Substituted tetrazolyl compounds as T cell activators

Abstract

Disclosed are compounds of formula (I): # imgabs0 # or a salt thereof, wherein: X, Y, Z, R1, R2, R3 and n are as defined herein. Also disclosed are methods of inhibiting the activity of one or both of diacylglycerol kinase alpha (DGK alpha) and diacylglycerol kinase zeta (DGK zeta) using such compounds, as well as pharmaceutical compositions comprising such compounds. These compounds are useful for the treatment of viral infections and proliferative diseases such as cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 370,734, filed on August 8, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present application generally relates to substituted tetrazolyl compounds that activate T cells, promote T cell proliferation, and / or exhibit antitumor activity. The present application provides substituted tetrazolyl compounds, compositions comprising such compounds, and their application methods. The present invention further relates to pharmaceutical compositions comprising at least one compound according to the present invention, which can be used to treat proliferative diseases such as cancer, and viral infections.

[0004] Reference to a sequence listing submitted electronically via EFS-WEB

[0005] This application incorporates by reference in its entirety the sequence listing entitled "14166WOPCT", which contains SEQ ID NO:1 to SEQ ID NO:6, which includes the nucleic acid and / or amino acid sequences disclosed in this application. The sequence listing has been submitted in XML format through the Patent Center, thus constituting its paper form and computer readable form. The sequence listing was first created using WIPOSequence on July 25, 2023, and is 16.0KB in size. Background Art

[0006] Human cancers have numerous genetic and epigenetic changes that produce neoantigens 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, has a powerful anti-cancer potential, with a wide range of capabilities and fine specificity in response to a variety of tumor antigens. In addition, the immune system exhibits considerable plasticity and memory components. Successful use of all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities. However, although endogenous immune responses to cancer have been observed in preclinical models and patients, this response is ineffective, and established cancers are considered "self" and tolerated by the immune system. Tumors may use several different mechanisms to actively subvert anti-tumor immunity, leading to this state of tolerance. These mechanisms include dysfunctional T cell signaling (Mizoguchi et al., (1992) Science 258:1795-98), suppressive regulatory T cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and co-optation of endogenous "immune checkpoints" that serve to downregulate the magnitude of adaptive immune responses and protect normal tissues from collateral damage by tumors in order to evade immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-489).

[0007] Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid, thereby terminating T cell function propagated through the TCR signaling pathway. Therefore, DGKs are used as intracellular checkpoints, and inhibition of DGKs is expected to enhance T cell signaling pathways and T cell activation. Supporting evidence includes knockout mouse models of DGKα or DGKζ, which show a highly reactive T cell phenotype and improved anti-tumor 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, it was observed that tumor-infiltrating lymphocytes isolated from human renal cell carcinoma patients overexpressed DGKα, which resulted in suppressed T cell function (Prinz, PU et al., J Immunology (2012) 12: 5990-6000). Therefore, DGKα and DGKζ are considered targets for cancer immunotherapy (Riese MJ et al., Front Cell Dev Biol. (2016) 4:108; Chen, S Setal., 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).

[0008] There remains a need for compounds that are inhibitors of one or both of DGKα and DGKζ. Additionally, there remains a need for compounds that are inhibitors of one or both of DGKα and DGKζ that are selective relative to other diacylglycerol kinases, protein kinases, and / or other lipid kinases.

[0009] Therefore, agents that are safe and effective in restoring T cell activation, lowering antigenic thresholds, enhancing anti-tumor function, and / or overcoming the inhibitory effects of one or more endogenous immune checkpoints (e.g., PD-1, LAG-3, and TGFβ) are important additions to the treatment of patients with proliferative diseases such as cancer and viral infections. Summary of the invention

[0010] Applicants have discovered compounds that are active as inhibitors of one or both of DGKα and DGKζ. In addition, applicants have discovered compounds that are active as inhibitors of one or both of DGKα and DGKζ and are selective relative to other diacylglycerol kinases, protein kinases, and / or other lipid kinases. These compounds are provided so that they can be used as drugs with desired stability, bioavailability, therapeutic index, and toxicity values, which are important for their drugability.

[0011] The present invention provides substituted tetrazolyl compounds of formula (I) useful as inhibitors of DGKα, DGKζ, or both DGKα and DGKζ, including salts and prodrugs thereof.

[0012] 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.

[0013] The present invention also provides a method for treating a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ, which comprises administering a compound of formula (I) and / or a pharmaceutically acceptable salt thereof to a mammalian patient.

[0014] The present invention also provides processes and intermediates for preparing compounds of formula (I) and / or salts thereof.

[0015] The present invention also provides a compound of formula (I) and / or a pharmaceutically acceptable salt thereof for use in therapy.

[0016] The present invention also provides the use of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating proliferative diseases such as cancer and viral infection.

[0017] The compounds of formula (I) and compositions comprising the compounds of formula (I) can be used to treat, prevent or cure viral infections and various proliferative diseases such as cancer. Pharmaceutical compositions comprising these compounds are used to treat, prevent or slow the progression of diseases or disorders in various therapeutic areas, such as viral infections and cancer.

[0018] The following disclosure will set forth these and other features of the present invention in detail. Specific implementation plan

[0019] A first aspect of the present invention provides at least one compound of formula (I):

[0020]

[0021] or a salt thereof, wherein:

[0022] (i) X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; provided that 0 or 1 of X and Y is N; or

[0023] (ii) X is CH or CR1; Y is NR 1a ; Z is C(=O);

[0024] When Z is C(=O), represents a single bond, or when Z is CH or CR1, represents a double bond;

[0025] 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;

[0026] R 1a is hydrogen or -CH3;

[0027] R2 is C 3-4 Alkyl or a cyclic group selected from the following: C 3-6 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 3 R 2a ;

[0028] 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);

[0029] 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 xR 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);

[0030] Alternatively, R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each substituted with 0 to 2 R 3a ;

[0031] R 3a Each is independently F, Cl, -CN, -OH, C 1-3 Alkyl, or C 1-3 Fluoroalkyl;

[0032] R x are each independently hydrogen or -CH3; and

[0033] n is 0, 1, 2, or 3;

[0034] The prerequisites are:

[0035] Part (i) no as well as

[0036] (ii) wherein the compound of formula (I) is not

[0037] The following implementation includes precondition (i) and precondition (ii) of the first aspect.

[0038] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; represents a double bond; provided that 0 or 1 of X and Y is N. The compound of this embodiment has the structure of formula (II):

[0039]

[0040] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is CH or CR1; Y is CH or CR1; Z is CH or CR1; The compound of this embodiment has the structure of formula (IIa):

[0041]

[0042] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is N; Y is CH or CR1; Z is CH or CR1; The compound of this embodiment has the structure of formula (IIb):

[0043]

[0044] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is CH or CR1; Y is N; Z is CH or CR1; The compound of this embodiment has the structure of formula (IIc):

[0045]

[0046] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; represents a double bond; one of X and Y is N.

[0047] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is CH or CR1; Y is NR 1a ; Z is C(=O); The compound of this embodiment has the structure of formula (III):

[0048]

[0049] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein (i) X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; provided that 0 or 1 of X and Y is N; or (ii) X is CH or CR1; Y is NR 1a ; Z is C(=O); When Z is C(=O), represents a single bond, or when Z is CH or CR1, represents a double bond; 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 1-2 Alkyl), or -NO2; R 1a is hydrogen or -CH3; R2 is C 3-4 Alkyl or a cyclic group selected from the following: C 3-6cycloalkyl, 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 3 R 2a ; R 2a Each is 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); R x are each independently hydrogen or -CH3; n is 0, 1, 2, or 3.

[0050] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; provided that 0 or 1 of X and Y is N; represents a double bond; 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 3-4Alkyl or a cyclic group selected from the following: C 3-6 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 3 R 2a ; R 2a Each is 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); or, R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each of which is substituted with 0 to 2 R 3a ; R 3a Each is independently F, Cl, -CN, -OH, C 1-3 Alkyl, or C 1-3 Fluoroalkyl; R x are each independently hydrogen or -CH3; n is 0, 1, 2, or 3.

