Substituted Tetrazolyl Compounds Useful as T Cell Activators

Abstract

What is disclosed is TIFF2025528134000064.tif36141 [wherein X, Y, Z, R1, R2, R3, and n 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 / 370,734, filed August 8, 2022, which is incorporated herein by reference in its entirety.

[0002] Description of the invention The present invention generally relates to substituted tetrazolyl compounds that activate T cells, promote T cell proliferation, and / or exhibit antitumor activity. Provided herein are substituted tetrazolyl compounds, compositions containing such compounds, and methods of using them. The present invention further relates to pharmaceutical compositions containing at least one compound of the present invention, which are useful for treating 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 "14166WOPCT," 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 substituted tetrazolyl 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: (i) X is N, CH, or CR1; Y is N, CH, or CR1; and Z is CH or CR1; provided that 0 or 1 of X and Y is N; or (ii) X is CH or CR; Y is NR 1a and Z is C(=O); [ka] represents either a single bond when Z is C(=O) or a double bond when Z is CH or CR1; Each R1 is independently F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, C1-2 Fluoroalkoxy, -C(O)OH, -C(O)O(C 1-3 alkyl), or -NO2; R 1a is hydrogen or -CH3; R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, wherein each cyclic group is selected from 0-3 R 2a is replaced by; Each R 2a are independently F, Cl, Br, -OH, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or -C(O)O(C 1-2 alkyl); R3 is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxy Hydroxyalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -CH2 (phenyl), -CR x R x CR x (OH)(phenyl), -CR x R x CR x =CR x R x , -(CR x R x ) 1-2 C(O)O(C 1-2 alkyl), or -(CR x R x ) 1-3 NR xIs it C(O)(phenyl); Alternatively, R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl, each of which may contain 0 to 2 R 3a is replaced by; Each R 3a are independently F, Cl, -CN, -OH, C 1-3 Alkyl, or C 1-3 is a fluoroalkyl; Each R x are independently hydrogen or -CH; n is 0, 1, 2, or 3; however: (i) Group [ka] teeth, [ka] is a group other than (ii) The compound of formula (I) [ka] compounds other than or a salt thereof.

[0012] The embodiments herein below include proviso (i) and proviso (ii) of the first aspect. In one embodiment, a compound of formula (I) or a salt thereof, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; [ka] represents a double bond; and provided that 0 or 1 of X and Y is N. The compound of this embodiment has the formula (II): [ka] It has the structure shown below.

[0013] In one embodiment, a compound of formula (I) or a salt thereof, wherein X is CH or CR1; Y is CH or CR1; Z is CH or CR1; [ka] represents a double bond. The compound of this embodiment has the formula (IIa): [ka] It has the structure shown below.

[0014] In one embodiment, a compound of formula (I) or a salt thereof, wherein X is N; Y is CH or CR1; Z is CH or CR1; [ka] represents a double bond. The compound of this embodiment has the formula (IIb): [ka] It has the structure shown below.

[0015] In one embodiment, a compound of formula (I) or a salt thereof, wherein X is CH or CR1; Y is N; Z is CH or CR1; [ka] represents a double bond. The compound of this embodiment has the formula (IIc): [ka] It has the structure shown below.

[0016] In one embodiment, a compound of formula (I) or a salt thereof, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; [ka] represents a double bond; and one of X and Y is N, or a salt thereof.

[0017] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein X is CH or CR; and Y is NR 1a and Z is C(=O); [ka] represents a single bond. The compound of this embodiment has the formula (III): [ka] It has the structure shown below.

[0018] In one embodiment, a compound of formula (I) or a salt thereof, wherein (i) X is N, CH, or CR1; Y is N, CH, or CR1; and Z is CH or CR1; provided that 0 or 1 of X and Y is N; or (ii) X is CH or CR1; and Y is NR 1a and Z is C(=O); [ka] represents either a single bond when Z is C(=O) or a double bond when Z is CH or CR; each R is independently F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, C 1-2 Fluoroalkoxy, -C(O)OH, -C(O)O(C 1-2 alkyl), or -NO2; R 1ais hydrogen or -CH3; R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, wherein each cyclic group is selected from 0-3 R 2a and each R 2a are independently F, Cl, Br, -OH, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or -C(O)O(C 1-2 alkyl); R3 is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -CH2 (phenyl), -CR x R x CR x (OH)(phenyl), -CR x R x CR x =CR x R x , -(CR x R x ) 1-2 C(O)O(C 1-2 alkyl), or -(CR x R x ) 1-3 NR x C(O)(phenyl); each R x is independently hydrogen or —CH 3 ; and n is 0, 1, 2, or 3, or a salt thereof.

[0019] In one embodiment, a compound of formula (I) or a salt thereof, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; with the proviso that 0 or 1 of X and Y is N; [ka] represents a double bond; each R1 is independently F, Cl, Br, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Alkoxy, C 1-2 Fluoroalkoxy, -C(O)OH, -C(O)O(C 1-3 alkyl), or -NO2; R 1a is hydrogen or -CH3; R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, wherein each cyclic group is selected from 0-3 R 2a and each R 2a are independently F, Cl, Br, -OH, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, or -C(O)O(C 1-2 alkyl); R3 is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -CH2 (phenyl), -CR x R x CR x (OH)(phenyl), -CRx R x CR x =CR x R x , -(CR x R x ) 1-2 C(O)O(C 1-2 alkyl), or -(CR x R x ) 1-3 NR x C(O)(phenyl); or R2 and R3 together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl, each containing 0 to 2 R 3a and each R 3a are independently F, Cl, -CN, -OH, C 1-3 Alkyl, or C 1-3 fluoroalkyl; each R x is independently hydrogen or —CH 3 ; and n is 0, 1, 2, or 3, or a salt thereof.

