WO2024137865A1 - Compounds useful as t cell activators - Google Patents

Compounds useful as t cell activators Download PDF

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Publication number
WO2024137865A1
WO2024137865A1 PCT/US2023/085230 US2023085230W WO2024137865A1 WO 2024137865 A1 WO2024137865 A1 WO 2024137865A1 US 2023085230 W US2023085230 W US 2023085230W WO 2024137865 A1 WO2024137865 A1 WO 2024137865A1
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compound
formula
cancer
pharmaceutically acceptable
racemate
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PCT/US2023/085230
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French (fr)
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Anthony David CASAREZ
Rachel ROWLANDS
Martin W. Rowbottom
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Gossamer Bio Services, Inc.
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Publication of WO2024137865A1 publication Critical patent/WO2024137865A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention generally relates to compounds that activate T cells, promote T cell proliferation, and/or exhibit antitumor activity.
  • compounds, compositions comprising such compounds, and methods of their use are useful for the treatment of proliferative disorders, such as cancer, and viral infections.
  • tumors may exploit several distinct mechanisms to actively subvert anti-tumor immunity. These mechanisms include dysfunctional T- cell signaling (Mizoguchi et al, Science, 1992, 258, 1795-98), suppressive regulatory cells (Facciabene et al, Cancer Res, 2012, 72, 2162-71), and the co-opting of endogenous ''immune checkpoints", which serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction (Topalian et al, Curr. Opin. Immunol., 2012, 24, 1-6; Mellman et al, Nature, 2011, 480, 480-489).
  • DGKs Diacylglycerol kinases
  • DGKs are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T cell functions propagated through the TCR signaling pathway.
  • DGKs serve as intracellular checkpoints and inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation.
  • Supporting evidence include knock-out mouse models of either DGK ⁇ or DGK ⁇ which show a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese et al, Journal of Biological Chemistry, 2011, 7, 5254-5265; Zha et al, Nature Immunology, 2006, 12, 1343).
  • Described herein are compounds that have activity as inhibitors of one or both of DGK ⁇ and DGK ⁇ . Further, the compounds that have activity as inhibitors of one or both of DGK ⁇ and DGK ⁇ and have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases.
  • the compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof is provided wherein X is -S-.
  • a pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof are useful as inhibitors of DGK ⁇ or DGK ⁇ , or both DGK ⁇ and DGK ⁇ .
  • the compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof are useful in therapy.
  • the therapy is treatment of proliferative disorders, such as cancer and viral infections.
  • a method of modulating the activity of DGK ⁇ or DGK ⁇ , or both DGK ⁇ and DGK ⁇ comprising contacting the kinase with an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
  • a method for treating a disease or disorder associated with the activity of DGK ⁇ or DGK ⁇ , or both DGK ⁇ and DGK ⁇ comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
  • a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is provided, in the manufacture of a medicament.
  • the medicament is useful for the treatment of proliferative disorders, such as cancer and viral infections.
  • the compounds of Formula (I) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing viral infections and various proliferative disorders, such as cancer.
  • Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as viral infections and cancer.
  • processes are provided for the preparation of the compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 100 ⁇ L” means “about 100 ⁇ L” and also "100 ⁇ L.” In some embodiments, about means within 5% of the value. Hence, “about 100 ⁇ L” means 95–105 ⁇ L. In some embodiments, about means within 4% of the value. In some embodiments, about means within 3% of the value.
  • alkyl means a straight chain or branched saturated hydrocarbon group.
  • “Lower alkyl” means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms.
  • straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to ⁇ C ⁇ CH, ⁇ C ⁇ C(CH 3 ), ⁇ C ⁇ C(CH 2 CH 3 ), ⁇ CH 2 C ⁇ CH, ⁇ CH 2 C ⁇ C(CH 3 ), and ⁇ CH 2 C ⁇ C(CH 2 CH 3 ), among others.
  • alkylene means a divalent alkyl group.
  • straight chain lower alkylene groups include, but are not limited to, methylene (i.e., ⁇ CH 2 ⁇ ), ethylene (i.e., ⁇ CH 2 CH 2 ⁇ ), propylene (i.e., ⁇ CH2CH2CH2 ⁇ ), and butylene (i.e., ⁇ CH2CH2CH2CH2 ⁇ ).