[0051] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein: R1 is independently F, Cl, Br, -CN, C 1-3 Alkyl, -CHF2, -CF3, -OCH3, -OCF3, -C(O)OH, -C(O)O(C 1-2alkyl), or -NO2; R2 is C 3-4 Alkyl or a cyclic group selected from the following: C 3-6 Cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each substituted with 0 to 2 R 2a ; R 2a Each is 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 alkyl), or -CH2CH2CH2NHC(O)(phenyl); or, R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each of which is substituted with 0 to 2 R 3a ; R 3a Each is independently -CN, -OH, -CH3, or -CF3; n is 0, 1, 2, or 3.

[0052] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein: R1 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 a cyclic group selected from the following: C 3-6 Cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each substituted with 0 to 2 R 2a ; R 2a Each is 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 alkyl), or -CH2CH2CH2NHC(O)(phenyl).

[0053] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R1 is each independently F, Cl, Br, -CN, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, or -NO2; R2 is -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, substituted with 0 to 2 R 2a cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl substituted with -C(O)OCH2CH3, or phenyl; R 2a R3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2OH, cyclopropyl, -CH2(cyclopropyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)OCH3, or -CH2CH2CH2NHC(O)(phenyl); or, R2 and R3 together with the nitrogen atom to which they are attached form a substituted 2 R 3a Pyrrolidinyl; R 3a Each is -CH3; n is 1 or 2.

[0054] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R1 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 This embodiment includes the following compounds, wherein R1 is independently F, Cl, Br, -CN, C 1-3 Alkyl, -CHF2, -CF3, -OCH3, -OCF3, or -NO2. This embodiment also includes the following compounds, wherein R1 is independently F, Cl, Br, -CN, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, or -NO2.

[0055] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 is C 3-4 Alkyl or a cyclic group selected from the following: C 3-6Cycloalkyl, 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 2 R 2a This embodiment includes compounds wherein R2 is C 3-4 Alkyl or a cyclic group selected from the following: C 3-6 Cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each substituted with 0 to 2 R 2a This embodiment also includes compounds wherein R2 is -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, substituted with 0 to 2 R 2a The cyclohexyl group, tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group substituted with -C(O)OCH2CH3, or phenyl group can be used.

[0056] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 is C 3-4 Alkyl. This embodiment includes compounds wherein R2 is -CH(CH3)2 or -CH2CH(CH3)2.

[0057] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 is a cyclic group selected from the following: 3-6 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 3 R 2a This embodiment includes the following compounds, wherein R2 is a cyclic group selected from the following: 3-6 Cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each substituted with 0 to 2 R 2a This embodiment also includes compounds wherein R2 is cyclopropyl substituted with 0 to 2 R 2a The cyclohexyl group, tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group substituted with -C(O)OCH2CH3, or phenyl group can be used.

[0058] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 is cyclohexyl.

[0059] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R 2a Each is independently F, Cl, Br, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, or -C(O)O(C 1-2 This embodiment includes the following compounds, wherein R 2a Each independently is -OH, -CN, -CH3, -CH2F, -CHF2, -CF3, or -C(O)OCH2CH3. This embodiment also includes the following compounds, wherein R 2a Each is independently -OH, -CH3, or -C(O)OCH2CH3.

[0060] In one embodiment, a compound of formula (I) or a salt thereof is provided, 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). This embodiment includes compounds wherein 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 1-2The present embodiment also includes compounds wherein R3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2OH, cyclopropyl, -CH2(cyclopropyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)OCH3, or -CH2CH2CH2NHC(O)(phenyl).

[0061] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R3 is -CH3.

[0062] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 is cyclohexyl and R3 is -CH3.

[0063] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each of which is substituted with 0 to 2 R 3a This embodiment includes compounds wherein R2 and R3 together with the nitrogen atom to which they are attached form a substituted 2 R 3a This embodiment also includes compounds wherein R2 and R3 together with the nitrogen atom to which they are attached form a substituted 2 R 3a The piperidinyl group.

[0064] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein R 3a Each is independently F, Cl, -CN, -OH, C 1-2 Alkyl, or C 1-2 This embodiment includes the following compounds, wherein R 3a Each independently is -CN, -OH, -CH3, or -CF3. This embodiment also includes the following compounds, wherein R 3a Each is -CN or -CH3. In addition, this embodiment includes the following compounds, wherein R 3a Each is -CH3.

[0065] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein the compound has a structure selected from the group consisting of:

[0066]

[0067]

[0068] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein the compound has a structure selected from the group consisting of:

[0069]

[0070] In one embodiment, a compound of formula (I) or a salt thereof is provided, wherein the compound is: 3-(cyclohexyl((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)amino)propanoic acid methyl ester (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)cyclohexylamine (3); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile (4); 5-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (5); 5); 5-(5-((allyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (6); 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); 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)cyclohexylamine (18); N-((1-(3-fluorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (19); 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)cyclohexylamine (23); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methoxybenzonitrile (24); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methylbenzonitrile (25); 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); N-((1-(4-chloro-3-nitrophenyl)-1H-tetrazolyl)- -5-yl)methyl)-N-methylcyclohexylamine (28); N-((1-(4-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (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-methylcyclohexylamine (31); N-methyl-N-((1-(4-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclohexylamine (32); 3-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)benzoic acid methyl ester (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)cyclohexylamine (35); N-((1-(3-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (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-tetrazol-5-yl)methyl)amino)ethan-1-ol (43); N-methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclopropylamine (44); N-((1-(3-bromophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (45);N-((1-(6-fluoropyridin-3-yl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (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-methylcyclohexylamine (49); 2-chloro-5-(5-((2,5-dimethylpyrrolidin-1-yl)methyl)-1H-tetra 4-(((1-(4-chloro-3-cyanopyridin-2-yl)-1H-tetrazol-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylic acid ethyl ester (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); 4-(((1-(5-chloro-6-cyanopyridin-2-yl)-1H-tetrazol-5-yl)methyl)(cyclopropyl)amino)cyclohexane-1-carboxylic acid ethyl ester (56); 3-chloro-6-(5-((cyclohexyl(2-hydroxy-2-phenylethyl)amino)methyl)-1H-tetrazol-1-yl)picolinonitrile (57); 6-(5-((benzyl((1R,2R)-2-hydroxycyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-3-chloropicolinonitrile (58); 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). ;

[0071] The present invention can be implemented in other specific forms without departing from its spirit and essential features. The present invention encompasses all combinations of aspects of the present invention and / or embodiments mentioned in the present application. It should be understood that any and all embodiments of the present invention can be extracted in conjunction with any other one or more embodiments to describe other embodiments. It should also be understood that each of the elements of the embodiments independently is intended to be combined with any and all other elements from any embodiment to describe other embodiments.

[0072] definition

[0073] After reading the following detailed description, those skilled in the art can more easily understand the features and advantages of the present invention. It should be understood that, for clear reasons, some features of the present invention described above and below in the context of a separate embodiment may also be combined to form a single embodiment. On the contrary, for reasons of simplicity, the various features of the present invention described in the context of a single embodiment may also be combined to form its sub-combination. The application is determined to be exemplary or preferred embodiments are intended to be illustrative and not restrictive.

[0074] Unless otherwise specifically stated herein, items mentioned in the singular may also include the plural form. For example, "a" and "an" may refer to one or one or more.

[0075] As used herein, the phrase "compound and / or its salt" refers to at least one compound, at least one salt of the compound, or a combination thereof. For example, the compound of formula (I) and / or its salt includes one compound of formula (I); two compounds of formula (I); one salt of the compound of formula (I); a compound of formula (I) and one or more salts of the compound of formula (I); and two or more salts of the compound of formula (I).

[0076] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0077] Definitions set forth in this application take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated by reference into this application.

[0078] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms (unless limited in specific instances) when the terms are used throughout the specification either individually or as part of a larger group.

[0079] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide a stable moiety or compound.

[0080] According to conventional use in the art, It is used herein in structural formulae to describe the bond that serves as the point of attachment of a moiety or substituent to a core or backbone structure.

[0081] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0082] The term "cyano" refers to the group -CN.

[0083] The term "amino" refers to the group -NH2.

[0084] The term "oxo" refers to the group =0.