[0020] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently F, Cl, Br, —CN, C 1-3 Alkyl, -CHF2, -CF3, -OCH3, -OCF3, -C(O)OH, -C(O)O(C 1-2 alkyl), or -NO2; R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each of which is selected from 0 to 2 R 2a and each R 2a are independently -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, or -C(O)OCH2CH3; R3 is C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl, -CH2(C 3-4cycloalkyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)O(C 1-2 alkyl), or —CHCHCHNHC(O)(phenyl); or R and R taken together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl, each containing 0 to 2 R 3a and each R 3a is independently -CN, -OH, -CH3, or -CF3; and n is 0, 1, 2, or 3, or a salt thereof.

[0021] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently F, Cl, Br, —CN, C 1-3 alkyl, -CHF2, -CF3, -OCH3, -OCF3, -C(O)OH, -C(O)OCH3, or -NO2; R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each of which is selected from 0 to 2 R 2a and each R 2a are independently -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, or -C(O)OCH2CH3; R3 is C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl, -CH2(C 3-4 cycloalkyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)O(C 1-2 -CH2CH2CH2NHC(O)(alkyl), or -CH2CH2CH2NHC(O)(phenyl), or a salt thereof.

[0022] In one embodiment, a compound of formula (I) or a salt thereof, wherein each R is independently F, Cl, Br, —CN, —CH, —CF, —OCH, —C(O)OH, —C(O)OCH, or —NO; R is —CH(CH), —CHCH(CH), cyclopropyl, cyclohexyl (0 to 2 R 2a substituted with —C(O)OCH2CH3), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl (substituted with —C(O)OCH2CH3), or phenyl; 2a are independently -OH, -CH, or -C(O)OCHCH; R is -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCHOH, cyclopropyl, -CH(cyclopropyl), -CH(phenyl), -CHCH(OH)(phenyl), -CHCH=CH, -CHCHC(O)OCH, or -CHCHCHNHC(O)(phenyl); or R and R, together with the nitrogen atom to which they are attached, are pyrrolidinyl (two R 3a each R 3a is —CH 3 ; and n is 1 or 2, or a salt thereof.

[0023] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, wherein each R is independently F, Cl, Br, —CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, -C(O)OH, -C(O)O(C 1-3 In this embodiment, each R is independently selected from F, Cl, Br, —CN, C, C, C alkyl, or —NO. 1-3Included in this embodiment are compounds where each R is independently F, Cl, Br, —CN, —CH, —CF, —OCH, —OCF, or —NO. Also included in this embodiment are compounds where each R is independently F, Cl, Br, —CN, —CH, —CF, —OCH, —C(O)OH, —C(O)OCH, or —NO.

[0024] In one embodiment, the compound of formula (I) or a salt thereof, wherein R2 is C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, wherein each cyclic group is selected from 0-2 R 2a In this embodiment, compounds or salts thereof are provided in which R2 is substituted with C 3-4 Alkyl, or C 3-6 a cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each of which is selected from 0 to 2 R 2a This embodiment also includes compounds where R is substituted with -CH(CH), -CHCH(CH), cyclopropyl, cyclohexyl (where 0 to 2 R 2a Also included are compounds wherein the alkyl group is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl (substituted with -C(O)OCH2CH3), or phenyl.

[0025] In one embodiment, the compound of formula (I) or a salt thereof, wherein R2 is C 3-4

[0023] Provided herein is a compound, or a salt thereof, wherein R2 is -CH(CH3)2 or -CH2CH(CH3)2. This embodiment includes compounds where R2 is -CH(CH3)2 or -CH2CH(CH3)2. In one embodiment, the compound of formula (I) or a salt thereof, wherein R2 is C 3-6 and a cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, wherein each cyclic group is selected from 0-3 R 2a In this embodiment, the compound or salt thereof is provided, wherein R2 is substituted with C 3-6 a cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each of which is selected from 0 to 2 R 2a This embodiment also includes compounds where R2 is substituted with cyclopropyl, cyclohexyl (0 to 2 R 2a Also included are compounds wherein the alkyl group is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl (substituted with -C(O)OCH2CH3), or phenyl.

[0026] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R2 is cyclohexyl. In one embodiment, a compound of formula (I) or a salt thereof, wherein each R 2a are independently F, Cl, Br, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, or -C(O)O(C 1-2 In this embodiment, each R is a substituted or unsubstituted alkyl group, or a salt thereof. 2ais independently -OH, -CN, -CH, -CHF, -CHF, -CF, or -C(O)OCHCH. This embodiment also includes compounds where each R 2a Also included are compounds where is independently -OH, -CH3, or -C(O)OCH2CH3.

[0027] In one embodiment, the compound of formula (I) or a salt thereof, wherein R3 is C 1-5 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -CH2 (phenyl), -CR x R x CR x (OH)(phenyl), -CR x R x CR x =CR x R x , -(CR x R x ) 1-2 C(O)O(C 1-2 alkyl), or -(CR x R x ) 1-3 NR x C(O)(phenyl), or a salt thereof. 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl, -CH2(C 3-4 cycloalkyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)O(C 1-2Also included in this embodiment are compounds where R is -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCHOH, cyclopropyl, -CH(cyclopropyl), -CH(phenyl), -CHCH(OH)(phenyl), -CHCH=CH, -CHCHC(O)OCH, or -CHCHCHNHC(O)(phenyl).

