclopropylmethyl)(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (87); 4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-di Methyl-[1,1'-biphenyl]-3-carboxamide (88); 8-((cyclopropylmethyl)(3'-(dimethylamino)-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (89); 8-((cyclopropylmethyl)(4-(2-methoxypyridin-4-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90);

[0036] 8-((cyclopropylmethyl)(4'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (91); 8-((cyclopropylmethyl)(3'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (92); 8-((cyclopropylmethyl)(2'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl 8-((3'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (93); 8-((3'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (94); 8-((cyclopropylmethyl)(3'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (95); 8-((cyclopropylmethyl)(3'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile 8-((2'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (96); 8-((2'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (97); 8-((cyclopropylmethyl)(2'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6 -oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (98); 8-((cyclopropylmethyl)(3'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (99); N-(3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)methanesulfonamide (100);3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (101); N-((3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-yl)methyl)methanesulfonamide (102); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5- Naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-carboxamide (103); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-carboxamide (104); N-((3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)methyl)methane Sulfonamide (105); 8-((cyclopropylmethyl)(3-(pyridin-3-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (106); 8-((cyclopropylmethyl)(4'-(dimethylamino)-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-yl) (Cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-3-carboxamide (108); 8-((cyclopropylmethyl)(3'-(dimethylamino)-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (109); 8-((cyclopropylmethyl)(3-(2-methoxypyridin-4-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110);8-(Benzo[d][1,3]dioxol-5-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (111); 8-((cyclopropylmethyl)(6-(difluoromethoxy)pyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((4-cyclopropyl-2-methylphenyl)(cyclopropylmethyl)amino)-5- Methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (113); 8-((cyclopropylmethyl)(6-cyclopropylpyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (114); 8-((cyclopropylmethyl)(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile aryl (115);8-((cyclopropylmethyl)(4-(dimethylamino)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (116);8-((cyclopropylmethyl)(4-(difluoromethoxy)-3-methylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (117);8-((4-cyclobutylphenyl)(cyclopropylmethyl)amino)-5-methyl 8-((4-cyclohexylphenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (119); 8-((cyclopropylmethyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (120);

[0037] 8-((cyclopropylmethyl)((1r,4r)-4-phenylcyclohexyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (121); 8-((6-cyclopropyl-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (122); 8-((cyclopropylmethyl)(5-(difluoromethoxy)pyridin-2-yl )amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (123);8-((6-cyclopropyl-4'-morpholino-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (124);8-((cyclopropylmethyl)(4',6-dicyclopropyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5 ,6-Dihydro-1,5-naphthyridine-2-carbonitrile (125);8-((6-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (126);8-((6-cyclopropyl-4'-fluoro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine 8-((4'-chloro-6-cyclopropyl-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (128); 8-((6-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (129);5'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-2'-cyclopropyl-[1,1'-biphenyl]-4-carboxamide (130); or 8-((6-cyclopropyl-4'-(cyclopropylmethoxy)-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (131); or a salt thereof.

[0038] In one embodiment, the compound of formula (I) or a salt thereof is selected from the group consisting of: 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (1); 4-((4'-methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (2); 1-methyl-4-(methyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine -6-carbonitrile (3); 6-chloro-4-(cyclohexyl(methyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (30); 6-chloro-4-((cyclopropylmethyl)(propyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (31); 4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (57); or 6-chloro-4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (58). or a salt thereof.

[0039] The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes 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 other embodiment to describe additional embodiments. It should also be understood that individual elements of an embodiment may be combined with any and all other elements from any embodiment to describe additional embodiments.

[0040] 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.

[0041] Unless stated otherwise herein, references made in the singular may also include the plural, for example, "a" and "an" may refer to either one, or one or more. 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).

[0042] Unless otherwise specified, any atom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences. 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.

[0043] 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. Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0044] 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. As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I. The term "cyano" refers to the group --CN. The term "amino" refers to the group -NH2. The term "azido" refers to the group -N3. The term "oxo" refers to the group =O.

[0045] 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.

[0046] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 The term "fluoroalkyl" is intended 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. As used herein, the term "bromoalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more bromine atoms. For example, "C 1-4 "Bromoalkyl" is intended to include C, C, C, and C alkyl groups substituted with one or more bromine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CHBr and -CHCHBr.

[0047] 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 1-4Contains hydroxyalkyl. The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CHCN, -CHCHCN, and -C 1-3 Cyanoalkyl is included.

[0048] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Representative examples of such groups include ethenyl or allyl. For example, "C 2-6 "Alkenyl" means straight and branched chain alkenyl groups having 2 to 6 carbon atoms. The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Representative examples of such groups include ethynyl. For example, "C 2-6 "Alkynyl" means straight and branched chain alkynyl groups having 2 to 6 carbon atoms.

[0049] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic 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.

[0050] As used herein, the term "fluorocycloalkyl" is intended to embrace cycloalkyl groups substituted with one or more fluorine atoms. 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. 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.

[0051] The terms "cyanoalkoxy" and "-O(cyanoalkyl)" refer to a cyanoalkyl group, as defined above, attached through an oxygen linkage. For example, "C 1-3 "Cyanoalkoxy" is intended to encompass C1, C2, and C3 cyanoalkoxy groups. The terms "carbocycle," "carbocyclic," or "carbocyclyl" can be used interchangeably and 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 contain one or more substituents, as valences permit. Thus, the term encompasses non-aromatic rings such as, for example, cycloalkyl, cycloalkenyl, and cycloalkynyl rings. Exemplary bicyclic carbocyclyl groups include indanyl, indenyl, dihydronaphthalenyl, tetrahydronaphthenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, bicycloheptanyl, bicyclooctanyl, and bicyclononanyl.

[0052] As used herein, the term "aryl" refers to a group of groups derived from a molecule containing an aromatic carbon ring by removing one hydrogen atom attached to the aromatic ring. Bicyclic aryl groups include aryl groups having two aromatic carbon rings and aryl groups having one aromatic carbon ring and one non-aromatic carbon ring. Representative examples of aryl groups include monocyclic aryl groups such as phenyl, and bicyclic aryl groups such as naphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indenyl, and indanyl. Aryl groups may be unsubstituted or may contain one or more substituents, as valence allows.

[0053] As used herein, the term "benzyl" refers to a methyl group in which one of the hydrogen atoms has been replaced with a phenyl group. The phenyl ring may be unsubstituted or may contain one or more substituents, valence permitting. The term "heteroatom" refers to oxygen (O), sulfur (S), and nitrogen (N).

[0054] The terms "heterocycle," "heterocyclic," or "heterocyclyl" can be used interchangeably and refer to a cyclic group having a saturated or partially saturated non-aromatic ring, wherein one or more of the rings contain at least one heteroatom (O, S, or N), and the heteroatom-containing rings preferably have 1 to 4 heteroatoms independently selected from O, S, and / or N. The rings of such heteroatom-containing groups can 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 further that the ring contains at least 1 carbon atom. The nitrogen and oxygen atoms can be optionally oxidized, and the nitrogen atom can be optionally quaternized. The heterocyclo group can be attached at any available nitrogen or carbon atom. The heterocyclo ring can be unsubstituted or can contain one or more substituents, where valence allows.

[0055] Exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, piperazinonyl, piperidinonyl, pyrrolidinonyl, azepinyl, azepinonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxolanyl, and tetrahydro-1,1-dioxothienyl.

[0056] "Heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic or 9- or 10-membered bicyclic groups having at least one heteroatom (O, S, or N) in at least one ring, with the heteroatom-containing ring preferably having 1, 2, 3, or 4 heteroatoms independently selected from O, S, and / or N. Each ring of a heteroatom-containing heteroaryl group 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 has at least 1 carbon atom. Bicyclic heteroaryl groups include heteroaryl groups having two aromatic rings, one or both of which contains at least one heteroatom; and heteroaryl groups having one aromatic ring and one non-aromatic ring, one or both of which contains at least one heteroatom. The nitrogen and oxygen atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Heteroaryl ring systems may be unsubstituted or may contain one or more substituents.

[0057] Representative monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Representative bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

[0058] As used herein, the term "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.

[0059] Compounds of formula (I) can form salts, which 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 acidic and / or basic 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 (e.g., 1 equivalent) and precipitating the salt in a solvent, for example, or by subsequent lyophilization of the aqueous solution.

[0060] 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.

[0061] Exemplary base salts include ammonium salts; alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can 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 sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

[0062] 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.

[0063] 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, the solvate may be isolated, 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 solvating are known in the art.

[0064] 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). 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.

[0065] By "stable compound" and "stable structure" is meant 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. A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with a claimed compound, 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 disorders (e.g., cancer).

[0066] As used herein, the terms "treating" or "treatment" cover the treatment of a condition in a mammal, particularly a human, and include (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.