[0085] The term "alkyl" used in this application refers to a branched and straight-chain saturated aliphatic hydrocarbon group, which comprises, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. The example of alkyl includes, but is not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in the subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may include. For example, "C 1-4 "Alkyl" refers to straight-chain and branched alkyl groups having 1 to 4 carbon atoms.

[0086] The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0087] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxy groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C 1-4 Hydroxyalkyl.

[0088] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon atom by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in a subscript after the symbol "C", the subscript more specifically defines 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.

[0089] 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 (-OCH3). 1-3 The "alkoxy group" refers to an alkoxy group having 1 to 3 carbon atoms.

[0090] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as defined above attached through an oxygen linker (-O-). 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0091] The phrase "pharmaceutically acceptable" is used in this application to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0092] The compound of formula (I) can form salts, which are also within the scope of the present invention. Unless otherwise indicated, reference to the compounds of the present invention should be understood to include one or more salts thereof. The term "salt" means an acid salt formed with an inorganic and / or organic acid. Moreover, the term "salt" can include zwitterions (inner salts), for example, when the compound of formula (I) comprises both a basic part (such as an amine or pyridine or imidazole ring) and an acidic part (such as a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts, wherein the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts can be used, for example, in the separation or purification steps used in the preparation process, and are therefore also expected to be within the scope of the present invention. The salt of the compound of formula (I) can be formed as follows, for example, by reacting the compound of formula (I) with a certain amount of acid (such as an equal amount of acid) in a medium (such as a medium in which the salt is precipitated, or an aqueous medium), and then lyophilizing.

[0093] Exemplary acid addition salts include acetates (e.g., those formed with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide),

[00136] Examples of the invention include, for example, hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate (such as those mentioned herein), tartrate, thiocyanate, benzenesulfonate such as toluenesulfonate, undecanoate, and the like.

[0094] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. Lyophilization may be used to provide the compound of formula (I) as a solid.

[0095] It should be further understood that solvates (e.g., hydrates) of compounds of formula (I) are also 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 solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvent will be able to separate, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" includes both solution phase and separable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0096] Various forms of prodrugs are known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0097] Moreover, the compound of formula (I) can be isolated and purified after its preparation to obtain a composition comprising a compound of formula (I) in an amount equal to or greater than 99% by weight ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also included in this application as part of the present invention.

[0098] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention contemplates the implementation of stable compounds.

[0099] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, an amount of a combination of the claimed compounds, or an amount of a compound of the invention in combination with other active ingredients, which makes it effective as an inhibitor of DGKα and / or DGKζ, or effective in treating or preventing viral infections and proliferative diseases such as cancer.

[0100] As used herein, "treating" or "treatment" includes treating a disease state in a mammal, particularly a human, and includes: (a) preventing the disease state from being found in a mammal, particularly when such mammal is susceptible to such disease state but has not yet been diagnosed as having such disease state; (b) inhibiting the disease state, i.e., preventing its occurrence; and / or (c) relieving the disease state, i.e., causing regression of the disease state.

[0101] The compounds of the present invention are intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0102] 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.

[0103] The present invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof; and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to as "carrier" materials in this application), and other active ingredients (if necessary). The compound of formula (I) can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, and in a dose that can be effectively used for a predetermined treatment. The compounds and compositions of the present invention can be, for example, orally, mucosally or parenterally administered, including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal administration in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier can include a mixture of mannitol or lactose with microcrystalline cellulose. The mixture can include additional components, for example, lubricants such as magnesium stearate, and disintegrants such as cross-linked polyvinylpyrrolidone. The carrier mixture can be filled into a gelatin capsule or compressed into a tablet. For example, the pharmaceutical composition can be administered as an oral dosage form or an infusion.

[0104] For oral administration, the pharmaceutical composition can be in the following forms, for example, tablets, capsules, liquid capsules, suspensions, or liquid dosage forms. The pharmaceutical composition is preferably prepared as a dosage unit comprising a specific amount of active ingredient. For example, the pharmaceutical composition can be provided as a tablet or capsule, and the amount of the active ingredient included in the tablet or capsule is about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, more preferably about 0.5 to 100 mg. The suitable daily dose for people or other mammals can be widely varied according to the patient's condition and other factors, but can be determined using conventional methods.

[0105] Any pharmaceutical composition that the application may include can, for example, be delivered through any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art of preparing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, the pharmaceutical composition according to the present invention can include at least one selected from the following agents: sweeteners, flavoring agents, coloring agents, demulsifiers, antioxidants and preservatives.

[0106] Tablets can be prepared as follows, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for preparing tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating agents and disintegrants, such as microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, corn starch, and alginic acid; binders, such as starch, gelatin, polyvinyl pyrrolidone, and gum arabic; and lubricants, such as magnesium stearate, stearic acid, and talc. In addition, tablets can be uncoated, or can be coated by known techniques to mask the bad taste of bad-tasting drugs, or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient for a longer period of time. Exemplary water-soluble taste masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0107] 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, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0108] 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 such as polyethylene glycol; and at least one oil vehicle such as peanut oil, liquid paraffin and olive oil.

[0109] Aqueous suspensions are prepared as follows, for example, by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for preparing an aqueous suspension. Exemplary excipients suitable for preparing aqueous suspensions include, but are not limited to, for example, suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinyl pyrrolidone, tragacanth gum and gum arabic; dispersants or wetting agents, for example, naturally occurring phospholipids, for example, lecithin; condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecyl-oxyhexadecanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example, polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, for example, sucrose, saccharin and aspartame.

[0110] Oily suspensions can be prepared as follows, for example, by suspending at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil, for example, peanut oil; olive oil; sesame oil; and coconut oil; or a mineral oil, for example, liquid paraffin. Oily suspensions may also contain at least one thickener, for example, beeswax; hard paraffin; hexadecanol. In order to provide a palatable oily suspension, at least one of the sweeteners described above and / or at least one flavoring agent may be added to the oily suspension. The oily suspension may further contain at least one preservative, including, but not limited to, for example, an antioxidant, for example, butylated hydroxyanisole, and alpha-tocopherol.

[0111] 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 been described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, such as ascorbic acid. Furthermore, dispersible powders and granules may also contain at least one excipient, including, but not limited to, for example, sweeteners; flavoring agents; and coloring agents.

[0112] 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 the emulsion comprising the compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but not limited to, the following oils, for example, vegetable oils, for example, olive oil and peanut oil; mineral oils, for example, liquid paraffin; and mixtures thereof. Although the phase can contain only an emulsifier, it can contain a mixture of at least one emulsifier with a fat or with an oil or with both a fat and an oil. Suitable emulsifiers include, but are not limited to, for example, naturally occurring phospholipids, for example, soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included in the emulsion together with a lipophilic emulsifier, used as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers together with or without stabilizers constitute so-called emulsifying waxes, which together with oils and fats constitute so-called emulsifying ointment bases, which form the oily dispersed phase of cream formulations. Emulsions may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, distearin alone or with wax, or other materials well known in the art.

[0113] The compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can also be delivered intravenously, subcutaneously and / or intramuscularly, for example, through any pharmaceutically acceptable and suitable injectable dosage form. Exemplary injectable dosage forms include, but are not limited to, for example, a sterile aqueous solution containing an acceptable vehicle and a solvent, wherein the vehicle and solvent are, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsion; and aqueous or oily suspensions.

[0114] The form of the preparation for parenteral administration can be aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more carriers mentioned for preparations for oral administration or by using other suitable dispersants or wetting agents and suspending agents. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and / or various buffers. Other adjuvants and modes of administration are well known and widely known in the pharmaceutical field. The active ingredient can also be administered by injection as a composition containing a suitable carrier, including saline, glucose, water, or containing cyclodextrin (i.e., Captisol), co-solvent solubilization (i.e., propylene glycol) or micellar solubilization (i.e., Tween 80).

[0115] Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are especially water, Ringer's solution, and isotonic sodium chloride solution. Moreover, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any odorless fixed oil can be used, including synthetic monoglycerides or diglycerides. Moreover, fatty acids such as oleic acid can be used in the preparation of injectables.

[0116] 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, for example, 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) processing the combination to form a microemulsion.