[0028] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R3 is -CH3. In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein R2 is cyclohexyl and R3 is -CH3. In one embodiment, a compound of formula (I) or a salt thereof, wherein R and R together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl, each containing 0 to 2 R 3a In this embodiment, R and R, together with the nitrogen atom to which they are attached, form a pyrrolidinyl (two R 3a This embodiment also includes compounds where R2 and R3, together with the nitrogen atom to which they are attached, form two R 3a Also included are compounds that form piperidinyl substituted with:

[0029] In one embodiment, a compound of formula (I) or a salt thereof, wherein each R 3a are independently F, Cl, -CN, -OH, C 1-2 Alkyl, or C 1-2 In this embodiment, each R is fluoroalkyl, or a salt thereof. 3a is independently -CN, -OH, -CH, or -CF. This embodiment also includes compounds where each R 3aAlso included are compounds where each R 3a Also included are compounds where is -CH3.

[0030] In one embodiment, a compound of formula (I) or a salt thereof, wherein [ka] Compounds or salts thereof are provided having a structure selected from:

[0031] In one embodiment, a compound of formula (I) or a salt thereof, wherein [ka] Compounds or salts thereof are provided having a structure selected from:

[0032] In one embodiment, the compound of formula (I) or a salt thereof is selected from the group consisting of methyl 3-(cyclohexyl((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)amino)propanoate (1); N,4-dimethyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclohexan-1-amine (2); N-ethyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclohexanamine (3); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl) 2-chloro-5-(5-((cyclohexyl(2-hydroxyethyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (7); 2-chloro-5-(5-((cyclohexyl(propyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (8); 5-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (9); 5-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (10); 2-chloro-5-(5-((cyclohexyl(propyl)amino)methyl) -1H-tetrazol-1-yl)benzonitrile (8); 2-chloro-5-(5-((isobutyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (9); 2-chloro-5-(5-((cyclohexyl(cyclopropylmethyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (10); 2-chloro-5-(5-((isopropyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (11); 2-chloro-5-(5-((cyclohexyl( (isopropyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (12); 2-chloro-5-(5-((cyclohexyl(ethyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (13); 3-chloro-6-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (14); 3-chloro-6-(5-((cyclohexyl(cyclopropylmethyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (15);3-chloro-6-(5-((cyclohexyl(ethyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (16); 6-(5-((allyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-3-chloropicolinonitrile (17); N-methyl-N-((1-(3-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl)methyl)cyclohexanamine (18); N-((1-(3-fluorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (1 9); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (20); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-fluorobenzonitrile (21); 2-chloro-5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (22); N-methyl-N-((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-tetrazol-5-yl)methyl)cyclohexaneamino 2-Bromo-5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (26); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-5-nitrobenzonitrile (27); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methoxybenzonitrile (28); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methylbenzonitrile (29); 2-Bromo-5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (30); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-5-nitrobenzonitrile (31); (27); N-((1-(4-chloro-3-nitrophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (28); N-((1-(4-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (29); 5-chloro-2-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (30); N-((1-(4-methoxyphenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (31);N-methyl-N-((1-(4-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclohexanamine (32); Methyl 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzoate (33); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzoic acid (34); N-methyl-N-((1-(m-tolyl)-1H-tetrazol-5-yl)methyl)cyclohexanamine (35); N-((1-(3-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (36); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)propan-2-amine (37); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)tetrahydro-2H-pyran-4-amine (38); tert-butyl 3-(Methyl((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)amino)pyrrolidine-1-carboxylate (39); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)tetrahydrofuran-3-amine (40); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)aniline (41); N,2-dimethyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)propan-1-amine (42); 2-(Cyclohexyl((1-(3-nitrophenyl)-1H N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclopropanamine (44); N-((1-(3-bromophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (45); N-((1-(6-fluoropyridin-3-yl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (46); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (47);5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (48); N-((1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexanamine (49); 2-chloro-5-(5-((2,5-dimethylpyrrolidin-1-yl)methyl)-1H-tetrazol-1-yl)benzonitrile (50); Ethyl 4-(((1-(4-chloro-3-cyanophenyl)-1H-tetrazol-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylate (51); 2-chloro-5-(5-((cyclohexyl(2-hydroxy-2-phenylethyl)amino)methyl)-1H-tetrazol-1-yl)benzonitrile (52); 3-chloro-6-(5-((cyclohexyl(propyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (53); N-(3-(((1-(5-chloro-6-cyanopyridin-2-yl)-1H-tetrazol-5-yl)methyl)(cyclohexyl)amino)propyl)benzamide (54); 3-chloro-6-(5-((cyclohexyl(isopropyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (55); Ethyl 4-(((1-(5-chloro-6-cyanopyridin-2-yl)-1H-tetrazol-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylate (56); 3-chloro-6-(5-((cyclohexyl(2-hydroxy-2-phenylethyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (57); 6-(5-((benzyl((1R,2R)-2-hydroxycyclohexane 3-chloro-6-(5-((cyclopropyl((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (59); 3-chloro-6-(5-((isopropyl(methyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (60);3-chloro-6-(5-((isobutyl(methyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (61); 3-chloro-6-(5-((cyclohexyl(2-hydroxyethyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (62); or 6-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-3-chloropicolinonitrile (63); or a salt thereof.

[0033] 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.

[0034] 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.

[0035] 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).

[0036] 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.

[0037] 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.

[0038] 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 "oxo" refers to the group =O.

[0039] 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.

[0040] 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.

[0041] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and C 1-4 Hydroxyalkyl is an example. As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic hydrocarbon molecule or a non-aromatic polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms.

[0042] 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.

[0043] 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.

[0044] 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 acid salts formed with inorganic and / or organic acids. 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) can be formed, for example, by reacting a compound of formula (I) with a certain amount of acid (e.g., one equivalent) and then precipitating the salt in a solvent, for example, or by lyophilizing the aqueous solution.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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).

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] 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).