[0067] The compounds of the present invention are intended to contain 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 14C. 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.

[0068] 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.

[0069] The present invention also includes a series 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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). 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).

[0074] 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 Condensation products of ethylene oxide with 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).

[0075] 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., butylated hydroxyanisole and α-tocopherol).

[0076] 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 dispersant and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersants, 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).

[0077] 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 an oil and a fat. Together, the emulsifier, with or without a stabilizer, makes up a so-called emulsifying wax, and the wax, together with the oil and fat, makes up a 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.

[0078] 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.

[0079] 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 using one or more of the carriers or diluents described for use in oral preparations, or other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well known and widely used 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 a cyclodextrin (e.g., Captisol), a solubilizing cosolvent (e.g., propylene glycol), or a solubilizing micelle (e.g., Tween 80).

[0080] 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.

[0081] 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 oil phase containing the compound of formula (I) with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0082] 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).

[0083] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may 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.

[0084] 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).

[0085] 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.

[0086] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants suitable for the intended route of administration.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.

[0087] Pharmaceutical compositions of the present invention may optionally include at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and any additive selected from pharmaceutically acceptable carriers, adjuvants, and vehicles. 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.

[0088] usefulness The compounds of formula (I) are useful in the treatment of cancer. 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.

[0089] 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).

[0090] 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.

[0091] 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.

[0092] 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).

[0093] 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. In another embodiment, the compounds of formula (I) may be formulated together with an immuno-oncology agent.

[0094] 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.

[0095] 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).

[0096] 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 costimulatory 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, and R ANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, Includes EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0097] In certain embodiments, T cell responses may be stimulated by a combination of a compound of Formula (I) and one or more (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.

[0098] 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.

[0099] 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).

[0100] In another embodiment, the compounds of formula (I) may be used in conjunction with one or more agents that activate innate immunity and / or induce inflammation in the tumor microenvironment, such as agonistic agents that bind positive co-stimulatory 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 anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or T cell depletion), and one or more agents that cause innate immune activation and / or inflammation in the tumor area.

[0101] 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. 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.

[0102] 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). 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).

[0103] 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). 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).

[0104] 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). 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.

[0105] 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). 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. In another embodiment, the immuno-oncology agent is a CD27 agonist, such as an antagonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0106] In another embodiment, the immuno-oncology agent directed against B7H3 is MGA271 (WO11 / 109400). 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, and the therapeutic agents, or at least two therapeutic agents, are administered 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 route or by 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. When 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.

[0107] As used herein, the term "cell" refers to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell can be part of a tissue sample removed from an organism (e.g., a mammal). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a living cell in an organism (e.g., a mammal).

[0108] 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.

[0109] 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 and stimulating 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.

[0110] Types of cancer 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 such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and thyroid cancer. These include: Jimen lymphoma, Burkitt 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.

[0111] 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.

[0112] 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.

[0113] Suitable agents for use in combination with compounds of formula (I) in the treatment of melanoma include dacarbazine (DTIC), optionally with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; or the combination of cisplatin, vinblastine, and DTIC, temozolomide, or Yervoy®). Compounds of formula (I) may also be combined with immunotherapeutic agents (e.g., cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF)) in the treatment of melanoma.

[0114] 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.

[0115] 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 bodily 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.

[0116] 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.

[0117] 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.

[0118] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene. 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.

[0119] 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). Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors (eg, CCR2 and CCR4). Other anti-cancer drugs also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer. Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0120] 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 (1995))). (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, or 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 an STI is used, the compounds may be administered in any order.

[0121] 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. Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0122] 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 one or more compounds of formula (I) and / or chemotherapeutic agents 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).

[0123] Chronic viral infections that can be treated using this 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) can be treated by the above methods, optionally substituting compounds known for the treatment of parasitic diseases for antiviral agents.

[0124] 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.

[0125] 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'-dicreoxy-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 medications include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0126] 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 may 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, may also be included in the kit.

[0127] 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, and the therapeutic agents or at least two therapeutic agents are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form of each therapeutic agent in a fixed ratio, 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 route or by 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). When 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.

[0128] 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.

[0129] 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.

[0130] As used herein, the term "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 harmful to the patient.

[0131] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier.

[0132] 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 index. 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 (Vol. 2), 22nd Edition (2012), Pharmaceutical Press.

[0133] 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.

[0134] 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.

[0135] 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. 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.

[0136] 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.

[0137] 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. The present invention encompasses within its scope pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the present invention as an active ingredient, alone or in combination with a pharmaceutical carrier. If desired, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances), as appropriate.

[0138] 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. 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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. 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).

[0143] 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.

[0144] 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 the 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 example compounds can be prepared by known methods that provide enantiomerically enriched or diastereomerically enriched products.

[0145] 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 the description of the synthetic methods set forth below, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup procedures) 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 apparent to those skilled in the art, and alternatives may be required if the existing substituents are not suitable. The reactions may require the determination to change 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 in this invention. 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).

[0146] Example The following examples illustrate specific and preferred embodiments of the present 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 herein are as defined below. Common intermediates are generally useful in the preparation of one or more examples and are identified sequentially (e.g., Intermediate 1, Intermediate 2, etc.) and abbreviated as 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. Those skilled in the art of synthesis will frequently devise desirable alternative preparation methods based on one or more considerations (e.g., shorter reaction times, cheaper starting materials, ease of handling and isolation, improved yields, catalyst handling, avoidance of toxic reagents, availability of specialized equipment, and a reduction in the number of linear steps). The intent of describing alternative preparation methods is to further enable the preparation of examples of the present invention. In some cases, some functional groups in the outlined examples and claims may be replaced by well-known bioisosteric substitutions known to those skilled in the art (e.g., replacement of a carboxylic acid group with a tetrazole or phosphate moiety). Collected with deuterated dimethyl sulfoxide. 1 H NMR data used water suppression in data processing. Spectra are reported without correction for the effects of water suppression. Protons adjacent to the water suppression frequency at 3.35 ppm show a decrease in signal intensity.

[0147] Abbreviation [Table 1] [Table 2]

[0148] LCMS Methods: The following analytical LCMS methods were used to characterize the compounds shown in Tables 1-5. Method 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0149] Method 2: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0150] Method 3: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0151] Method 4: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0152] Method 5: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.50 minutes; Flow Rate: 1 mL / min; Detection: MS and UV (220 nm); Injection 2 Result: Purity: 99%; Observed Mass: 421.13; Retention Time: 2.39 minutes

[0153] Method 6: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0154] Method 7: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0155] Method 8: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0156] Method 9: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0157] Method 10: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0158] Method 11: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0159] Method 12: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0160] Method 13: Column: Waters Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0161] Intermediate 1 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile [ka]

[0162] To a stirred solution of 4-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (200 mg, 0.91 mmol) in acetonitrile (5 mL) was added DIPEA (0.46 mL, 2.72 mmol) and 4'-cyclopropyl-[1,1'-biphenyl]-3-amine (190 mg, 0.91 mmol) at room temperature. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with diethyl ether to give 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (180 mg, 47% yield). LCMS: m / z = 394.1 (M+H); retention time = 2.07 min; LCMS method: Column: Xbridge BEH C18 XP (50 x 2.1 mm), 2.5 μm; Mobile phase A: 5:95 acetonitrile:water + 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water + 10 mM NH4OAc; Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min

[0163] Intermediate 2 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka]

[0164] To a stirred solution of 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (30 mg, 0.090 mmol) in acetonitrile (5 mL), DIPEA (0.016 mL, 0.090 mmol) and 4'-cyclopropyl-[1,1'-biphenyl]-3-amine (18.84 mg, 0.090 mmol) were added at room temperature. The reaction mixture was heated to 85°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was washed with diethyl ether to give 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (2.8 mg, 8% yield). LCMS: m / z = 393.1 (M+H); retention time = 2.22 min; LCMS method: Column: Xbridge BEH C18 XP (50 x 2.1 mm), 2.5 μm; Mobile phase A: 5:95 acetonitrile:water + 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water + 10 mM NH4OAc; Temperature: 50 °C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min

[0165] Intermediate 3 4-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile [ka]

[0166] Intermediate 3 was prepared according to the method described in WO 2020006018.

[0167] Intermediate 4 6-Bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0168] Intermediate 4 was prepared according to the method described in WO2020006016.