[0117] Sterile aqueous or oleaginous suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared with non-toxic parenterally acceptable diluents or solvents such as 1,3-butanediol; sterile oleaginous suspensions can be prepared with sterile non-toxic acceptable solvents or suspending media, for example, sterile fixed oils, for example, synthetic monoglycerides or diglycerides; and fatty acids, for example, oleic acid.

[0118] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol, polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tweens, polyethoxylated castor oils such as CREMOPHOR surfactant (BASF), or other well-known polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene oxide block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2-hydroxypropylcyclodextrin and 3-hydroxypropylcyclodextrin), or other solubilized derivatives may also be advantageously used to enhance the delivery of compounds of the formulae described herein.

[0119] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare pharmaceutical agents for administration to patients (including humans and other mammals). Pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, emulsifiers, buffers, etc. Tablets and pills can also be prepared with enteric coatings. Such compositions can also contain adjuvants, such as wetting agents, sweeteners, flavoring agents, and aromatics.

[0120] The amount of the compound to be administered and the dosage regimen for treating disease symptoms with the compound and / or composition of the present invention depend on various factors, including the age, body weight, sex, physical condition, disease type, severity of the disease, route of administration and frequency of administration and the specific compound used of the subject. Therefore, the dosage regimen can be widely varied, but can be routinely determined using standard methods. The daily dosage of about 0.001 to 100mg / kg body weight, preferably about 0.0025 to about 50mg / kg body weight, most preferably about 0.005 to 10mg / kg body weight may be appropriate. The daily dosage can be administered by 1 to 4 dosages per day. Other dosing schedules include one dosage per week and one dosage per two-day cycle.

[0121] For therapeutic purposes, the active compound of the present invention is conventionally combined with one or more adjuvants suitable for the specified route of administration. If oral administration, the compound can be mixed with lactose, sucrose, starch powder, cellulose alkanoate, cellulose alkyl ester, talcum, stearic acid, magnesium stearate, magnesium oxide, sodium salt and calcium salt of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol, then tableted or packaged into capsules for easy administration. Such capsules or tablets can include controlled release preparations, and the preparation can provide the dispersion of the active compound in hydroxypropyl methylcellulose.

[0122] The pharmaceutical composition of the present invention comprises at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optional additional agents selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. The alternative composition of the present invention comprises a compound of formula (I) described herein or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0123] Practicality

[0124] The compounds of formula (I) are useful for treating cancer.

[0125] In another embodiment, the present invention provides a combination preparation of a compound of formula (I), and / or a pharmaceutically acceptable salt thereof, a stereoisomer or a tautomer thereof, and an additional therapeutic agent for simultaneous, separate or sequential use in the treatment and / or prevention of a variety of diseases or disorders associated with DGK target inhibition in T cells.

[0126] In another aspect, the present invention provides a method for treating a patient suffering from or susceptible to a disease condition associated with DGK target inhibition in T cells. A variety of disease conditions can be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof. For example, the compounds described herein can be used to treat or prevent viral infections and proliferative diseases such as cancer.

[0127] Compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) are used to treat or prevent any disease or condition associated with DGK target inhibition in T cells. These include viral infections and other infections (e.g., skin infections, GI infections, urinary tract infections, urogenital infections, systemic infections), and proliferative diseases (e.g., cancer). Compounds of formula (I) and pharmaceutical compositions comprising at least one compound of formula (I) can be administered to animals, preferably mammals (e.g., livestock, cats, dogs, mice, rats), more preferably humans. Any method of administration can be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, a compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered orally. In other embodiments, a compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered parenterally.

[0128] The compound of formula (I) can inhibit the activity of diacylglycerol kinase α and diacylglycerol kinase ζ (DGKα / ζ). For example, the compound of formula (I) can be used to inhibit the activity of DGKα and DGKζ in cells or in individuals who need to regulate DGKα and DGKζ by administering an inhibitory amount of the compound of formula (I) or a salt thereof.

[0129] The present invention further provides a method for treating a disease associated with the activity or expression (including 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. Exemplary diseases may include any disease, disorder, or condition that is directly or indirectly associated with the expression or activity of DGKα and DGKζ enzymes, such as overexpression or abnormal activity. Diseases associated with DGKα and DGKζ may also include any disease, disorder, or condition that can be prevented, improved, or cured by regulating the activity of DGKα and DGKζ enzymes. Examples of diseases associated with DGKα and DGKζ include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.

[0130] In one aspect, the compound of formula (I) is administered sequentially before the immuno-oncology agent. In another aspect, the compound of formula (I) is administered simultaneously with the immuno-oncology agent. In yet another aspect, the compound of formula (I) is administered sequentially after the immuno-oncology agent.

[0131] In another aspect, the compounds of formula (I) may be co-formulated with an immuno-oncology agent.

[0132] 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 aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.

[0133] In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint regulators).

[0134] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to homologous TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RAN KL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR 3. EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0135] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of the following: (i) antagonists of proteins 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.

[0136] Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells, or agonists of activating receptors on NK cells. For example, compounds of formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0137] Other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0138] In another aspect, the compounds of Formula (I) can be used with one or more of the following agents: agonists (ligating positive co-stimulatory receptors), blockers (attenuating 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 binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 microbead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that elicit innate immune activation and / or inflammation at the tumor site.

[0139] In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tesimumab.

[0140] In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein fused to the extracellular domain of PD-L2 (B7-DC) and the Fc portion of IgG1, called AMP-224.

[0141] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0142] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0143] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, usellumab and PF-05082566 (WO12 / 32433).

[0144] In another aspect, 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).

[0145] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, BMS-986205, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0146] In another aspect, 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.

[0147] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0148] In another aspect, 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, lukatumomab or dacillinumab.

[0149] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varilumab.

[0150] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO 11 / 109400).

[0151] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at different times, and the administration of at least two of these therapeutic agents or therapeutic agents is administered in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished as follows, for example, a single dosage form of each therapeutic agent or multiple single dosage forms of each therapeutic agent with a fixed ratio is administered to the subject. The order or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate approach, including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same approach or by different approaches. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, and the other therapeutic agents of the combination can be administered orally. Or, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. Combination therapy can also include the administration of a combination of therapeutic agents as described above, further with other bioactive ingredients and non-drug treatments (e.g., surgery or radiotherapy). When combination therapy includes non-drug therapy, non-drug therapy can be performed at any appropriate time, as long as the beneficial effect of the combined action of the therapeutic agent and non-drug therapy is achieved. For example, in appropriate circumstances, beneficial effects may still be achieved when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, perhaps for a few days or even a few weeks.

[0152] As used herein, the term "cell" is intended to mean a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample cut from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture medium. In some embodiments, an in vivo cell is a cell that survives in an organism, such as a mammal.

[0153] As used herein, the term "contacting" refers to bringing together the components in an in vitro system or an in vivo system. For example, "contacting" the DGKα and DGKζ enzymes with a compound of formula (I) includes administering a compound of the invention to an individual or patient, such as a human, having DGKα and DGKζ, and, for example, introducing a compound of formula (I) into a sample including a cell preparation or a purified preparation containing the DGKα and DGKζ enzymes.

[0154] The term "DGKα and DGKζ inhibitor" refers to an agent that is capable of inhibiting the activity of diacylglycerol kinase α and / or diacylglycerol kinase ζ (DGKα and DGKζ) in T cells, resulting in T cell stimulation. DGKα and DGKζ inhibitors can be reversible or irreversible DGKα and DGKζ inhibitors. "Reversible DGKα and DGKζ inhibitors" are compounds that reversibly inhibit the enzymatic activity of DGKα and DGKζ at the catalytic site or at the non-catalytic site, and "irreversible DGKα and DGKζ inhibitors" are compounds that irreversibly destroy the enzymatic activity of DGKα and DGKζ by forming a covalent bond with the enzyme.

[0155] The types of cancers that can 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 cancers such as rectal cancer, colon cancer, common adenomatous polyposis cancers and hereditary non-polyposis colorectal cancers, 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 corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma lymphoma, Burkitt's lymphoma, acute lymphoblastic 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 tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0156] One or more additional agents or treatment methods such as antiviral agents, chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressants, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors can be optionally combined with the compounds of formula (I) for the treatment of diseases, disorders or conditions associated with DGKα and DGKζ. The agents can be combined with the compounds of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0157] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, nitrogen mustard hydrochloride, cyclophosphamide Ifosfamide, melphalan, chlorambucil, pipobroman, triethylene melamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide.