[0059] 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).

[0060] 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).

[0061] 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.

[0062] 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.

[0063] 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).

[0064] 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.

[0065] 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.

[0066] 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).

[0067] 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-10 ... 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.

[0068] 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).

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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).

[0074] 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.

[0075] 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.

[0076] 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).

[0077] 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.

[0078] 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.

[0079] 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).

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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).

[0084] 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.

[0085] 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.

[0086] 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).

[0087] 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).

[0088] 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.

[0089] 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.

[0090] In another embodiment, the immuno-oncology agent directed against B7H3 is MGA271 (WO11 / 109400). Combination therapy includes administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same 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.

[0091] 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).

[0092] 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.

[0093] 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.

[0094] 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 cancer, and Tumors include glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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).

[0107] 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.

[0108] 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.

[0109] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir; BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also called β-L-D4C, which is named β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary 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. Exemplary 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.

[0110] 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.

[0111] Combination therapy includes administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. Combination therapy can also include the administration of the above-mentioned therapeutic agents in combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy). 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The compounds are typically 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 standards. 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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).

[0127] 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.

[0128] 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.

[0129] 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).

[0130] Methods that can be utilized to synthesize intermediates useful in the preparation of embodiments of the present invention are shown in the following schemes.

[0131] 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 above. 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.

[0132] Abbreviation [Table 1]

[0133] Example 4 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile [ka]

[0134] Step 1: Preparation of 2-chloro-N-(3-cyano-4-(trifluoromethyl)phenyl)acetamide [ka]

[0135] A solution of 5-amino-2-(trifluoromethyl)benzonitrile (4.8 g, 25.8 mmol) in tetrahydrofuran (103 mL) was cooled to 0 °C, and triethylamine (10.78 mL, 77 mmol) and 2-chloroacetyl chloride (2.054 mL, 25.8 mmol) were added. The reaction mixture was stirred at 0 °C for 10 minutes. LC / MS showed the reaction was complete. The crude reaction mixture was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel chromatography using a hexane:ethyl acetate gradient (10:1 to 1:1) to give 6 g of the desired product as a light yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.21 (dd, J = 1.4, 0.6 Hz, 1H), 8.18-8.07 (m, 2H), 4.92 (s, 2H)

[0136] Step 2: Preparation of 5-(5-(chloromethyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile [ka]

[0137] In a screw-top reaction vessel, 2-chloro-N-(3-cyano-4-(trifluoromethyl)phenyl)acetamide (2 g, 7.62 mmol) and sodium azide (1.980 g, 30.5 mmol) were combined in acetonitrile (40 mL), and tetrachlorosilane (3.50 mL, 30.5 mmol) was added. The reaction mixture was placed under nitrogen and stirred at 130 °C for 4 h. The reaction was quenched with saturated sodium bicarbonate. The reaction mixture was adsorbed onto Celite. Chromatography on a 40 g silica gel column using 20-100% ethyl acetate in hexanes gave the title compound (575 mg, 26% yield). 1 H NMR(400MHz, chloroform-d) δ 7.53(d,J=8.7Hz,1H), 7.02(d,J=1.9Hz,1H), 6.88(brd,J=8.6Hz,1H), 4.26(brs,2H);19F NMR(471MHz, DMSO-d6) δ -60.78(s,CF3)

[0138] Step C: Preparation of 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile [ka]

[0139] In a 100 mL round-bottom flask, Hunig's base (699 μL, 4.00 mmol) and 5-(5-(chloromethyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile (575 mg, 2.000 mmol) were dissolved in DMF (10 mL). To this solution, N-methylcyclohexanamine (272 mg, 2.400 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 200 mL of ethyl acetate and extracted five times with 25 mL of water and once with 20 mL of brine. The organic portion was adsorbed onto Celite and chromatographed on a 24 g silica gel cartridge using a 20-100% gradient of ethyl acetate in hexane. Fractions consisting of the desired product were combined, and the solvent was removed to give the title compound (570 mg, 78% yield) as an oil. The oil was stirred under hexane to form a white solid. 1 H NMR (400MHz, chloroform-d) δ 8.81(d,J=1.6Hz,1H), 8.35(dd,J=8.6, 1.3Hz,1H), 8.04(d,J=8.6Hz,1H), 3.99(s,2H), 2.49(ddd,J=11.0, 7.8, 3 .5Hz,1H), 2.27(s,3H), 1.91-1.79(m,4H), 1.69(brd,J=12.9Hz,1H), 1.42-1.21(m,5H), 1.20-1.06(m,1H);LC / MS 1.1 minutes, M+1:364.9

[0140] Examples 1-30 in the table were prepared by following the general procedure disclosed in Example 4, by substituting the desired aniline (RAr-NH2) in step 1 and the desired secondary amine (R'R''NH) in step 3.

[0141] [ka]

[0142] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0143] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14]

[0144] The compounds were characterized using the following analytical LCMS methods. Method A: Waters XBridge BEH XP C18 (50x2.1 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

[0145] Method B: Column: Waters XBridge BEH XP C18 (50x2.1 mm) 2.5 μm; Mobile phase A: 5:95 acetonitrile:water + 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water + 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B over 3 min; Flow rate: 1.1 mL / min

[0146] Method AA: Conditions: 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)

[0147] Method AB: Gradient: Start at 0% B and finish at 100% B; Gradient time: 1.80 min, Stop time: 2.00 min; Flow rate: 1.0 mL / min; Wavelength 1: 220 nm; Solvent A: 0.05% TFA in CH3CN:water (5:95), Solvent B: 0.05% TFA in CH3CN:water (95:5); Column: Acquity BEH C18 1.7 μm 2.1 x 50 mm

[0148] Method BB: 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 C: Column: Waters BEH C18, 2.0 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: 0-100% B over 3 min, then hold at 100% B for 0.5 min; Flow rate: 1.0 mL / min; Detection: UV (220 nm).