[0169] Intermediate 5 6-Bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0170] DIPEA (74.8 mL, 428 mmol) was added to a slurry of 6-bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carbonitrile (20 g, 71.4 mmol) in acetonitrile (600 mL). The solid dissolved, forming a clear solution. Phosphorus oxychloride (26.6 mL, 286 mmol) was added slowly dropwise with stirring at room temperature. After stirring for 10 minutes, benzyltriethylammonium chloride (21.14 g, 93 mmol) was added immediately and all at once, and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated to remove the solvent and POCl3. The crude material was diluted with chloroform, cooled to 0 °C, and aqueous potassium phosphate dibasic (saturated) was added until the pH was approximately 9. The solution was extracted repeatedly with a 1:1 mixture of chloroform:dichloromethane (5 x 500 mL), then dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using a gradient of ethyl acetate in dichloromethane, and the product (9 g) was eluted at 10% ethyl acetate. 1H NMR (400MHz, DMSO-d6) δ ppm 8.16(d,J=8Hz,1H), 8.08(d,J=8Hz,1H), 8.16(d,J=8Hz,1H), 3.65(s,3H)

[0171] Intermediate 6 4-chloro-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0172] Intermediate 6 was prepared according to the method described in WO2020006016.

[0173] Intermediate 7 6-Bromo-4-chloro-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0174] Intermediate 7 was prepared according to the method described in Chupak et al., WO2020006016.

[0175] Example 1 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile [ka]

[0176] To a stirred solution of NaH (31 mg, 0.76 mmol) in THF (5 mL) was added 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (150 mg, 0.38 mmol) at 0 °C. After 10 min, methyl iodide (0.02 mL, 0.23 mmol) in THF (5 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The reaction was quenched with saturated NH4Cl solution (10 mL). The reaction mixture was extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with water, brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude product, which was purified via preparative LC / MS to give 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (16 mg, 10% yield). (Preparative LC / MS method: Column: Waters Xbridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 25% B hold for 0 min, 25-55% B over 20 min, then 100% B hold for 5 min; Flow rate: 20 mL / min; Column temperature: 25 °C); LCMS: m / z = 408.1 (M + H); rt 1.96 min; LCMS method: Column: Xbridge BEH C18 XP (50 x 2.1 mm), 2.5 μm; Mobile phase A: 5:95 acetonitrile:water + 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water + 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min; 1H NMR (400MHz, DMSO-d6) δ ppm 8.07-7.99(m,1H), 7.93(d,J=8.8Hz,1H), 7.58(td,J=1.2, 8.1Hz,1H), 7.53-7.40(m,4H), 7.22(ddd,J=1.0, 2.1, 7.9Hz,1H), 7.16-7.06(m,2H), 3.59(s,3H), 3.48(s,3H), 1.98-1.84(m,1H), 0.99-0.89(m,2H), 0.75-0.60(m,2H)

[0177] The examples in Table 1 were prepared following the general procedure described in Example 1 by using the appropriate amine. Table 1 [Table 3]

[0178] Example 4 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka]

[0179] To a stirred solution of 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (150 mg, 0.38 mmol) in THF (5 mL) was added cesium carbonate (125 mg, 0.38 mmol). After 5 minutes, methyl iodide (0.02 mL, 0.23 mmol) was added at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was filtered through a bed of Celite and concentrated under reduced pressure to give the crude compound, which was purified via preparative LC / MS to give 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (10.3 mg, 7% yield). Preparative LC / MS conditions: Column: Waters Xbridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 25% B at 0 min, 25-55% B over 20 min, then 100% B at 5 min; Flow rate: 20 mL / min; Column temperature: 25 °C; LCMS: m / z = 407.2 (M + H); Retention time = 2.05 min; LCMS method: Column: Xbridge BEH C18 XP (50 x 2.1 mm), 2.5 μm; Mobile phase A: 5:95 acetonitrile:water + 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water + 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min); 1 H NMR (400MHz, DMSO-d6) δ ppm 8.10-7.93(m,2H), 7.45(d,J=8.3Hz,2H), 7.38-7.31(m,2H), 7.16-7.05(m,2H), 7.04-6.95(m,2H ), 6.35(s,1H), 3.57(s,3H), 3.44(s,3H), 2.00-1.85(m,1H), 1.04-0.89(m,2H), 0.75-0.62(m,2H)

[0180] The examples in Table 2 were prepared following the general procedure described in Example 4 by using the appropriate amine. Table 2 [Table 4]

[0181] Example 7 6-Bromo-4-[cyclohexyl(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0182] To a solution of N-methylcyclohexanamine (6.83 mg, 0.060 mmol) and 6-bromo-4-chloro-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15 mg, 0.050 mmol) in DMF (1 mL) was added Hunig's base (0.026 mL, 0.151 mmol). The reaction mixture was placed on a shaker at room temperature for 2 hours. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 19 x 200 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Gradient: 35-75% B over 20 minutes, then hold at 100% B for 5 minutes; Flow rate: 20 mL / min. The product-containing fractions were combined and dried via centrifugal evaporation. The product yield was 11.2 mg, and its purity was estimated to be 100% by LCMS analysis. 1H NMR (500MHz, DMSO-d6) δ 7.96-7.92(m,1H), 7.91-7.87(m,1H), 4.27(brt,J=11.6Hz,1H), 3.51(s,2H), 3.22(s,2H), 2.00(brd,J=11.6Hz,2H), 1.82(brd,J=12.5Hz,2H), 1.74(q,J=11.9Hz,2H), 1.61(brd,J=13.4Hz,1H), 1.36(q,J=12.8Hz,2H), 1.21-1.10(m,1H)

[0183] The examples in Table 3 were prepared following the general procedure described in Example 7 by using the appropriate starting amine. Table 3 [Table 5]

[0184] Example 10 8-[Cyclohexyl(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka]

[0185] In a microwave reactor, 6-bromo-4-(cyclohexyl(methyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (10 mg, 0.027 mmol, see Example 7), zinc (2.92 mg, 0.045 mmol), zinc cyanide (15.72 mg, 0.134 mmol), and PdCl(dppf) (1.95 mg, 2.7 μmol) were combined. The reaction mixture was placed under vacuum and refilled with nitrogen. NMP (2 mL) from a fresh bottle was added under nitrogen. The reaction vial was heated at 75° C. for 1 hour. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 19x200mm, 5μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10mM ammonium acetate; Gradient: 24-65% B over 24 minutes, then hold at 100% B for 5 minutes; Flow Rate: 20mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The product yield was 4.5mg, and its purity estimated by LCMS analysis was 100%. LCMS Method 2 Results: Purity: 100.0%; Observed Mass: 322.11; Retention Time: 1.75min; LCMS Method 1 Results: Purity: 100.0%; Observed Mass: 322.1; Retention Time: 1.79min 1 H NMR (500 MHz, DMSO-d6, water peak suppressed): δ 8.25 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 4.35-4.27 (m, 1H), 3.53 (s, 2H), 3.26 (s, 2H), 1.99 (brd, J = 11.0 Hz, 2H), 1.88-1.72 (m, 4H), 1.62 (brd, J = 11.3 Hz, 1H), 1.34 (q, J = 12.7 Hz, 2H), 1.22-1.10 (m, 1H).

[0186] Example 11 8-[(1-cyclopropylethyl)(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka]

[0187] The title compound was prepared starting from Example 9 and following the general procedure described in Example 10. The yield of the product was 7.6 mg with a purity of 94%. LCMS Method 2: Purity: 94.0%; Observed Mass: 308.16; Retention Time: 1.62 min; LCMS Method 1: Purity: 98.4%; Observed Mass: 308.2; Retention Time: 1.62 min. 1 H NMR (500 MHz, DMSO-d6, water peak suppressed): δ 7.96 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 3.71-3.62 (m, 1H), 3.14 (s, 2H), 3.00 (s, 2H), 2.28 (brs, 4H), 1.29 (d, J = 6.5 Hz, 3H), 1.06-0.94 (m, 1H), 0.43-0.32 (m, 1H), 0.31-0.21 (m, 1H), 0.15-0.05 (m, 1H), 0.02 (dt, J = 9.4, 4.8 Hz, 1H).