  • heteroalkylene is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.
  • Alkoxy refers to an alkyl as defined above joined by way of an oxygen atom (i.e., ⁇ O ⁇ alkyl).
  • lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.
  • the terms "carbocyclic” and "carbocycle” denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic. Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Unless specifically indicated to the contrary, the cycloalkyl ring can be substituted.
  • Representative substituted cycloalkyl groups can be mono-substituted, such as, but not limited to, 1-, 2-, 3-, or 4- substituted cyclobutyl, or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, straight or branched chain alkyl groups as defined above, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons in the ring portions of the groups.
  • aryl and aryl groups include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Unless specifically indicated to the contrary, aryl can be substituted.
  • Carbocyclealkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like.
  • heterocycle or “heterocyclyl” groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P.
  • a heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
  • heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom.
  • a dioxolanyl ring and a benzodioxolanyl ring system are both heterocycle groups within the meaning herein.
  • a heterocycle group designated as a C 2 -heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms.
  • the heterocycle can be substituted with as many as N substituents wherein N is the size of the heterocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Representative substituted heterocycle groups can be mono-substituted, such as, but not limited to, 2-, or 3- substituted oxetan-3-yl or 2-, 3-, or 4- substituted tetrahydropyran-4-yl.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heteroaryl group designated as a C2-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heteroaryl can be a 5- membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quina
  • heteroaryl and heteroaryl groups include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.
  • Heterocyclealkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like.
  • “Halo” or “halogen” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • lower haloalkyl groups include, but are not limited to, ⁇ CF 3 , ⁇ CH 2 CF 3 , and the like.
  • Haloalkoxy refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to ⁇ OCF3, ⁇ OCH2CF3, and the like.
  • Hydroxyalkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with ⁇ OH.
  • lower hydroxyalkyl groups include, but are not limited to ⁇ CH 2 OH, ⁇ CH 2 CH 2 OH, and the like.
  • optionally substituted refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0–25, 0–20, 0–10 or 0–5 substituents.
  • Substituents include, but are not limited to –OR a , ⁇ NR a R b , ⁇ S(O)2R a or ⁇ S(O)2OR a , halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R a and R b is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or R a and R b , together with the atom to which they are attached, form a 3–8 membered carbocycle or heterocycle.
  • Racemic is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S).
  • R or S the plane of plane polarized light and designated R or S.
  • the term also encompasses isomers arising from substitution patterns across double bonds, in particular (E)- and (Z)- isomers, or cis- and trans- isomers.
  • E–Z configuration describes the absolute stereochemistry across double bonds having two, three or four substituents.
  • each substituent on a double bond is assigned a priority, and the positions of the higher of the two substituents on each carbon determined. If the two groups of higher priority are on the same side of the double bond (cis to each other), the bond is assigned Z ("zusammen", German for "together”). If the two groups of higher priority are on opposite sides of the double bond (trans to each other), the bond is assigned E ("ent ought", German for "opposite”).
  • Each isomer may be isolated separately or exist as mixtures. The mixtures may be predominantly one isomer, e.g.99.9%, or 99% or 90%, predominantly the other isomer, enriched in one or the other of the isomer(e.g.
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.
  • substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
  • the terms “racemate” and “racemic mixture” refer to an equal mixture of two enantiomers. A racemate is labeled “( ⁇ )" because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
  • a "hydrate” is a compound that exists in combination with water molecules.
  • the combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a "solvate” is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric.
  • solvate refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • “Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formulas (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
  • carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
  • an isotope of a compound having the structure of Formulas (I) includes, but not limited to, compounds of Formulas (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.
  • Salt generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion.
  • acid addition salts salts formed between acids in their anionic form and cations
  • base addition salts salts formed between bases in the cationic form and anions
  • pharmaceutically acceptable refers an agent that has been approved for human consumption and is generally non-toxic.
  • pharmaceutically acceptable salt refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J.
  • Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), and procaine.
  • Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesul
  • the compounds are pharmaceutically acceptable salts.
  • the compounds are isomers.
  • the compounds are racemates.
  • the compounds are solvates.
  • the compounds are hydrates.
  • the compounds are isotopes.