[0150] Biological assays DGK Alpha ADPGLO Full-Length IC 50 (μM) DGK Alpha ADPGLO (near full-length) IC 50 (μM) In vitro DGK inhibition assay DGKα (full-length and near-full-length) ADPG1 assays were performed using extruded liposome preps with either 5% or 10% DAG. Enzyme 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). Lipid substrate concentrations for extruded liposome reactions were 1.9 mM PS, 0.25 mM DAG (5% liposome prep) or 0.5 mM DAG (10% liposome prep), and 2.7 mM PC. Reactions were performed with 150 μM ATP. The enzyme concentration was 5 nM for DGKα (near-full-length) and DGKα (FL).

[0151] Compound inhibition experiments were performed as follows: 25 nL droplets of each test compound solubilized in DMSO (11 points, serial 3-fold dilutions for each compound) were transferred to wells of a white 1536-well plate (Corning 3725). 5 mL of enzyme / substrate (substrate is 5x or 10x liposome preparation) solution was prepared at 2x final reaction concentration by combining 5 mL of extruded liposome preparation with 10 nM (2x final) DGKα (near-full length) or DGKα (full length) prepared as shown below, and incubated for 10 minutes at room temperature. Next, 1 μL of the 2x enzyme / substrate solution was added to wells containing test compound, and the reaction was initiated by the addition of 1 μL of 300 μM ATP. To measure background, substrate alone was added to wells containing DMSO alone. The reaction was allowed to proceed for 1 hour, after which 2 μL of Glo reagent (Promega V9101) was added and incubated for 40 minutes. Next, 4 μL of kinase detection reagent was added and incubated for 30 minutes. Luminescence was recorded using an EnVision microplate reader. Percent inhibition was calculated from the amount of ATP conversion, where 100% inhibition was obtained from the enzyme-free control reaction and 0% inhibition was obtained from the vehicle-only reaction. Compounds were evaluated at 11 concentrations and IC 50 was measured.

[0152] 2x liposome preparation (5% DAG) 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. The 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 the liposome size (radius 50-60 nm). The liposome preparation was stored at 4°C for 4 weeks.

[0153] 2x liposome preparation (10% DAG) The lipid composition was 9.7 mol%, 1 mM DAG (Avanti 800811O), 37.3 mol% PS (Avanti 840035P), and 53 mol%, 5.4 mM PC (Avanti 850457). The total lipid concentration of the 2x liposome solution was 7-8 mg / mL (10.2 mM total lipid). To prepare these liposomes, PC, DAG, and PS were dissolved in chloroform, combined, and dried to a thin film under vacuum. The lipids were hydrated to 10 mM in 50 mM MOPS (pH 7.5), 100 mM NaCl, 1 μM CaCl2, 10 mM MgCl2, and 1 mM DTT 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 liposome size (radius 50-60 nm). The liposome preparation was stored at ambient temperature for 4 weeks.

[0154] Cloning and expression of full-length human DGKα in baculovirus A DNA fragment encoding full-length DGKα (Ref Seq _NP_958852.1) was codon-optimized for expression in insect cells, gene synthesis was performed by GenScript, USA Inc. (Piscataway, NJ), and the fragment was cloned as an NdeI-XhoI fragment into a modified pFastBac1 vector (Invitrogen, Carlsbad, CA).

[0155] Baculovirus expressing hDGKα-TVMV was generated using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's protocol.

[0156] Scale-up of hDGKα-TVMV-His expression was performed at 2x10 in ESF921 insect medium (Expression Systems). 6This was performed on Sf9 cell (Expression Systems, Davis, CA) cultures grown to a density of 1000 cells / mL and infected with virus stock at a ratio of 1:200 virus / cell. Cultures were grown in a volume of 800 mL at 130 rpm for 65 hours at 27°C post-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.

[0157] Purification of full-length human DGK-α Full-length human DGKα (SEQ ID NO: 2) was expressed with a TVMV-cleavable C-terminal HexaHis tag and purified from SF9 baculovirus-infected insect paste. Cell pellets were resuspended in a 1:6 mass ratio of cells to lysis buffer (50 mM HEPES, pH 7.4, 0.3 M NaCl, 5% glycerol, 1 mM TCEP) supplemented with 20 mM imidazole, Complete® EDTA-free protease inhibitor tablets, and benzonase. Cells were lysed by nitrogen vacuum using a nitrogen breaker (Parr Instrument) at 300 psi for 30 minutes at 4°C. The lysate was clarified by ultracentrifugation at 100,000 x g for 45 minutes. Purification was performed using an AKTA Purifier Plus system. The clarified supernatant was applied to a 5 mL HisTrap FF crude nickel affinity column, washed to baseline, and eluted with 50 mM HEPES (pH 7.4), 0.3 M NaCl, 5% glycerol, 1 mM TCEP, and 500 mM imidazole. Fractions containing the target protein were pooled, concentrated, and further purified by HiLoad 26 / 600 Superdex 200 pg Size Exclusion chromatography pre-equilibrated with 50 mM HEPES (pH 7.4), 0.2 M NaCl, 5% glycerol, and 1 mM TCEP. Fractions containing the target protein were pooled and diluted 4-fold with dilution buffer [50 mM HEPES (pH 7.4), 5% glycerol, and 1 mM TCEP], reducing the NaCl concentration from 0.2 M to 0.005 M. The diluted sized pool was applied to a 5 mL HiTrap Q Sepharose FF Anion Exchange column, washed to baseline, and eluted over 10 column volumes with 0% to 100% elution buffer [50 mM HEPES (pH 7.4), 1.0 M NaCl, 5% glycerol, 1 mM TCEP]. Fractions containing the target protein were pooled, concentrated to between 2 and 5 mg / mL, flash-frozen in liquid nitrogen, and stored at -80°C in 0.1 mg aliquots.A final purity of 80% was achieved, with yields of 0.5-2 mg per L of cell culture.