[0188] Example 12 4-[Cyclohexyl(methyl)amino]-6-methoxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0189] To 6-bromo-4-(cyclohexyl(methyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (9.6 mg, 0.026 mmol, Example 7) was added sodium methoxide (0.5 N in MeOH) (0.208 mL, 0.104 mmol), resulting in the formation of a solid. DMF (0.5 mL) was added, and the mixture was heated at 100° C. in a microwave for 2 hours. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Gradient: 38% B hold for 0 min, 38-78% B over 20 min, then 100% B hold for 4 min; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Product-containing fractions were combined and dried via centrifugal evaporation. The yield of the product was 5.6 mg, and its purity was estimated to be 100% by LCMS analysis. LCMS Method 2: Results: Example: 100.0%; Found Mass: 327.14; Retention Time: 1.87 min; LCMS Method 1: Results: Purity: 100.0%; Found Mass: 327.14; Retention Time: 1.91 min

[0190] Example 13 4-[Cyclohexyl(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0191] To a solution of 4-chloro-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20 mg, 0.086 mmol, Intermediate 6) in DMF (1 mL) was added N-methylcyclohexanamine (19.38 mg, 0.171 mmol) and Hunig's base (0.045 mL, 0.257 mmol). The reaction mixture was placed on a shaker at room temperature overnight. Then, 1.5 mL of DMF was added, and the reaction mixture was filtered. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Gradient: 32% B hold for 0 min, 32-72% B over 20 min, then 100% B hold for 4 min; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fractions were collected and triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 11.3 mg, and its purity was estimated to be 100% by LCMS analysis. LCMS Method 2: Purity: 100.0%; Found Mass: 311.17; Retention Time: 1.97 min; LCMS Method 1: Purity: 100.0%; Found Mass: 311.16; Retention Time: 2.07 min

[0192] Example 14 4-[(1-cyclopropylethyl)(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0193] Example 14 was prepared following the general procedure used to prepare Example 13, except using 1-cyclopropyl-N-methylethan-1-amine. The product yield was 14.0 mg and its purity was 100%. LCMS Method 2: Purity: 100.0%; Observed Mass: 297.1; Retention Time: 1.79 min; LCMS Method 1: Purity: 100.0%; Observed Mass: 297.26; Retention Time: 1.75 min

[0194] Example 15 6-(cyanomethyl)-4-[(1-cyclopropylethyl)(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0195] A mixture of 6-bromo-4-((1-cyclopropylethyl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (40 mg, 0.111 mmol, Example 9), 4-isoxazoleboronic acid pinacol ester (104 mg, 0.533 mmol), second generation xanthophosphine catalyst (25.2 mg, 0.032 mmol) and KPO (113 mg, 0.533 mmol) in dioxane (3 mL) and water (0.3 mL) was heated in a microwave vial at 110° C. for 90 minutes. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Gradient: 2% B hold for 0 min, 2-42% B over 25 min, then 100% B hold for 4 min; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fractions were collected and triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of the product was 2.4 mg, and its purity was estimated to be 98% by LCMS analysis. LCMS Method 2: Purity: 99.3%; Found Mass: 322.11; Retention Time: 1.47 min; LCMS Method 1: Purity: 98.4%; Found Mass: 322.12; Retention Time: 1.45 min

[0196] Example 16 6-Bromo-4-[cyclohexyl(methyl)amino]-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile [ka]

[0197] To a solution of 6-bromo-4-chloro-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (20 mg, 0.062 mmol, Intermediate 7) in DMF (1 mL) was added N-methylcyclohexanamine (7.02 mg, 0.062 mmol), followed by Hunig's base (0.032 mL, 0.186 mmol). The reaction mixture was placed on a shaker at room temperature overnight. The crude material was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 19x200mm, 5μm particles; Mobile Phase A: 5:95 acetonitrile:water + 10mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water + 10mM ammonium acetate; Gradient: 45-85% B over 20 min, then hold at 100% B for 4 min; Flow Rate: 20mL / min. Fractions containing the product were combined and dried via centrifugal evaporation. The product yield was 8.8mg, and its purity estimated by LCMS analysis was 100%. LCMS Method 2 Results: Purity: 100.0%; Observed Mass: 399.07; Retention Time: 2.23 min; LCMS Method 1 Results: Purity: 100.0%; Observed Mass: 399.05; Retention Time: 2.23 min

[0198] Example 17 8-[Cyclohexyl(methyl)amino]-6-oxo-5-(prop-2-yn-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile [ka]

[0199] The title compound was prepared following the general procedure for the preparation of Example 10, starting from Example 16. LCMS Method 2: Purity: 100.0%; Observed Mass: 346.15; Retention Time: 1.9 min; LCMS Method 1: Purity: 100.0%; Observed Mass: 346.15; Retention Time: 1.89 min

[0200] Example 18 8-[(4-Bromophenyl)(cyclopropylmethyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile [ka]

[0201] Step 1: 4-Bromo-N-(cyclopropylmethyl)aniline [ka]

[0202] To a solution of 4-bromoaniline (2.5 g, 14.27 mmol) in dichloromethane (100 mL) was added cyclopropanecarbaldehyde (1.1 mL, 14.27 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (1.8 g, 28.5 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The crude reaction was diluted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After concentration, the residue was purified on an 80 g silica column using a gradient of 0-50% ethyl acetate in hexanes to give the product (3.2 g, 50% yield) as a colorless oil, which slowly formed a white solid. LCMS: 1.1 min, M+1: 225.9

[0203] Step 2: Example 18 In a microwave vial, 6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl trifluoromethanesulfonate (50 mg, 0.143 mmol) was combined with 4-bromo-N-(cyclopropylmethyl)aniline (48.3 mg, 0.214 mmol) in acetonitrile (2 mL) and BEMP (1 M in hexane, 0.29 mL, 0.29 mmol). The reaction vial was sealed and heated in a microwave at 150 °C for 2 hours. The crude material was diluted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removing the solvent, the residue was purified on 24 g of silica gel with a gradient of ethyl acetate in hexane, where the title compound (8 mg, 14% yield) was eluted at 80% ethyl acetate. 1 H NMR (400MHz, chloroform-d) δ 7.69-7.60(m,2H), 7.48-7.40(m,3H), 6.99(d,J=8.8Hz,2H), 3.73-3.66(m ,5H), 1.24-1.14(m,1H), 0.52(dd,J=8.1, 1.0Hz,2H), 0.17(d,J=5.8Hz,2H)

[0204] The examples shown in Table 4 were prepared following the general procedure described in Step 2 of Example 18 by using the appropriate disubstituted amine. Table 4 [Table 6] [Table 7] [Table 8]

[0205] The examples shown in Table 5 were prepared following the general two-step procedure described in Example 18 by using the appropriate aniline. Table 5 [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0206] The examples shown in Table 6 were prepared according to the following method, starting from the product of either Example 18 or Example 44 and the appropriate aryl boronic acid. [ka]

[0207] To a preweighed stubby tube containing the R-boronic acid reagent (0.037 mmol), 8-((4-bromophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (10 mg, 0.024 mmol) or 8-((3-bromophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (10 mg, 0.024 mmol) in dioxane (1.0 mL) was added, followed by tribasic potassium phosphate (0.033 mL, 0.098 mmol). The reaction mixture was degassed, and the PdCl(dppf)-CHCl adduct (5.99 mg, 7.33 μmol) was added. The reaction mixture was heated for 16 hours at 90° C. The reaction was concentrated, redissolved in 2 mL of DMF, filtered through a 0.45 mm filter, and purified using reverse phase HPLC.

[0208] Table 6 [Table 16] [Table 17] [Table 18] [Table 19] [Table 20]

[0209] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25]

[0210] [Table 26] [Table 27] [Table 28]

[0211] Biological assays The pharmacological properties of the compounds of this invention can be confirmed by a number of biological assays. The exemplary biological assays set out below have been carried out with the compounds of this invention.

[0212] 1. In vitro DGK inhibition assay DGKα and DGKζ reactions were performed using either extruded liposomes (DGKα and DGKζ LIPGLO assay) or detergent / lipid micelle substrates (DGKα and DGKζ assay). Reactions were performed in 50 mM MOPS (pH 7.5), 100 mM NaCl, 10 mM MgCl2, 1 μM CaCl2, and 1 mM DTT (assay buffer). Reactions using detergent / lipid micelle substrates also contained 50 mM octyl BD-glucopyranoside. Lipid substrate concentrations were 11 mM PS and 1 mM DAG for detergent / lipid micelle reactions. Lipid substrate concentrations were 2 mM PS, 0.25 mM DAG, and 2.75 mM PC for extruded liposome reactions (5 mM total lipid). Reactions were performed in 150 μM ATP. The enzyme concentration was 5 nM for DGKα and DGKζ.

[0213] Compound inhibition experiments were performed as follows: 25 nL (ADPGLO assay) or 50 nL (LIPGLO assay) droplets of each test compound solubilized in DMSO (top concentration 10 mM, 3-fold serial dilutions for each compound, 11 points) were transferred to wells of a white 1536-well plate (Corning 3725). 2.5 mL of 4x enzyme solution (20 nM DGKα or DGKζ in assay buffer (prepared as described below)) was combined with 2.5 mL of either 4x liposome or 4x detergent / lipid micelle solution (compositions described below) to prepare 5 mL of enzyme / lipid substrate solution at 2x final reaction concentration and incubated for 10 minutes at room temperature. Next, 1 μL of the 2x enzyme / lipid substrate solution was added to the well containing the test compound, and the reaction was initiated by adding 1 μL of 300 μM ATP. The reaction was allowed to proceed for 2 hours (ADPGLO assay) or 1 hour (LIPGLO assay), after which 2 μL of Glo reagent (Promega V9101) was added and incubated for 40 minutes. 4 μL of kinase detection reagent was then added and incubated for 30 minutes. Luminescence was recorded using an EnVision microplate reader. Percent inhibition was calculated from the amount of ATP conversion, with 100% inhibition achieved by a no-enzyme control reaction and 0% inhibition achieved by a vehicle-only reaction. Compounds were evaluated at 11 concentrations and IC 50 was measured.