[0158] In the treatment of melanoma, agents suitable for use in combination with the compounds of formula (I) include: dacarbazine (DTIC), optionally in combination with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY TM In the treatment of melanoma, the compounds of formula (I) may also be combined with immunotherapeutic drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0159] In the treatment of melanoma, the compounds of formula (I) may also be used in combination with vaccine therapy. Anti-melanoma vaccines are similar in some ways to antiviral vaccines, which are used to prevent viral diseases such as polio, measles and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.

[0160] Melanoma confined to the arms or legs may also be treated with a combination of agents including one or more compounds of formula (I) using a hyperthermic ex vivo limb perfusion technique. This treatment regimen temporarily separates the circulation of the affected limb from the rest of the body and injects high doses of the chemotherapy agent into the arteries that supply the limb, thereby providing high doses to the tumor area without exposing internal organs to these doses, which could otherwise cause serious side effects. The fluid is usually warmed to 38.9°C to 40°C. Melphalan is the drug most commonly used for this chemotherapy process. This can be provided together with another agent called tumor necrosis factor (TNF).

[0161] Suitable chemotherapeutic agents or other anticancer 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, pentobarbital and gemcitabine.

[0162] Suitable chemotherapeutic or other anticancer 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, vinblastine, bleomycin, doxycycline, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol), mitomycin, deoxymethamphenicol, mitomycin C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.

[0163] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.

[0164] Also suitable are cytotoxic agents such as epididymoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutics; folinic acid; tegafur; and hematopoietic growth factors.

[0165] Other anticancer agents include antibody therapies such as trastuzumab Antibodies to co-stimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies to cytokines (IL-10 or TGF-β).

[0166] Other anticancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4.

[0167] Other anti-cancer agents also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0168] Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[0169] The pharmaceutical composition of the present invention may optionally include at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more important steps in the signaling pathway in the normal function of cancer cells, thereby causing cell apoptosis. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors, for example, STI 571 (ii) epidermal growth factor (EGF) receptor inhibitors, for example, kinase inhibitors ( (iii) her-2 / neu receptor inhibitors such as farnesyl transferase inhibitors (FTIs), for example, L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of Akt family kinases or Akt pathways, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 1(8):792-797 (1995)); Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors, for example, flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidylinositol kinase inhibitors, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of formula (I) may be in separate pharmaceutical compositions. In a specific embodiment of the present invention, at least one compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, at least one STI may be administered first, or at least one compound of formula (I) and at least one STI may be administered at the same time. Additionally, when more than one compound of formula (I) and / or STI is used, the compounds may be administered in any order.

[0170] The present invention further provides a pharmaceutical composition for treating a chronic viral infection in a patient, 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.

[0171] The present application also provides a method for treating chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

[0172] In a specific embodiment of the present invention, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to the patient simultaneously or sequentially. In other words, at least one compound of formula (I) can be administered first, at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one STI can be administered at the same time. In addition, when more than one compound of formula (I) and / or chemotherapeutic agent is used, the compounds can be administered in any order. Similarly, any antiviral drug or STI can also be administered at any time point compared to the administration of the compound of formula (I).

[0173] Chronic viral infections that can be treated using the combination therapy of the present invention include, but are not limited to, diseases caused by: Hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). It is worth noting that parasitic infections (e.g., malaria) can also be treated by the above method, wherein compounds known to treat parasitic conditions are optionally added in place of antiviral drugs.

[0174] Suitable antiviral drugs 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 drugs.

[0175] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobcavir; BCH-I0652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, named for β-L-2′,3′-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and ferulosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delavirdin (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir; DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral drugs include hydroxyurea, ribavirin, IL-2, IL-12, enfuvirtide, and Yissum Project No. 11607.

[0176] The present invention also includes a pharmaceutical kit, which is used, for example, to treat or prevent a disease or disorder associated with DGKα and DGKζ and other diseases mentioned in this application, which includes one or more containers, the container including a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I). Such a kit may further include, if necessary, one or more of the various conventional pharmaceutical kit components, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, as will be readily appreciated by those skilled in the art. The kit may also include instructions, whether as an insert or a label, indicating the amount of the ingredients to be taken, dosing instructions, and / or instructions for mixing the ingredients.

[0177] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at different times, and at least two of these therapeutic agents or therapeutic agents are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved as follows, for example, a single dosage form of each therapeutic agent or multiple single dosage forms of each therapeutic agent with a fixed ratio is administered to the subject. The order or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral route, intravenous route, intramuscular route, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, and the other therapeutic agents of the combination can be administered orally. Or, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. Combination therapy can also include the administration of a combination of therapeutic agents as described above and further with other bioactive ingredients and non-drug treatments (e.g., surgery or radiotherapy). When combination therapy includes non-drug therapy, non-drug therapy can be performed at any appropriate time, as long as the beneficial effect of the combined action of the therapeutic agent and the non-drug therapy is achieved. For example, in appropriate circumstances, beneficial effects may still be achieved when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, perhaps for a few days or even a few weeks.

[0178] 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 (additives) and / or diluents, and optionally one or more additional therapeutic agents as described above.

[0179] The compounds of the present invention can be administered by any suitable means for any use described herein, for example, orally, such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; intraorally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to the nasal mucosa, such as by inhalation of an aerosol; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. They can be administered alone, but will usually be administered together with a pharmaceutical carrier according to the selected route of administration and pharmaceutical practice.

[0180] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, pharmaceutical auxiliary (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, which is involved in the process of carrying or transporting the subject 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 of the formulation, including, that is, adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form; and will not cause harm to the patient.

[0181] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier.

[0182] Pharmaceutically acceptable carriers are formulated according to numerous factors within the purview of those skilled in the art. These include, but are not limited to: the type and properties of the active agent to be formulated; the patient to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication to be targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as a variety of solid and semisolid dosage forms. Such carriers may include a variety of different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons (e.g., stability of the active agent, adhesive, etc.), which are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in numerous readily available sources, for example, Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0183] The dosage regimen of the compounds of this invention will, of course, vary with known factors, such as the pharmacokinetic properties of the particular agent and the route of administration; the species, age, sex, health, physical condition and weight of the recipient; the nature and extent of the symptoms; kind of concurrent treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect.

[0184] As a general guide, when used for the specified effect, the daily oral dosage of each active ingredient is about 0.001 to about 5000 mg / day, preferably about 0.01 to about 1000 mg / day, and most preferably about 0.1 to about 250 mg / day. For intravenous administration, the most preferred dosage is about 0.01 to about 10 mg / kg / minute during a constant rate infusion. The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be divided into doses twice a day, three times a day, or four times a day.

[0185] The compound is usually administered in a mixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) which is appropriately selected for the intended administration form (e.g., oral tablets, capsules, tinctures, and syrups) and in accordance with conventional pharmaceutical practice.

[0186] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg / dose unit to about 2000 mg of active ingredient / dose unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

[0187] A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh screen and filled into size L gelatin capsules.

[0188] A typical injectable preparation is prepared as follows: at least one compound of the present invention (250 mg) is aseptically placed in a vial, aseptically freeze-dried and sealed. When used, the contents of the vial are mixed with 2 mL of physiological saline to prepare an injectable preparation.

[0189] The present invention includes within its scope a pharmaceutical composition 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. Optionally, 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 such as anticancer agents or other pharmaceutically active substances.

[0190] Regardless of the administration route selected, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.

[0191] Actual dosage levels of the active ingredient in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve a therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0192] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the present invention employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and other like factors well known in the medical arts.

[0193] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can use a starting dose of the compound of the present invention for the pharmaceutical composition at a dose level lower than that required to achieve a therapeutic effect, and gradually increase the dose until the effect is achieved.

[0194] Usually, the suitable daily dose of the compounds of this invention will be the amount of the compound that can effectively produce the lowest dose of the therapeutic effect. Such an effective dose usually depends on the above factors. Usually, the dosage of oral, intravenous, intracerebroventricular and subcutaneous injection of the compounds of this invention for patients will be about 0.01 to about 50 mg / kg body weight / day.