[0158] Cloning and expression of human DGK.ALPHA. (near full-length) in baculovirus. A DNA fragment (Ref Seq _NP_958852.1) encoding nearly full-length DGKα (hDGKα(S9-S727)) was codon-optimized for expression in insect cells, gene synthesis was performed by GenScript, USA Inc. (Piscataway, NJ), and the fragment was cloned as an NdeI-XhoI fragment into a modified pFastBac1 vector (Invitrogen, Carlsbad, CA).

[0159] Baculovirus expressing hDGKα(S9-S727)-TVMV- was generated using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's protocol.

[0160] Scale-up of hDGKα(S9-S727)-TVMV-His expression was performed at 2x10 in ESF921 insect medium (Expression Systems). 6 This was performed on Sf9 cell (Expression Systems, Davis, CA) cultures grown to a density of 1000 cells / mL and infected with virus stock at a ratio of 1:200 virus / cell. Cultures were grown in a volume of 800 mL at 130 rpm for 65 hours at 27°C post-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.

[0161] Purification of nearly full-length human DGKα (S9-S727) Near-full-length human DGKα (SEQ ID NO: 2), containing amino acids 9-727, was expressed with a TVMV-cleavable C-terminal HexaHis tag and purified from SF9 baculovirus-infected insect paste. Cell pellets were resuspended in a 1:6 mass ratio of cells to lysis buffer (50 mM HEPES, pH 7.3, 0.3 M NaCl, 5% glycerol, 1 mM TCEP) supplemented with 20 mM imidazole, Complete® EDTA-free protease inhibitor tablets, and benzonase. Cells were lysed by nitrogen vacuum using a nitrogen breaker (Parr Instrument) at 300 psi for 30 minutes at 4°C. The lysate was clarified by ultracentrifugation at 100,000 x g for 45 minutes. Purification was performed using an AKTA Purifier Plus system. The clarified supernatant was applied to a 5 mL HisTrap FF crude nickel affinity column, washed to baseline, and eluted with 50 mM HEPES (pH 7.3), 0.3 M NaCl, 5% glycerol, 1 mM TCEP, and 500 mM imidazole. Fractions containing the target protein were pooled, concentrated, and further purified by HiLoad 26 / 600 Superdex 200 pg Size Exclusion chromatography pre-equilibrated with 50 mM HEPES (pH 7.3), 0.3 M NaCl, 5% glycerol, and 1 mM TCEP. A final purity of 80% was achieved, with a yield of 4 mg per L of cell culture. The purified near-full-length hDGKα was concentrated to >1 mg / mL, flash-frozen in liquid nitrogen, and stored at -80°C in 0.5 mg aliquots. Liquid chromatography / mass spectrometry confirmed the protein's identity and verified that it was modified by acetylation with N-terminal methionine cleavage. Association data measured by size-exclusion chromatography with in-line multi-angle light scattering (SEC-MALS) demonstrated that the purified protein exists predominantly as a monomer, with <0.5% high molecular weight aggregates present.

[0162] In vitro DGKα translocation assay Jurkat cells were transfected with a lentiviral construct overexpressing DGKα-YFP (N-terminal tag), selected with puromycin, and FAC sorted to establish stable lines expressing each isoform (Jurkat-DGKa-YFP = BXA-212700-01-001, Jurkat-DGKz-YFP = BXA-212701-01-001). Cell lines were maintained in growth medium (RPMI supplemented with 10% FBS and pen / strep). All translocation assays were performed in assay medium (RPMI supplemented with 10% FBS and without antibiotics).

[0163] For the translocation assay, cells were plated in 40 μL of assay medium at a density of 30,000 cells / well in a Perkin Elmer CellCarrier-384 Ultra Microplate (Perkin Elmer catalog number 6057500). Compounds were then transferred to the cells using an Echo Acoustic Liquid Handler (Echo 655). A 40 nL droplet of each test compound solubilized in DMSO (11-point, 3-fold serial dilutions of each compound, with the highest concentration at 10 mM) was transferred to each well, resulting in a dose-response treatment with the highest concentration at 10 μM. Treated cells were then incubated at 37°C for 1 hour. Cells were then fixed with 4% formaldehyde (Thermo catalog number 28906) for 15 minutes, briefly centrifuged (250 rpm for 5 minutes) to enhance cell retention, and then washed with 50 μL of PBS (2x). The cells were then stained with Hoechst and washed with 50 μl of PBS (2x). 50 μL of PBS was then added to each well, the plate was sealed, and the plate was imaged using the Opera Phenix High Content Screening System. Imaging was performed with a 40x water immersion objective. The YFP channel was set at 100% power for 500 seconds. Ten fields per well were imaged and analyzed. Data analysis was performed using Columbus Image Analysis software (Perkin Elmer).

[0164] Table A [Table 15] [Table 16] [Table 17]

[0165] The compounds of the present invention have activity as inhibitors of one or both of the DGKα and DGKζ enzymes and may therefore be used in the treatment of diseases associated with the inhibition of DGKα and DGKζ activity.