[0214] Preparation of 4x detergent / lipid micelles Detergent / lipid micelles were prepared by combining 15 g of phosphatidylserine (Avanti 840035P) and 1 g of diacylglycerol (8008110) in a 2 L round-bottom flask and dissolving in 150 mL of chloroform. The chloroform was removed under high vacuum by rotary evaporation. The resulting colorless, viscous oil was suspended in 400 mL of 50 mM MOPS (pH 7.5), 100 mM NaCl, 20 mM NaF, 10 mM MgCl2, 1 μM CaCl2, 1 mM DTT, and 200 mM octylglucoside by vigorous mixing. The lipid / detergent solution was divided into 5 mL aliquots and stored at -80°C.

[0215] 2x liposome preparation The lipid composition was 5 mol% DAG (Avanti 800811O), 40 mol% PS (Avanti 840035P), and 55 mol% PC (Avanti 850457), with a total lipid concentration of 7-8 mg / mL. PC, DAG, and PS were dissolved in chloroform, combined, and dried to a thin film under vacuum. Lipids were hydrated to 20 mM in 50 mM MOPS (pH 7.5), 100 mM NaCl, and 5 mM MgCl2 and subjected to five freeze-thaw cycles. The lipid suspension was extruded 10-12 times through a 100 nm polycarbonate filter. Dynamic light scattering was performed to confirm liposome size (radius 50-60 nm). Liposome preparations were stored at 4°C for 4 weeks.

[0216] 4x liposome preparation The lipid composition was 5 mol% DAG (Avanti 800811O), 40 mol% PS (Avanti 840035P), and 55 mol% PC (Avanti 850457), with a total lipid concentration of 15.2 mg / mL for the 4x liposome solution. PC, DAG, and PS were dissolved in chloroform, combined, and dried to a thin film under vacuum. The lipids were hydrated to 20 mM in 50 mM MOPS (pH 7.5), 100 mM NaCl, 5 mM MgCl2, and subjected to five freeze-thaw cycles. The lipid suspension was extruded 11 times through a 100 nm polycarbonate filter. Dynamic light scattering was performed to confirm the size of the liposomes (radius 50-60 nm). The liposome preparation was stored at 4 °C for 4 weeks.

[0217] Baculovirus expression of human DGKα and DGKζ Human DGK-alpha-TVMV-His-pFBgate and human DGK-zeta-transcript variant-2-TVMV-His-pFBgate baculovirus samples were generated using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's protocol. The DNA used for expression of DGK-alpha and DGK-zeta has SEQ ID NOs: 1 and 3, respectively. Baculovirus amplification was achieved using Sf9 cells infected at a virus / cell ratio of 1:1500 and grown at 27°C for 65 hours after transfection. Scale-up of the expression of each protein was performed in a Cellbag 50L WAVE-Bioreactor System 20 / 50 (GE Healthcare Bioscience). 12 L of 2x10 cells grown in ESF921 insect medium (Expression System) were used. 6 Sf9 cells (Expression Systems, Davis, CA) at 1000 cells / mL were infected with virus stock at a ratio of 1:200 virus / cell and grown for 66-68 hours at 27°C after infection. Infected cell cultures were harvested by centrifugation at 2000 rpm for 20 minutes at 4°C in a SORVALL® RC12BP centrifuge. Cell pellets were stored at -70°C until purification.

[0218] Purification of human DGK-alpha and DGK-zeta Full-length human DGKα and DGKζ, each containing a TVMV-cleavable C-terminal Hexa-His tag sequence (SEQ ID NOs: 2 and 4, respectively), were expressed and purified from Sf9 baculovirus-infected insect cell paste as described above. Cells were lysed using nitrogen cavitation with a nitrogen disrupter (Parr Instruments), and the lysate was clarified by centrifugation. The clarified lysate was purified to approximately 90% homogeneity using three consecutive column chromatography runs on an AKTA Purifier Plus system. The three-step column chromatography included capture with a nickel affinity resin (i.e., HisTrap FF crude, GE Healthcare) followed by size exclusion chromatography (i.e., HiLoad 26 / 600 Superdex 200 prep grade (GE Healthcare) for DGK-alpha and HiPrep 26 / 600 Sephacryl S 300 HR (GE Healthcare) for DGK-zeta). The third step was ion exchange chromatography, which differed between the two isoforms. DGKα was refined using Q-Sepharose anion exchange chromatography (GE Healthcare). DGKζ was refined using SP-Sepharose cation exchange chromatography (GE Healthcare). Proteins were purified by ion exchange chromatography. > They were delivered at a concentration of 2 mg / mL. The buffer formulation was the same for both proteins: 50 mM Hepes, pH 7.2, 500 mM NaCl, 10% v / v glycerol, 1 mM TCEP, and 0.5 mM EDTA.

[0219] 2. Raji CD4 T Cell IL2 Assay A 1536-well IL-2 assay was performed in a 4 μL volume using preactivated CD4 T cells and Raji cells. Prior to the assay, CD4 T cells were preactivated by treatment with α-CD3, α-CD28, and PHA at 1.5 μg / mL, 1 μg / mL, and 10 μg / mL, respectively. Raji cells were treated with staphylococcal enterotoxin B (SEB) at 10,000 ng / mL. Serially diluted compounds were first transferred to a 1536-well assay plate (Corning, #3727), followed by the addition of 2 μL of preactivated CD4 T cells (final density 6000 cells / well) and 2 μL of SEB-treated Raji cells (2000 cells / well). After 24 hours of incubation in a 37°C / 5% CO2 incubator, 4 μL of IL-2 detection reagent was added to the assay plate (Cisbio, #64IL2PEC). The assay plate was read on an Envision reader. To assess compound cytotoxicity, either Raji or CD4 T cells were incubated with serially diluted compounds. After 24 hours of incubation, 4 μL of Cell Titer Glo (Promega, #G7572) was added and the plate was read on an Envision reader. The 50% effective concentration (IC 50 ) was calculated using a four-parameter logistic equation: y = A + ((B A) / (1 + ((C / x)^D))) [where A and B represent the minimum and maximum % activation or inhibition, respectively, and C represents the IC 50 where D is the Hill slope and x represents the compound concentration.

[0220] 3. CellTiter-Glo CD8 T Cell Proliferation Assay Frozen naive human CD8 T cells were thawed in RPMI + 10% FBS, incubated at 37°C for 2 hours, and counted. 384-well tissue culture plates were coated overnight at 4°C with 20 μl of 0.1 μg / mL anti-human CD3 in plain RPMI, which was removed before adding 20k / 40 μL of CD8 T cells to each well along with 0.5 μg / ml soluble anti-human CD28. Compounds were injected into the cell plates immediately after plating. After 72 hours of incubation at 37°C in an incubator, 10 μL of CellTiter-glo reagent (Promega catalog number G7570) was added to each well. Plates were shaken vigorously for 5 minutes, incubated at room temperature for an additional 15 minutes, and read for CD8 T cell proliferation on an Envision. In the analysis, the background CD8 T cell signal stimulated with 0.1 μg / mL anti-CD3 and 0.5 μg / mL anti-CD28 served as the background. The control compound, 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile, was used at 3 μM to set the 100% range, and the EC 50 The data were normalized to an absolute value of 50%.

[0221] 4. DGK AP1-reporter assay Jurkat AP1-luciferase reporters were generated using the Cignal Lenti AP1 Reporter (luc) Kit (SABiosciences (CLS-011L)). Compounds were transferred from the Echo LDV plate to individual wells of a 384-well plate (white, solid-bottom, opaque PE Culture Plate 6007768) using an Echo550 instrument. Sample size was 30 nL per well; one destination plate per source plate. Cell suspensions were prepared by transferring 40 mL of cells (2 x 20 mL) to clean 50 mL conical tubes. Cells were concentrated by centrifugation (1200 rpm; 5 min; ambient temperature). The supernatant was removed, and all cells were suspended in RPMI (Gibco 11875) + 10% FBS to a concentration of 1.35 x 10 cells. 6 Using a multichannel pipette, 30 μL / well of the cell suspension was dispensed into the compound-containing 384-well TC plate at a density of 4.0 x 10 cells per well. 4 The cells were manually added. The cell plate was incubated at 37°C and 5% CO2 for 20 minutes.