[0195] If desired, the effective daily dose of active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, administration is once daily.

[0196] 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).

[0197] When used in combination with the compounds of the present invention, the above-mentioned other therapeutic agents can be used in amounts such as those indicated in the U.S. Physicians' Desk Reference (PDR) or otherwise determined by those of ordinary skill in the art. In the methods of the present invention, such other therapeutic agents can be administered before, simultaneously with, or after the administration of the compounds of the present invention.

[0198] Preparation method

[0199] The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry. The general synthesis scheme for preparing the compounds of the present invention is described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed in the present application. The different methods for preparing the compounds of the present invention are readily conceivable to those skilled in the art. Examples of the compounds of the present invention prepared by the methods described by the general schemes are given in the Examples section stated below. The preparation of homochiral embodiments 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 through chiral phase preparation HPLC. Alternatively, the embodiment compounds can be prepared by methods known to obtain products enriched in enantiomers or diastereomers.

[0200] The reactions and techniques described in this section are carried out in solvents suitable for reagents and materials, and are suitable for conversion. Similarly, in the description of the synthetic method given below, it should be understood that all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, duration of experiment and post-processing process, are selected as standard conditions for the reaction, which is also what those skilled in the art should easily recognize. It should be understood by those skilled in the art that the functional groups present on each part of the molecule must be compatible with the proposed reagents and reactions. For those skilled in the art, this restriction to substituents compatible with reaction conditions is easy to think of, and when there are incompatible substituents, alternatives are needed. This sometimes requires judgment to modify the order of the synthetic steps or select a specific method scheme rather than another, to obtain the compound of the present invention. It should also be recognized that another major consideration when planning any synthetic route in the art is to judiciously select the protecting group for protecting the reactive functional groups present in the compounds of the present invention. An authoritative account that describes many alternatives for the trained practitioner is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007).

[0201] Methods that can be used to synthesize intermediates used to prepare examples of the present invention are shown in the following schemes.

[0202] Example

[0203] The following examples illustrate specific and preferred embodiments of the present invention and do not limit the scope of the present invention. Unless otherwise specified, chemical abbreviations and symbols and scientific abbreviations and symbols have their usual and customary meanings. Other abbreviations used in the examples and other places of the application are defined as above. Common intermediates are usually used to prepare more than one example, and are named in order (e.g., intermediate 1, intermediate 2, etc.) and abbreviated as Int.1 or I1, Int.2 or I2, etc. The compounds of the examples are named by the examples and steps of preparing them (e.g., "1-A" represents Example 1, Step A), or only by the examples in which the compounds are the title compounds of the examples (e.g., "1" represents the title compound of Example 1). In some cases, alternative preparation schemes for intermediates and examples are described. Generally, chemical technicians in the field of synthesis can design alternative preparation schemes that may be desired based on one or more of the following considerations, such as shorter reaction times, less expensive starting materials, easy to operate or separate, improved yields, easy to catalyze, avoid toxic reagents, accessibility of special instruments, and reduced number of linear steps, etc. The purpose of describing alternative preparation schemes is to further enable the preparation of the embodiments of the present invention. In some cases, some functional groups in the outlined embodiments and claims can be replaced by well-known bioisosteric substitution methods known in the art, for example, replacing a carboxylic acid group with a tetrazole or phosphate moiety. 1 H NMR data were processed using water suppression. The reported spectra were not corrected for the effects of water suppression. Protons near the water suppression frequency of 3.35 ppm showed reduced signal intensity.

[0204] abbreviation

[0205] Ac Acetyl

[0206] anhyd. anhydrous

[0207] aq.Water-based

[0208] Bu Butyl

[0209] DMF Dimethylformamide

[0210] DMSO Dimethyl sulfoxide

[0211] EDTA Ethylenediaminetetraacetic acid

[0212] Et Ethyl

[0213] EtOH

[0214] H, hours or hrs hours

[0215] HCl

[0216] HPLC High Pressure Liquid Chromatography

[0217] LC Liquid Chromatography

[0218] LCMS liquid chromatography-mass spectrometry

[0219] M molar concentration

[0220] M +1 (M+H) +

[0221] Me Methyl

[0222] MeOH Methanol

[0223] MHz Megahertz

[0224] mins minutes

[0225] mM millimolar concentration

[0226] MS

[0227] n or N equivalent concentration

[0228] nM nanomolar concentration

[0229] Ph Phenyl

[0230] rt or Ret time retention time

[0231] sat. saturated

[0232] TFA trifluoroacetic acid

[0233] Example 4

[0234] 5-(5-((Cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile

[0235]

[0236] Step 1: Preparation of 2-chloro-N-(3-cyano-4-(trifluoromethyl)phenyl)acetamide

[0237]

[0238] 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 min. LC / MS indicated that the reaction was complete. The crude reaction mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue was purified on silica gel chromatography using a hexane:ethyl acetate gradient (10: 1 to 1: 1) to give 6 g of the desired product as a pale 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).

[0239] Step 2: Preparation of 5-(5-(chloromethyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile

[0240]

[0241] In a screw cap reaction vessel, 2-chloro-N-(3-cyano-4-(trifluoromethyl)phenyl)acetamide (2g, 7.62mmol) and sodium azide (1.980g, 30.5mmol) are combined in acetonitrile (40mL), tetrachlorosilane (3.50mL, 30.5mmol) is added. The reaction mixture is placed under nitrogen and stirred at 130°C for 4 hours. The reaction is quenched with saturated sodium bicarbonate solution. The reaction mixture is absorbed on diatomaceous earth. Chromatography with 20-100% ethyl acetate / hexane on a 40g silica gel column provides the title compound (575mg, 26% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.53 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.88 (br d, J = 8.6 Hz, 1H), 4.26 (br s, 2H). 19 F NMR (471MHz, DMSO-d6) δ-60.78 (s, CF3).

[0242] Step C: Preparation of 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile

[0243]

[0244] 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 was added N-methylcyclohexylamine (272 mg, 2.400 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 200 mL of ethyl acetate and extracted 5 times with 25 mL of water and once with 20 mL of brine. The organic portion was absorbed onto celite and purified by chromatography using a gradient of 20-100% ethyl acetate in hexanes on a 24 g silica gel short column. Fractions consistent with the desired product were combined and the solvent removed to give the title compound (570 mg, 78% yield) as an oil. The oil was stirred under hexanes and a white solid formed. 1 H NMR (400MHz, chloroform-d) δ8.81 (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 (br d, J=12.9Hz, 1H), 1.42-1.21 (m, 5H), 1.20-1.06 (m, 1H). LC / MS1.1min.,M +1 :364.9.

[0245] Examples 1-30 in the table were prepared according to the general procedure disclosed in Example 4 by substituting the desired aniline in Step 1 (RAr-NH2) and the desired secondary amine (R'R"NH) in Step 3.

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] The following analytical LCMS method was used to characterize the compounds.

[0259] Method A: Waters XBridge BEH XP C18 (50 x 2.1 mm) 2.5 μm; Mobile phase A: 5:95 acetonitrile:water containing 10 mM NH4OAc; Mobile phase B: 95:5 acetonitrile:water containing 10 mM NH4OAc; Temperature: 50°C; Gradient: 0-100% B in 3 minutes; Flow rate: 1.1 mL / min.

[0260] Method B: Column: Waters XBridge BEH XP C18 (50 x 2.1 mm) 2.5 μm; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B in 3 minutes; Flow rate: 1.1 mL / min.

[0261] Method AA: Conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water containing 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water containing 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0262] Method AB: Gradient: starting %B: 0, final %B: 100, 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.

[0263] Method BB: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50°C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0264] Method C: Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water containing 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water containing 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then 0.5 minute hold at 100% B; Flow rate: 1.0 mL / min; Detection: UV at 220 nm.