[0166] Nucleotide sequence encoding hDGKα-(M1-S735)-Ct-TVMV-His [Table 18] [Table 19]

[0167] Amino acid sequence of hDGKα-(M1-S735)-Ct-TVMV-His [Table 20]

[0168] Nucleotide sequence encoding hDGKζ-(M1-A928)-transcript variant-2 Ct-TVMV-His [Table 21] [Table 22]

[0169] Amino acid sequence of hDGKζ-(M1-A928)-transcript variant-2 Ct-TVMV-His [Table 23]

[0170] Nucleotide sequence encoding MA-hDGKα-(S9-S727)-Ct-TVMV-His [Table 24] [Table 25]

[0171] AND - Amino acid sequence of hDGKα-(S9-S727)-Ct-TVMV-His [Table 26]

Claims

1. Equation (I): 【Chemistry 1】 [In the formula: (i) X is N, CH, or CR １ And; Y is N, CH, or CR １ And; Z is CH or CR １ is; however, zero or one of X and Y is N; or (ii) X is CH or CR １ And; Y is NR １ａ And; Z is C (=O); 【Chemistry 2】 This is a single bond when Z is C (=O), or when Z is CH or CR １ In this case, it represents either of the double bonds; Each R １ is independently F, Cl, Br, -CN, C １－３ alkyl, C １－２ fluoroalkyl, C １－３ alkoxy, C １－２ fluoroalkoxy, -C(O)OH, -C(O)O(C １－３ alkyl), or -NO ２ ; R １ａ is hydrogen or -CH ３ And; R ２ C ３－４ Alkyl, or C ３－６ A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, spiro[2.5]octanyl, cubanyl, phenyl, and a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, where each cyclic group has 0 to 3 R ２ａ It has been replaced with; Each R ２ａ These are independently F, Cl, Br, -OH, -CN, and C. １－３ Alkyl, C １－２ Fluoroalkyl, or -C(O)O(C １－２ It is alkyl; R ３ C １－６ Alkyl, C １－３ Fluoroalkyl, C １－４ Hydroxyalkyl, C ３－６ Cycloalkyl, -CH ２ (C ３－６ Cycloalkyl), -CH ２ (Phenyl), -CR ｘ R ｘ CR ｘ (OH)(phenyl), -CR ｘ R ｘ CR ｘ =CR ｘ R ｘ ,-(CR ｘ R ｘ ) １－２ C(O)O(C １－２ Alkyl), or -(CR ｘ R ｘ ) １－３ NR ｘ Is it C(O)(phenyl)? Or, R ２ and R ３ These, together with the nitrogen atom to which they bond, form pyrrolidinyl or piperidinyl, each containing 0 to 2 R ３ａ It has been replaced with; Each R ３ａ These are independently F, Cl, -CN, -OH, C １－３ Alkyl, or C １－３ It is a fluoroalkyl; Each R ｘ These are, independently, hydrogen or -CH ３ And; n is 0, 1, 2, or 3; however: (i) base 【Transformation 3】 teeth, 【Chemistry 4】 It is a base other than; and (ii) Compounds of formula (I) 【Transformation 5】 [It is a compound other than] The compound or salt thereof indicated by [the symbol].

2. Each R １ However, independently, F, Cl, Br, -CN, C １－３ Alkyl, -CHF ２ , -CF ３ , -OCH ３ , -OCF ３ , -C(O)OH, -C(O)O(C １－２ Alkyl), or -NO ２ And; R ２ However, C ３－４ Alkyl, or C ３－６ A cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each having 0 to 2 R groups. ２ａ It has been replaced with; Each R ２ａ However, independently, -OH, -CN, -CH ３ ien-CH ２ F, -CHF ２ , -CF ３ , or -C(O)OCH ２ CH ３ And; R ３ is C １－４ alkyl, C １－２ fluoroalkyl, C １－３ hydroxyalkyl, C ３－４ cycloalkyl, -CH ２ (C ３－４ cycloalkyl), -CH ２ (phenyl), -CH ２ CH(OH)(phenyl), -CH ２ CH=CH<​​​​​​​​​​​​ Or, R ２ and R ３ However, together with the nitrogen atom to which they bond, they form pyrrolidinyl or piperidinyl, each with 0 to 2 R ３ａ It has been replaced with; Each R ３ａ is independently --OH, --CN, --CH ３ , or --CF ３ and; n is 0, 1, 2, or 3. The compound or a salt thereof according to claim 1.

3. Each R １ However, independently, F, Cl, Br, -CN, -CH ３ , -CF ３ , -OCH ３ , -C(O)OH, -C(O)OCH ３ , or -NO ２ And; R ２ However, -CH(CH ３ ) ２ ien-CH ２ CH (CH ３ ) ２ , cyclopropyl, cyclohexyl (0 to 2 R ２ａ Substituted with), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl (-C(O)OCH ２ CH ３ It is substituted with, or phenyl; Each R ２ａ However, independently, -OH and -CH ３ , or -C(O)OCH ２ CH ３ And; R ３ However, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH ２ CH ２ CH ３ ien-CH ２ CH ２ OH, cyclopropyl, -CH ２ (Cyclopropyl), -CH ２ (Phenyl), -CH ２ CH(OH)(phenyl), -CH ２ CH=CH ２ ien-CH ２ CH ２ C(O)OCH ３ , or -CH ２ CH ２ CH ２ Is it NHC(O)(phenyl)? Or, R ２ and R ３ However, together with the nitrogen atom to which they bond, pyrrolidinyl (two R ３ａ (which is replaced by) form; R ３ａ ga-CH ３ And; n is 1 or 2, The compound or a salt thereof according to claim 1.

4. X is N, CH, or CR １ And; Y is N, CH, or CR １ And; Z is CH or CR １ And; 【Transformation 6】 This represents a double bond; However, 0 or 1 of X and Y is N. The compound or a salt thereof according to claim 1.