[0222] During incubation, an anti-CD3 antibody (αCD3) solution was prepared by mixing 3 μL of αCD3 (1.3 mg / mL) with 10 mL of medium (final concentration = 0.4 μg / mL). Next, 1.5 μL of αCD3 (1.3 mg / mL) was mixed with 0.5 mL of medium (final concentration = 4 μg / mL). After 20 min, 10 μL of medium was added to all wells in column 1, wells A–M, and 10 μL of αCD3 (4 μg / mL) per well was added to rows N–P of column 1 as a control. Next, 10 μL of αCD3 (0.4 μg / mL) per well was added using a multichannel pipette. αCD3-stimulated + / - compound-treated cells were incubated at 37°C and 5% CO2 for 6 h.

[0223] During this incubation period, Steady-Glo (Promega E2520) reagent was slowly thawed at ambient temperature. Then, 20 μL of Steady-Glo reagent was added per well using a multidrop combi-dispenser. Air bubbles were removed by centrifugation (2000 rpm, ambient temperature, 10 seconds). Cells were incubated at room temperature for 5 minutes. Samples were characterized using an Envision Plate Reader Instrument to measure relative luminescence units (RLU) using the luminescence protocol. Data were analyzed using the control compound, 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile, and normalized to 100% inhibition.

[0224] 5. Murine Cytotoxic T Lymphocyte Assay We developed an antigen-specific cytolytic T cell (CTL) assay to functionally evaluate the ability of DGKα and DGKζ inhibitors to enhance effector T cell-mediated tumor cell killing. CD8+ T cells isolated from OT-1 transgenic mice recognize the antigen-presenting cell MC38, which displays the ovalbumin-derived peptide SIINFEKL. Recognition of the cognate antigen initiates the cytolytic activity of OT-1 antigen-specific CD8+ T cells.

[0225] Functional CTL cells were generated as follows: OT-1 spleen cells were isolated from 8- to 12-week-old mice and expanded in the presence of 1 μg / mL SIINFEKL peptide and 10 U / mL mIL2. After 3 days, fresh medium containing 2 U / mL mIL2 was added. On day 5 of expansion, CD8+ T cells were isolated and ready for use. Activated CTL cells can be cryopreserved for 6 months. Separately, 1 million MC38 tumor cells were pulsed with 1 μg / mL SIINFEKL-OVA peptide for 3 hours at 37°C. The cells were washed 3x with fresh medium to remove excess peptide. Finally, CTL cells pretreated with DGK inhibitor for 1 hour were combined with antigen-loaded MC38 tumor cells at a 1:10 ratio in a 96-well U-bottom plate. The cells were then spun at 700 rpm for 5 minutes and placed in an incubator at 37°C overnight. After 24 hours, supernatants were collected for analysis of IFN-γ cytokine levels on an AlphaLisa purchased from Perkin Elmer.

[0226] 6. PHA Proliferation Assay Phytohemagglutinin (PHA)-stimulated blast cells from frozen stocks were incubated in RPMI medium (Gibco, ThermoFisher Scientific, Waltham, MA) supplemented with 10% fetal bovine serum (Sigma-Aldrich, St. Louis, MO) for 1 hour and then added to each well of a 384-well plate (10,000 cells per well). Compounds were transferred to individual wells of the 384-well plate, and treated cells were maintained in culture medium containing human IL2 (20 ng / mL) at 37°C and 5% CO for 72 hours before proliferation was measured using MTS reagent [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] according to the manufacturer's instructions (Promega, Madison, WI). The inhibition rate was calculated by comparing the value of IL2 stimulation (0% inhibition) with the value of the unstimulated control (100% inhibition). 50) was calculated based on 50% inhibition of fold induction between IL2-stimulated and unstimulated treatments.

[0227] 7. Human CD8 T cell IFN-γ assay Frozen naive human CD8 T cells were thawed in AIM-V medium, incubated at 37°C for 2 hours, and counted. 384-well tissue culture plates were coated overnight at 4°C with 20 μL of 0.05 μg / mL anti-human CD3 in PBS, which was then removed from the plate. 40,000 CD8 T cells per 40 microliters were then added to each well along with 0.1 μg / mL soluble anti-human CD28. Immediately after plating the cells, compounds were transferred to the cell plates using an Echo liquid handler. After 20 hours of incubation in a 37°C incubator, 3 μL / well of the supernatant was transferred to a new 384-well white assay plate for cytokine measurement.

[0228] Interferon-γ (IFN-γ) was quantified using an AlphaLISA kit (catalog no. AL217) as described in the manufacturer's manual (Perkin Elmer). Counts from each well were converted to IFN-γ concentration (pg / mL). EC 50 Values ​​were determined using 0.05 μg / mL anti-CD3 + 0.1 μg / mL anti-CD28 as baseline, and 100% activation was determined by costimulating 3 μM of the control compound, 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile, with anti-CD3 + anti-CD28.

[0229] 8. Human CD8 T cell pERK assay Frozen naive human CD8 T cells were thawed in AIM-V medium, incubated at 37°C for 2 hours, and counted. CD8 positive T cells were added to 384-well tissue culture plates at 20,000 cells per well in AIM-V medium. One compound was added to each well, followed by the addition of bead-bound anti-human CD3 and anti-CS28 mAbs at a final concentration of 0.3 μg / mL. Cells were incubated at 37°C for 10 minutes. The reaction was stopped by adding lysis buffer from the AlphaLISA Surefire kit (Perkin Elmer, catalog number: ALSU-PERK-A). Lysates (5 μL / well) were transferred to a new 384-well white assay plate for measuring pERK activation.

[0230] EC of the compound 50 Values ​​were determined by setting anti-CD3 + anti-CD28 as baseline and co-stimulating anti-CD3 + anti-CD28 with 3 μM 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile as 100% activation.

[0231] 9. Human whole blood IFN-γ assay Human venous whole blood (22.5 μL / well) obtained from healthy donors was pretreated with compound for 1 hour at 37° C. in a humidified 95% air / 5% CO2 incubator. Blood was stimulated with 2.5 μL of anti-human CD3 and anti-CD28 mAb at a final concentration of 1 μg / mL for 24 hours at 37° C. IFN-γ in the supernatant was measured using an AlphaLISA kit (catalog no. AL217).

[0232] EC of the compound 50Values ​​were determined by setting anti-CD3 + anti-CD28 as baseline and co-stimulating 3 μM of the control compound, 8-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-5-methyl-7-nitro-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile, with anti-CD3 + anti-CD28 as 100% activation.

[0233] Table A In vitro DGK inhibitory activity [Table 29] [Table 30] [Table 31] [Table 32]

[0234] Table A shows the in vitro DGK inhibition IC20 measured in DGKα and DGKζ liposome assays. 50 Activity values ​​are listed.

[0235] The compounds of the present invention have activity as inhibitors of one or both of the DGKα and DGKζ enzymes and may thus be used in the treatment of diseases associated with the inhibition of DGKα and DGKζ activity.

[0236] Nucleotide sequence encoding hDGKα-(M1-S735)-Ct-TVMV-His [Table 33] [Table 34]

[0237] Amino acid sequence of hDGKα-(M1-S735)-Ct-TVMV-His [Table 35]

[0238] Nucleotide sequence encoding hDGKζ-(M1-A928)-transcript variant-2 Ct-TVMV-His [Table 36] [Table 37]

[0239] Amino acid sequence of hDGKζ-(M1-A928)-transcript variant-2 Ct-TVMV-His [Table 38]

[0240] Nucleotide sequence encoding MA-hDGKα-(S9-S727)-Ct-TVMV-His [Table 39] [Table 40]

[0241] AND - Amino acid sequence of hDGKα-(S9-S727)-Ct-TVMV-His [Table 41]