[0265] Biological assays

[0266] DGKαADPGLO full-length IC 50 (uM)

[0267] DGKαADPGLO (near full length) IC 50 (uM)

[0268] In vitro DGK inhibition assay

[0269] DGKα (full length and near full length) ADP Glo assays were performed using extruded liposome preparations at 5% DAG or at 10% DAG. Enzymatic reactions were performed in 50 mM MOPS pH 7.5, 100 mM NaCl, 10 mM MgCl2, 1 mM CaCl2, and 1 mM DTT (assay buffer). For extruded liposome reactions, lipid substrate concentrations were 1.9 mM PS, one of 0.25 mM DAG (5% liposome preparations) or 0.5 mM DAG (10% liposome preparations), and 2.7 mM PC. Reactions were performed at 150 mM ATP. Enzyme concentrations for DGKa (near full length) and DGKa (FL) were 5 nM.

[0270] Compound inhibition studies were performed as follows: 25 nL drops of each test compound (11 points, 3-fold dilution series for each compound) dissolved in DMSO were transferred to the wells of a white 1536-well plate (Corning 3725). A 5 mL enzyme / substrate (substrate was 5x or 10x liposome preparation) solution at 2x final ammonium salt concentration was prepared as follows: 5 ml of extruded liposome preparation was combined with 10 nM (2x final) DGKa (near full length) or DGKα (full length) prepared as described below and incubated at room temperature for 10 minutes. Next, 1 mL of 2x enzyme / substrate solution was added to the wells containing the test compound, and the reaction was initiated by adding 1 mL of 300 uM ATP. Substrate was added only to the wells containing only DMSO for background measurement. The reaction was allowed to proceed for 1 hr, after which 2 mL 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 ATP conversion, which resulted from 100% inhibition of the no enzyme control reaction and 0% inhibition of the vehicle only reaction. Compounds were evaluated at 11 concentrations to determine the IC 50 .

[0271] 2x Liposomal formulation (5% DAG)

[0272] Lipid composition is 5mol% DAG (Avanti 800811O), 40mol% PS (Avanti 840035P), and 55mol% PC (Avanti 850457), and for liposome solution, total lipid concentration is 7-8mg / mL. PC, DAG and PS are dissolved in chloroform, merged, and vacuum dried into a film. Lipid is hydrated to 20mM in 50mM MOPS pH 7.5, 100mM NaCl, 5mMMgCl2, and it is freeze-thawed five times. The lipid suspension is extruded through a 100nm polycarbonate filter 10-12 times. Dynamic light scattering is carried out to confirm liposome size (50-60nm radius). The liposome preparation is stored at 4°C for up to four weeks.

[0273] 2x Liposomal formulation (10% DAG)

[0274] Lipid composition is 9.7mol%, 1mM DAG (Avanti 800811O), 37.3mol%, 3.8mM PS (Avanti840035P), and 53mol%, 5.4mM PC (Avanti 850457), and for 2x liposome solution, total lipid concentration is 7-8mg / mL (10.2mM total lipid). In order to prepare these liposomes, PC, DAG and PS are dissolved in chloroform, merged, and dried into a film in a vacuum. Lipid is hydrated to 10mM in 50mM MOPS pH 7.5, 100mM NaCl, 1μM CaCl2, 10mM MgCl2, 1mM DTT, and it is frozen and thawed five times. The lipid suspension is extruded through a 100nm polycarbonate filter 11 times. Dynamic light scattering is carried out to confirm the liposome size (50-60nm radius). The liposome preparation is stored at ambient temperature for up to four weeks.

[0275] Cloning and expression of full-length human DGKα in baculovirus.

[0276] The DNA fragment encoding full-length DGKα (Ref Seq_NP_958852.1) was codon-optimized for insect cell expression and gene synthesized at GenScript, USA Inc. (Piscataway, NJ) and cloned as an NdeI-XhoI fragment into a modified pFastBac1 vector (Invitrogen, Carlsbad, CA).

[0277] Baculovirus expressing hDGKa-TVMV was generated using the Bac-to-Bac Baculovirus Expression System (Invitrogen) according to the manufacturer's protocol.

[0278] hDGKα-TVMV-His expression was scaled up in Sf9 cells (Expression Systems, Davis, CA) and grown to 2 × 10 6 The cells were inoculated with a virus stock at a virus / cell ratio of 1:200. The culture medium was maintained at a volume of 800 mL, 130 rpm, and allowed to grow at 27°C for 65 hours post infection. The infected cell culture medium was harvested by centrifugation at 2000 rpm for 20 minutes in a RC12BP centrifuge. The cell pellet was stored at -70°C until purification.

[0279] Purification of full-length human DGK-α

[0280] Full-length human DGKα (SEQ ID No. 2) was expressed as a TVMV-cleavable C-terminal Hexa His tag and purified from insect paste infected with SF9 baculovirus. The cell pellet was resuspended in a mass ratio of 1:6 cells to lysis buffer (50mM HEPES, pH 7.4, 0.3M NaCl, 5% glycerol, 1mM TCEP) and supplemented with 20mM imidazole and completely EDTA-free protease inhibitor tablets and Benzonase. The cells were lysed using a nitrogen bomb cell disruptor (nitrogenbomb) (Parr Instruments) using nitrogen decompression, and the suspended cells were pressurized at 300psi at 4°C for 30min. The lysate was clarified by ultracentrifugation at 100,000xg for 45min. Use Purifier Plus system was used for purification step. The clear 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 with 500 mM imidazole. The fractions containing the target protein were pooled, concentrated, and further purified on a HiLoad 26 / 600 Superdex 200 pg size exclusion chromatography, which was pre-equilibrated in 50 mM HEPES, pH 7.4, 0.2 M NaCl, 5% glycerol, 1 mM TCEP. The fractions containing the target protein were pooled and diluted 4-fold with dilution buffer [50 mM HEPES, pH 7.4, 5% glycerol, 1 mM TCEP] to reduce the NaCl concentration from 0.2 M to 0.05 M. The diluted sizing pool was applied to a 5 mL HiTrap Q Sepharose FF anion exchange column, washed to baseline, and eluted with: 0% to 100% elution buffer [50 mM HEPES, pH 7.4, 1.0 M NaCl, 5% glycerol, 1 mM TCEP] in 10 column volumes. Fractions containing the target protein were pooled and concentrated at 2-5 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 a yield of 0.5-2 mg / L cell culture medium.

[0281] Cloning and expression of human DGKa (near full length) in baculovirus.

[0282] A DNA fragment encoding nearly full-length DGKα (hDGKα(S9-S727) (Ref Seq_NP_958852.1) was codon-optimized for insect cell expression and gene synthesized at GenScript, USA Inc. (Piscataway, NJ) and cloned as an NdeI-XhoI fragment into a modified pFastBac1 vector (Invitrogen, Carlsbad, CA).

[0283] Baculovirus expressing hDGKα(S9-S727)-TVMV was generated using the Bac-to-Bac Baculovirus Expression System (Invitrogen) according to the manufacturer's protocol.

[0284] hDGKα(S9-S727)-TVMV-His was expressed on a large scale in Sf9 cells (Expression Systems, Davis, CA) and grown to 2 × 10 6 The cells were inoculated with a virus stock at a virus / cell ratio of 1:200. The culture medium was maintained at a volume of 800 mL, 130 rpm, and allowed to grow at 27°C for 65 hours post infection. The infected cell culture medium was harvested by centrifugation at 2000 rpm for 20 minutes in a RC12BP centrifuge. The cell pellet was stored at -70°C until purification.