5. Formula (IIa): 【Transformation 7】 A compound or salt thereof according to claim 1, having the structure shown by [the formula shown].

6. Formula (IIb) or Formula (IIc): 【Transformation 8】 A compound or salt thereof according to claim 1, having the structure shown by [the formula shown].

7. R ２ is cyclohexyl (0 or 2 R ２ａ The compound or salt thereof according to claim 1, wherein it is substituted with ().

8. R ２ ga-CH(CH ３ ) ２ or -CH ２ C (CH ３ ) ２ The compound or salt thereof according to claim 1.

9. R ３ C １－４ The compound or a salt thereof according to claim 1, wherein it is alkyl.

10. The following: 【Chemistry 9】 A compound or salt thereof according to claim 1, having a structure selected from the group consisting of the above.

11. The following: 【Chemistry 10】 A compound or salt thereof according to claim 1, having a more selectable structure.

12. The compound, Methyl 3-(cyclohexyl((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)amino)propanoate(1); N,4-dimethyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)cyclohexane-1-amine(2); N-ethyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)cyclohexaneamine(3); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-2-(trifluoromethyl)benzonitrile(4); 5-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazole-1-yl)-2-chlorobenzonitrile(5); 5-(5-((allyl(cyclohexyl)amino)methyl)-1H-tetrazole-1-yl)-2-chlorobenzonitrile(6); 2-Chloro-5-(5-((cyclohexyl(2-hydroxyethyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(7); 2-Chloro-5-(5-((cyclohexyl(propyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(8); 2-Chloro-5-(5-((isobutyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(9); 2-Chloro-5-(5-((cyclohexyl(cyclopropylmethyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(10); 2-Chloro-5-(5-((isopropyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(11); 2-Chloro-5-(5-((cyclohexyl(isopropyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(12); 2-Chloro-5-(5-((cyclohexyl(ethyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(13); 3-Chloro-6-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(14); 3-Chloro-6-(5-((cyclohexyl(cyclopropylmethyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(15); 3-Chloro-6-(5-((cyclohexyl(ethyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(16); 6-(5-((allyl(cyclohexyl)amino)methyl)-1H-tetrazole-1-yl)-3-chloropicolinonitrile(17); N-methyl-N-((1-(3-(trifluoromethyl)phenyl)-1H-tetrazole-5-yl)methyl)cyclohexaneamine(18); N-((1-(3-fluorophenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(19); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(20); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-2-fluorobenzonitrile(21); 2-Chloro-5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(22); N-methyl-N-((1-(6-(trifluoromethyl)pyridine-3-yl)-1H-tetrazole-5-yl)methyl)cyclohexaneamine(23); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-2-methoxybenzonitrile(24); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-2-methylbenzonitrile(25); 2-bromo-5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(26); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-5-nitrobenzonitrile(27); N-((1-(4-chloro-3-nitrophenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(28); N-((1-(4-chlorophenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(29); 5-Chloro-2-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile (30); N-((1-(4-methoxyphenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(31); N-methyl-N-((1-(4-nitrophenyl)-1H-tetrazole-5-yl)methyl)cyclohexaneamine(32); Methyl 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzoate(33); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)benzoic acid (34); N-methyl-N-((1-(m-tolyl)-1H-tetrazole-5-yl)methyl)cyclohexaneamine(35); N-((1-(3-chlorophenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(36); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)propan-2-amine(37); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)tetrahydro-2H-pyran-4-amine(38); tert-butyl 3-(methyl((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)amino)pyrrolidine-1-carboxylate(39); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)tetrahydrofuran-3-amine(40); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methylaniline(41); N,2-dimethyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)propan-1-amine(42); 2-(cyclohexyl((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)amino)ethane-1-ol(43); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazole-5-yl)methyl)cyclopropanamine(44); N-((1-(3-bromophenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(45); N-((1-(6-fluoropyridine-3-yl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(46); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile (47); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazole-1-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(48); N-((1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-tetrazole-5-yl)methyl)-N-methylcyclohexaneamine(49); 2-Chloro-5-(5-((2,5-dimethylpyrrolidine-1-yl)methyl)-1H-tetrazole-1-yl)benzonitrile (50); Ethyl 4-(((1-(4-chloro-3-cyanophenyl)-1H-tetrazole-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylate(51); 2-Chloro-5-(5-((cyclohexyl(2-hydroxy-2-phenylethyl)amino)methyl)-1H-tetrazole-1-yl)benzonitrile(52); 3-Chloro-6-(5-((cyclohexyl(propyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(53); N-(3-(((1-(5-chloro-6-cyanopyridine-2-yl)-1H-tetrazole-5-yl)methyl)(cyclohexyl)amino)propyl)benzamide(54); 3-Chloro-6-(5-((cyclohexyl(isopropyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(55); Ethyl 4-(((1-(5-chloro-6-cyanopyridine-2-yl)-1H-tetrazole-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylate(56); 3-Chloro-6-(5-((cyclohexyl(2-hydroxy-2-phenylethyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(57); 6-(5-((benzyl((1R,2R)-2-hydroxycyclohexyl)amino)methyl)-1H-tetrazole-1-yl)-3-chloropicolinonitrile(58); 3-Chloro-6-(5-((Cyclopropyl((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(59); 3-Chloro-6-(5-((isopropyl(methyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(60); 3-Chloro-6-(5-((isobutyl(methyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(61); 3-Chloro-6-(5-((cyclohexyl(2-hydroxyethyl)amino)methyl)-1H-tetrazole-1-yl)picolinonitrile(62); or 6-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazole-1-yl)-3-chloropicolinonitrile(63) The compound or salt thereof according to claim 1.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for the treatment of cancer or a viral infection, comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14, 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.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 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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