Claims

1. Formula (I): 【Chemical 1】 [In the formula: X is CR ６ or N; Y is CR ３ or N; R １ is H, F, Cl, Br, -CN, -OH, C １－３ Alkyl (0 to 4 R １ａ substituted with), C ３－４ Cycloalkyl (0 to 4 R １ａ substituted with), C １－３ Alkoxy (0 to 4 R １ａ substituted with —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 R ２ is H, C １－３ Alkyl (0 to 4 R ２ａ substituted with), C ３－４ Alkenyl, C ３－４ Alkynyl or C ３－４ Cycloalkyl (0 to 4 R ２ａ substituted with Each R ２ａ are independently F, Cl, —CN, —OH, C １－２ Alkoxy, C ３－４ Cycloalkyl, C ３－４ alkenyl or C ３－４ is alkynyl; R ３ is H, F, Cl, Br, -CN, C １－３ Alkyl, C １－２ Fluoroalkyl, C ３－４ Cycloalkyl, C ３－４ Fluorocycloalkyl or —NO ２ and R ４ is R ４ａ , -CHR ４ａ R ４ｂ , -CH ２ CHR ４ａ R ４ｂ or -CR ４ａ R ４ｂ R ４ｅ and R ４ａ is C ３－６ cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is 0 to 4 R ４ｃ is substituted with; R ４ｂ is hydrogen or C １－６ Alkyl (F, Cl, —CN, —OH, —OCH ３ , C １－２ Fluoroalkoxy, —NR ａ R ａ , -S(O) ２ R ｅ , or -NR ａ S (O) ２ R ｅ substituted with 0 to 4 more independently selected substituents; Each R ４ｃ are independently F, Cl, Br, —CN, —OH, C １－４ Alkyl, C １－３ Fluoroalkyl, C １－２ Bromoalkyl, C １－２ Cyanoalkyl, C １－２ Hydroxyalkyl, —CH ２ NR ａ R ａ , -(CH ２ ) １－２ O (C １－２ alkyl), -(CH ２ ) １－２ NR ｘ C(O)O(C １－２ alkyl), C １－４ Alkoxy, —O(C １－４ hydroxyalkyl), —O(CR ｘ R ｘ ) １－２ O (C １－２ alkyl), C １－３ Fluoroalkoxy, C １－３ Cyanoalkoxy, —O(CH ２ ) １－２ NR ａ R ａ , -OCH ２ CH=CH ２ , -OCH ２ C≡CH, -C(O)(C １－４ alkyl), —C(O)OH, —C(O)O(C １－３ alkyl), -NR ａ R ａ , -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 １－２ alkyl) ２ , -S(O) ２ (C １－３ alkyl), -(CH ２ ) １－２ (C ３－４ cycloalkyl) or cyclic group (C ３－６ cycloalkyl, furanyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolyl, oxazolyl, thiophenyl, pyridinyl, methoxypyridinyl, and phenyl), each of which is selected from 0 to 2 R ４ｄ is substituted with; Each R ４ｄ are independently F, Cl, —OH, C １－３ Alkyl, —C(O)NR ａ R ａ , -CH ２ NHSO ２ (C １－３ alkyl), C １－３ Alkoxy, C １－３ Fluoroalkoxy, —NR ａ R ａ , -NHSO ２ (C １－３ alkyl), —OCH ２ (C ３－６ cycloalkyl), C ３－６ cycloalkyl, piperidinyl, or morpholinyl; R ４ｅ is C １－６ Alkyl or C ３－６ cycloalkyl, each of which is F, Cl, —OH, C １－２ Alkoxy, C １－２ substituted with 0 to 4 substituents independently selected from fluoroalkoxy, and —CN; R ５ is -CN, C １－４ Alkyl (0 to 4 R ｇ substituted with), C ２－４ alkenyl (0 to 4 R ｇ substituted with) or —CH ２ (C ３－６ cycloalkyl); Each R ６ is H, F, Cl, -CN, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ or -OCH ３ and Each R ａ are independently H or C １－３ is alkyl; Each R ｅ are independently ３－４ Cycloalkyl or C １－３ Alkyl (0 to 4 R １ａ substituted with; 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) or -NR ａ R ａ and Each R ｘ are independently H or —CH ３ and n is 0, 1 or 2. or a salt thereof.

2. R １ H, F, Cl, Br, -CN, -OH, C １－３ Alkyl (0 to 4 R １ａ cyclopropyl (substituted with 0 to 3 R １ａ substituted with), C １－３ Alkoxy (0 to 3 R １ａ or -NR ａ R ａ and R ２ But H, C １－２ alkyl (0 to 2 R ２ａ substituted with) or C ３－４ is alkynyl; Each R ２ａ are independently F, Cl, —CN, —OH, —O(C １－２ alkyl) or cyclopropyl; R ３ H, F, Cl, Br, -CN, C １－２ Alkyl, C １－２ Fluoroalkyl or C ３－４ is cycloalkyl; R ４ But, R ４ａ , -CHR ４ａ R ４ｂ or -CH ２ CHR ４ａ R ４ｂ and R ４ａ But C ３－６ cycloalkyl, 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is 0-3 R ４ｃ is substituted with; R ４ｂ is hydrogen or C １－３ Alkyl (F, Cl, —CN, —OH, —OCH ３ , C １－２ fluoroalkoxy, or —NR ａ R ａ substituted with 0 to 4 substituents independently selected from the group consisting of: Each R ４ｃ are independently F, Cl, Br, —CN, —OH, C １－４ Alkyl, C １－３ Fluoroalkyl, C １－２ Bromoalkyl, C １－２ Cyanoalkyl, C １－２ Hydroxyalkyl, —CH ２ NR ａ R ａ , -(CH ２ ) １－２ O (C １－２ alkyl), -(CH ２ ) １－２ NR ｘ C(O)O(C １－２ alkyl), C １－４ Alkoxy, —O(C １－４ hydroxyalkyl), —O(CR ｘ R ｘ ) １－２ O (C １－２ alkyl), C １－２ Fluoroalkoxy, C １－２ Cyanoalkoxy, —O(CH ２ ) １－２ NR ａ R ａ , -C(O)(C １－４ alkyl), —C(O)OH, —C(O)O(C １－３ alkyl), -NR ａ R ａ , -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), -S(O) ２ (C １－３ alkyl), -(CH ２ ) １－２ (C ３－４ cycloalkyl) or cyclic group (C ３－６ cycloalkyl, furanyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolyl, oxazolyl, thiophenyl, pyridinyl, methoxypyridinyl, and phenyl), each of which is selected from 0 to 2 R ４ｄ is substituted with; Each R ４ｄ are independently F, Cl, —OH, C １－３ Alkyl, —C(O)NR ａ R ａ , -CH ２ NHSO ２ (C １－２ alkyl), C １－２ Alkoxy, C １－２ Fluoroalkoxy, —NR ａ R ａ , -NHSO ２ (C １－２ alkyl), —OCH ２ (C ３－６ cycloalkyl), C ３－６ cycloalkyl, piperidinyl, or morpholinyl; R ４ｅ But C １－３ Alkyl or C ３－６ cycloalkyl, each of which is F, Cl, —OH, C １－２ Alkoxy, C １－２ substituted with 0 to 4 substituents independently selected from fluoroalkoxy, and —CN; R ５ But C １－３ Alkyl, —CH ２ OH, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ NH ２ or -CH ２ (cyclopropyl); Each R ６ is H, F or -CH ３ and Each R ａ are independently H or —CH ３ is The compound according to claim 1 or a salt thereof.

3. R １ is H, Cl, Br, -CN, -CH ３ , -CH ２ CN or -OCH ３ and R ２ Ga-CH ３ or -CH ２ C≡CH; R ３ is H or —CN; R ４ is R ４ａ or -CHR ４ａ R ４ｂ and R ４ａ is cyclopropyl, cyclohexyl, phenyl, pyridinyl, benzo[d][1,3]dioxolyl, benzofuranyl, or dihydrobenzo[b][1,4]dioxinyl, each of which contains 0 to 2 R ４ｃ is substituted with; R ４ｂ is hydrogen or -CH ３ and Each R ４ｃ are independently F, Cl, Br, —CN, —CH ３ , -CF ３ , -CH ２ OCH ３ , -OCH ３ , -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , —C(O)OCH ３ , -N(CH ３ ) ２ , -N(CH ３ )C(O)CH ３ , cyclopropyl, cyclobutyl, cyclohexyl, pyrrolyl, oxazolyl, pyridinyl, methoxypyridinyl or phenyl (0 to 1 R ４ｄ substituted with; R ４ｄ is F, Cl, —OH, —CH ３ , —C(O)NH ２ , -C(O)N(CH ３ ) ２ , -CH ２ NHSO ２ CH ３ , -OCH ３ , -OCF ３ , -N(CH ３ ) ２ , -NHSO ２ CH ３ , -OCH ２ (cyclopropyl), cyclopropyl or morpholinyl; R ５ But -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ or -CH ２ (cyclopropyl); Each R ６ is H 3. A compound according to claim 1 or 2, or a salt thereof.

4. The compound according to any one of claims 1 to 3, or a salt thereof, wherein at least one of X and Y is N.

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

6. The compound according to any one of claims 1 to 3, wherein X is N; and Y is N, or a salt thereof.

7. R ４ is R ４ａ The compound according to any one of claims 1 to 6, or a salt thereof,

8. R ４ But -CHR ４ａ R ４ｂ , -CH ２ CHR ４ａ R ４ｂ or -CR ４ａ R ４ｂ R ４ｅ The compound according to any one of claims 1 to 6, or a salt thereof,

9. R ４ Ga-CHR ４ａ R ４ｂ The compound according to any one of claims 1 to 6, or a salt thereof,

10. R ５ But -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ or -CH ２ The compound according to any one of claims 1 to 9, or a salt thereof, wherein the compound is (cyclopropyl).