[0285] Purification of nearly full-length human DGKα (S9-S727)

[0286] Near full-length human DGKα (SEQ ID No. 2) comprising amino acids 9-727 was expressed as a TVMV-cleavable C-terminal Hexa His tag and purified from insect paste infected with SF9 baculovirus. The cell pellet was resuspended in a mass ratio of 1:6 cells to lysis buffer (50mM HEPES, pH 7.4, 0.3M NaCl, 5% glycerol, 1mM TCEP) and supplemented with 20mM imidazole and completely EDTA-free protease inhibitor tablets and Benzonase. The cells were lysed using a nitrogen bomb cell disruptor (Parr Instruments) using nitrogen decompression, and the suspended cells were pressurized at 300psi at 4°C for 30min. The lysate was clarified by ultracentrifugation at 100,000xg for 45min. Use Purifier Plus system was used for purification steps. The clear supernatant was applied to a 5 mL HisTrap FF crude NickelAffinity column, washed to baseline, and eluted with: 50 mM HEPES, pH 7.3, 0.3 M NaCl, 5% glycerol, 1 mM TCEP with 500 mM imidazole. Fractions containing the target protein were pooled, concentrated, and further purified on a HiLoad 26 / 600 Superdex 200 pg size exclusion chromatography pre-equilibrated in 50 mM HEPES, pH 7.3, 0.3 M NaCl, 5% glycerol, 1 mM TCEP. A final purity of 80% was achieved with a yield of 4 mg / L of cell culture medium. The purified near full-length hDGKα was concentrated to >1 mg / ml, flash frozen in liquid nitrogen, and stored in 0.5 mg aliquots at -80°C. The protein was identified by liquid chromatography / mass spectrometry and was shown to have acetylation modification as well as cleavage of the N-terminal methionine. The purified protein existed primarily in monomeric form with <0.5% high molecular weight aggregates as evidenced by the association state determined by size exclusion chromatography tandem multi-angle light scattering (SEC-MALS) data.

[0287] In vitro DGKα translocation assay

[0288] Jurkat cells were transduced with a lentiviral construct overexpressing DGKα-YFP (N-terminal tag) selected by puromycin and sorted by FACs to establish stable cell 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 run in assay medium (RPMI supplemented with 10% FBS and no antibiotics).

[0289] For the translocation assay, cells were plated onto Perkin Elmer CellCarrier-384Ultra microplates (Perkin Elmer cat#6057500) at a density of 30,000 cells / well in a volume of 40 μL assay medium. Compounds were then transferred to the cells by an Echo Acoustic liquid handler (Echo 655). A 40 nL droplet of each test compound (maximum concentration of 10 mM, 11 points, 3-fold dilution series for each compound) dissolved in DMSO was transferred to each well to obtain a dose response treatment with a maximum concentration of 10 μM. The treated cells were then incubated at 37°C for 1 hour. The cells were then fixed with 4% formaldehyde (Thermo cat#28906) for 15 minutes, briefly centrifuged to increase cell retention (250 rpm for 5 minutes), and then washed 3 times with 50 μL PBS. The cells were then stained with Hoechst and washed 2 times with 50 ul PBS. Next, 50 μL of PBS was added to each well, each plate was sealed, and the plates were imaged on the Opera Phenix High Content Screening System. Imaging was done with a 40X water objective. The YFP channel was set to 100% power for 500 milliseconds. Ten regions / well were imaged and analyzed. Data analysis was performed using Columbus Image Analysis software (Perkin Elmer).

[0290] Table A

[0291]

[0292]

[0293]

[0294] The compounds of the present invention have activity as inhibitors of one or both of the DGKα enzyme and the DGKζ enzyme and are therefore useful in treating diseases associated with the inhibition of DGKα and DGKζ activity.

[0295] Nucleotide sequence encoding hDGKα-(M1-S735)-Ct-TVMV-His:

[0296]

[0297] The amino acid sequence of hDGKα-(M1-S735)-Ct-TVMV-His:

[0298]

[0299] Nucleotide sequence encoding hDGKζ-(M1-A928)-transcription variant-2Ct-TVMV-His:

[0300]

[0301]

[0302] The amino acid sequence of hDGKζ-(M1-A928)-transcription variant-2Ct-TVMV-His:

[0303]

[0304] Nucleotide sequence encoding MA-hDGKα-(S9-S727)-Ct-TVMV-His:

[0305]

[0306] AND -Amino acid sequence of hDGKα-(S9-S727)-Ct-TVMV-His:

[0307]

Claims

1. Compounds of formula (I): or a salt thereof, wherein: (i) X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; provided that 0 or 1 of X and Y is N; or (ii) X is CH or CR1; Y is NR 1a ; Z is C(=O); When Z is C(=O), represents a single bond, or when Z is CH or CR1, represents a double bond; 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 a cyclic group selected from the following: C 3-6 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- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, wherein each cyclic radical is substituted with 0 to 3 R 2a ; R 2a Each is 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); Alternatively, R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each substituted with 0 to 2 R 3a ; R 3a Each independently is F, Cl, -CN, -OH, C 1-3 Alkyl, or C 1-3 Fluoroalkyl; R x are each independently hydrogen or -CH3; and n is 0, 1, 2, or 3; The prerequisites are: Part (i) no and (ii) wherein the compound of formula (I) is not 2. The compound or salt thereof according to claim 1, wherein: R1 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 a cyclic group selected from the following: C 3-6 Cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and phenyl, each substituted with 0 to 2 R 2a ; R 2a Each is 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 alkyl), or -CH2CH2CH2NHC(O)(phenyl); Alternatively, R2 and R3 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group, each substituted with 0 to 2 R 3a ; R 3a are each independently -OH, -CN, -CH3, or -CF3; and n is 0, 1, 2, or 3.

3. The compound or salt thereof according to claim 1, wherein: R1 is each independently F, Cl, Br, -CN, -CH3, -CF3, -OCH3, -C(O)OH, -C(O)OCH3, or -NO2; R2 is -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, substituted with 0 to 2 R 2a cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl substituted with -C(O)OCH2CH3, or phenyl; R 2a Each independently is -OH, -CH3, or -C(O)OCH2CH3; R3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2OH, cyclopropyl, -CH2(cyclopropyl), -CH2(phenyl), -CH2CH(OH)(phenyl), -CH2CH=CH2, -CH2CH2C(O)OCH3, or -CH2CH2CH2NHC(O)(phenyl); Alternatively, R2 and R3 together with the nitrogen atom to which they are attached form a substituted 3a of pyrrolidin; R 3a is -CH3; and n is 1 or 2.

4. The compound or salt thereof according to claim 1, wherein: X is N, CH, or CR1; Y is N, CH, or CR1; Z is CH or CR1; and represents a double bond; The prerequisite is that 0 or 1 of X and Y is N.

5. The compound or salt thereof according to claim 1, which has the structure of formula (IIa):

6. The compound or salt thereof according to claim 1, which has a structure of formula (IIb) or formula (IIc):

7. The compound or salt thereof according to claim 1, wherein R2 is substituted with 0 to 2 R 2a of cyclohexyl.

8. The compound or salt thereof according to claim 1, wherein R2 is -CH(CH3)2 or -CH2C(CH3)2.

9. The compound or salt thereof according to claim 1, wherein R3 is C 1-4 alkyl.

10. The compound or salt thereof according to claim 1, which has a structure selected from the following:

11. The compound or a salt thereof according to claim 1, which has a structure selected from the following:

12. The compound or salt thereof according to claim 1, wherein the compound is: 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)cyclohexylamine (3); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile (4); 5-(5-((butyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (5); 5-(5-((allyl(cyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-2-chlorobenzonitrile (6); 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); 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)cyclohexylamine (18); N-((1-(3-Fluorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (19); 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)cyclohexylamine (23); 5-(5-((cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methoxybenzonitrile (24); 5-(5-((Cyclohexyl(methyl)amino)methyl)-1H-tetrazol-1-yl)-2-methylbenzonitrile (25); 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); N-((1-(4-chloro-3-nitrophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (28); N-((1-(4-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (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-methylcyclohexylamine (31); N-Methyl-N-((1-(4-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclohexylamine (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-tetrazolyl-5-yl)methyl)cyclohexylamine (35); N-((1-(3-chlorophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (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-tetrazol-5-yl)methyl)amino)ethan-1-ol (43); N-Methyl-N-((1-(3-nitrophenyl)-1H-tetrazol-5-yl)methyl)cyclopropylamine (44); N-((1-(3-Bromophenyl)-1H-tetrazol-5-yl)methyl)-N-methylcyclohexylamine (45); N-((1-(6-fluoropyridin-3-yl)-1H-tetrazolyl-5-yl)methyl)-N-methylcyclohexylamine (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-methylcyclohexylamine (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-hydroxycyclohexyl)amino)methyl)-1H-tetrazol-1-yl)-3-chloropicolinonitrile (58); 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).

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

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for treating cancer or viral infection.

15. The use according to claim 14, wherein the cancer is selected from the group consisting of 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. Use of the 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 α (DGKα) and diacylglycerol kinase ζ (DGKζ).

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