11. R ５ But -CH ３ , -CH ２ CH ３ or -CH ２ CH ２ CH ３ The compound according to any one of claims 1 to 10, or a salt thereof,

12. R ５ Ga-CH ２ The compound according to any one of claims 1 to 10, or a salt thereof, wherein the compound is (cyclopropyl).

13. 4-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (1); 4-((4'-methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (2); 1-methyl-4-(methyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (3); 8-((4'-cyclopropyl-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (4); 8-((4'-methoxy-[1,1'-biphenyl]-3-yl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (5); 5-methyl-8-(methyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (6); 6-Bromo-4-[cyclohexyl(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (7); 6-Bromo-1-methyl-4-(methyl(4-methylcyclohexyl)amino)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (8); 6-bromo-4-((1-cyclopropylethyl)(methyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (9); 8-[cyclohexyl(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (10); 8-[(1-cyclopropylethyl)(methyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (11); 4-[cyclohexyl(methyl)amino]-6-methoxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (12); 4-[cyclohexyl(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (13) 4-[(1-cyclopropylethyl)(methyl)amino]-1,6-dimethyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (14); 6-(cyanomethyl)-4-[(1-cyclopropylethyl)(methyl)amino]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (15); 6-Bromo-4-[cyclohexyl(methyl)amino]-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (16); 8-[cyclohexyl(methyl)amino]-6-oxo-5-(prop-2-yn-1-yl)-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (17); 8-[(4-bromophenyl)(cyclopropylmethyl)amino]-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (18); 8-(cyclohexyl(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (19); 5-methyl-8-(methyl(p-tolyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (20); 8-((3-cyanophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (21); 5-methyl-8-(methyl(m-tolyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (22); 8-((4-fluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (23); 8-((4-methoxyphenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (24); 8-((3-fluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (25); 5-methyl-8-(methyl(o-tolyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (26); 8-((3-methoxyphenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (27); 8-((3,4-difluorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (28); 8-((4-chlorophenyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (29); 6-chloro-4-(cyclohexyl(methyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (30); 6-chloro-4-((cyclopropylmethyl)(propyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (31); 8-((1-cyclopropylethyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (32); 5-methyl-8-(methyl(4-(trifluoromethyl)phenyl)amino)-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (33); 8-(ethyl(4-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (34); 8-((cyclopropylmethyl)(4-fluorophenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (35); 8-((cyclopropylmethyl)(4-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (36); 8-((cyclopropylmethyl)(4-(2,2,2-trifluoroethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (37); 8-((cyclopropylmethyl)(3-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (38); 8-((cyclopropylmethyl)(4-(difluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (39); 8-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (40); 8-((cyclopropylmethyl)(4-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (41); 8-((cyclopropylmethyl)(4-(trifluoromethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (42); 8-((cyclopropylmethyl)(3-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (43); 8-((3-bromophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (44); Methyl 4-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)benzoate (45); 8-((cyclopropylmethyl)(5-cyclopropylpyridin-2-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (46); 8-((cyclopropylmethyl)(3-(trifluoromethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (47); 8-((5-bromopyridin-2-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (48); 8-((cyclopropylmethyl)(o-tolyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (49); 8-((2-chloro-4-(trifluoromethoxy)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (50); 8-((cyclopropylmethyl)(3-methyl-4-(trifluoromethoxy)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (51); 8-(benzyl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (52); 8-((cyclopropylmethyl)(4-(oxazol-5-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (53); 8-((4-(1H-pyrrol-1-yl)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (54); 8-((cyclopropylmethyl)(4-fluoro-3-methoxyphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (55); 8-((3-chlorophenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (56); 4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile (57); 6-chloro-4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methylpyrido[3,2-d]pyrimidin-2(1H)-one (58); 8-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2,7-dicarbonitrile (59); 4-((cyclopropylmethyl)(4-cyclopropylphenyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carbonitrile (60); 8-((cyclopropylmethyl)(4-(difluoromethoxy)-3-fluorophenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (61); 8-((cyclopropylmethyl)(p-tolyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (62); 8-((3-cyano-4-(difluoromethoxy)phenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (63); 8-((cyclopropylmethyl)(6-fluoropyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (64); 8-(benzofuran-5-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (65); 8-((6-cyanopyridin-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (66); 8-((cyclopropylmethyl)(2-(methoxymethyl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (67); 8-([1,1′-biphenyl]-4-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (68); 8-((cyclopropylmethyl)(4'-methyl-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (69); 8-([1,1′-biphenyl]-3-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (70); 8-((4'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (71); 8-((cyclopropylmethyl)(4'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (72); 8-((cyclopropylmethyl)(4'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (73); 8-((cyclopropylmethyl)(3'-methyl-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (74); 8-((cyclopropylmethyl)(2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (75); 8-((3'-chloro-[1,1'-biphenyl]-4-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (76); 8-((cyclopropylmethyl)(3'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (77); 8-((cyclopropylmethyl)(2'-methoxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (78); 8-((2'-chloro-[1,1'-biphenyl]-4-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (79); 8-((cyclopropylmethyl)(2'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (80); 8-((cyclopropylmethyl)(3'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (81); 4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (82); N-((4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-yl)methyl)methanesulfonamide (83); 4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-carboxamide (84); N-((4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-yl)methyl)methanesulfonamide (85); 8-((cyclopropylmethyl)(4-(pyridin-3-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (86); 8-((cyclopropylmethyl)(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (87); 4'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-3-carboxamide (88); 8-((cyclopropylmethyl)(3'-(dimethylamino)-[1,1'-biphenyl]-4-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (89); 8-((cyclopropylmethyl)(4-(2-methoxypyridin-4-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (90); 8-((cyclopropylmethyl)(4'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (91); 8-((cyclopropylmethyl)(3'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (92); 8-((cyclopropylmethyl)(2'-methyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (93); 8-((3′-chloro-[1,1′-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (94); 8-((cyclopropylmethyl)(3'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (95); 8-((cyclopropylmethyl)(2'-methoxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (96); 8-((2'-chloro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (97); 8-((cyclopropylmethyl)(2'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (98); 8-((cyclopropylmethyl)(3'-hydroxy-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (99); N-(3′-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1′-biphenyl]-3-yl)methanesulfonamide (100); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (101); N-((3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-yl)methyl)methanesulfonamide (102); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-4-carboxamide (103); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1'-biphenyl]-3-carboxamide (104); N-((3′-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-[1,1′-biphenyl]-3-yl)methyl)methanesulfonamide (105); 8-((cyclopropylmethyl)(3-(pyridin-3-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (106); 8-((cyclopropylmethyl)(4'-(dimethylamino)-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (107); 3'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-N,N-dimethyl-[1,1'-biphenyl]-3-carboxamide (108); 8-((cyclopropylmethyl)(3'-(dimethylamino)-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (109); 8-((cyclopropylmethyl)(3-(2-methoxypyridin-4-yl)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (110); 8-(benzo[d][1,3]dioxol-5-yl(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (111); 8-((cyclopropylmethyl)(6-(difluoromethoxy)pyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (112); 8-((4-cyclopropyl-2-methylphenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (113); 8-((cyclopropylmethyl)(6-cyclopropylpyridin-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (114); 8-((cyclopropylmethyl)(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (115); 8-((cyclopropylmethyl)(4-(dimethylamino)phenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (116); 8-((cyclopropylmethyl)(4-(difluoromethoxy)-3-methylphenyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (117); 8-((4-cyclobutylphenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (118); 8-((4-cyclohexylphenyl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (119); 8-((cyclopropylmethyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (120); 8-((cyclopropylmethyl)((1r,4r)-4-phenylcyclohexyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (121); 8-((6-cyclopropyl-[1,1′-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (122); 8-((cyclopropylmethyl)(5-(difluoromethoxy)pyridin-2-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (123); 8-((6-cyclopropyl-4'-morpholino-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (124); 8-((cyclopropylmethyl)(4',6-dicyclopropyl-[1,1'-biphenyl]-3-yl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (125); 8-((6-cyclopropyl-3'-fluoro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (126); 8-((6-cyclopropyl-4'-fluoro-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (127); 8-((4'-chloro-6-cyclopropyl-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (128); 8-((6-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (129); 5'-((6-cyano-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridin-4-yl)(cyclopropylmethyl)amino)-2'-cyclopropyl-[1,1'-biphenyl]-4-carboxamide (130); or 8-((6-cyclopropyl-4'-(cyclopropylmethoxy)-[1,1'-biphenyl]-3-yl)(cyclopropylmethyl)amino)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile (131) 2. The compound of claim 1, wherein:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or viral infection.

16. 16. The use according to claim 15, wherein the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and melanoma.

17. 14. Use of the compound of any one of claims 1 to 13, or a pharmaceutically acceptable 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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