  • the compound of Formula (I) has the structure of Formula (I-A), Formula (I-B) or Formula (I-C): , Formula (I-C) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • the compound of Formula (I) has the structure of Formula (I-A).
  • the compound of Formula (I) has the structure of Formula (I-B).
  • the compound of Formula (I) has the structure of Formula (I-C).
  • the compound of Formula (I) has the structure of Formula (I-A-1), Formula (I-A-2) or Formula (I-A-3): , , Formula (I-A-1) Formula (I-A-2) Formula (I-A-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • the compound of Formula (I) has the structure of Formula (I-A-1).
  • the compound of Formula (I) has the structure of Formula (I-A-2).
  • the compound of Formula (I) has the structure of Formula (I-A-3).
  • the compound of Formula (I) has the structure of Formula (I-B-1), Formula (I-B-2) or Formula (I-B-3): , Formula (I-B-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • the compound of Formula (I) has the structure of Formula (I-B-1).
  • the compound of Formula (I) has the structure of Formula (I-B-2).
  • the compound of Formula (I) has the structure of Formula (I-B-3).
  • the compound of Formula (I) has the structure of Formula (I-C-1), Formula (I-C-2) or Formula (I-C-3): Formula (I-C-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • the compound of Formula (I) has the structure of Formula (I-C-1).
  • the compound of Formula (I) has the structure of Formula (I-C-2).
  • the compound of Formula (I) has the structure of Formula (I-C-3).
  • the compound of Formula (I) has the structure of Formula (I-D-1) or Formula (I-D-2): , , Formula (I-D-1) Formula (I-D-2) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
  • the compound of Formula (I) has the structure of Formula (I-D-1).
  • the compound of Formula (I) has the structure of Formula (I-D-2).
  • R 1 is F.
  • R 1 is Cl.
  • R 1 is Br.
  • L is -CH 2 -.
  • R 2 is a 5- or 6-membered carbocycle. In other embodiments, R 2 is a 5- membered carbocycle. In other embodiments, R 2 is a 6-membered carbocycle. In some embodiments, R 2 is a 5- or 6-membered heterocycle.
  • R 2 is a 5-membered heterocycle In other embodiments, R 2 is a 6-membered heterocycle In other embodiments, R 2 cyclohexyl, phenyl or pyridyl. In other embodiments, R 2 cyclohexyl. In other embodiments, R 2 phenyl. In other embodiments, R 2 pyridyl. [070] In other embodiments, R 2 is unsubstituted. In other embodiments, R 2 is substituted with one substituent selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy.
  • R 2 is substituted with two substituents each independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy.
  • a compound of Formula (I) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 1.
  • Table 1 Compounds of Formula (I) Cmpd Structure Name Cmpd Structure Name Cmpd Structure Name Cmpd Structure Name Cmpd Structure Name Cmpd Structure Name (S)-4-chloro-2-(1-((5- (difluoromethoxy)pyridin-2- 16B yl)sulfonyl)piperidin-4-yl)-5-(((4,4- dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (R)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(4-(4- 17 fluorophenoxy)phenyl)pyridazin- 3(2H)-one (S)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(4-(4
  • compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof.
  • pharmaceutical compositions further comprise a pharmaceutically acceptable carrier, diluent, or excipient.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the term "pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • compositions of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods can further include the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • pharmaceutically acceptable carrier refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, B
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.
  • Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment.
  • Other dosage forms include delayed or controlled-release forms.
  • Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference.
  • DGK ACTIVITY AND TREATING DISEASES ASSOCIATED WITH DGK ⁇ AND/OR DGK ⁇ [080]
  • methods for inhibiting the activity of at least one diacylglycerol kinase comprising contacting the diacylglycerol kinase with a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof.
  • the diacylglycerol kinase is diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGK ⁇ ).
  • DGKa diacylglycerol kinase alpha
  • DGK ⁇ diacylglycerol kinase zeta
  • methods of treating a subject having a disease or disorder associated with the activity of DGK ⁇ , DGK ⁇ , or both DGK ⁇ and DGK ⁇ are disclosed, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof.
  • administering refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.
  • treatment refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition.
  • treatment also refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • a prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology.
  • a therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.
  • the terms cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development: and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • DGK-mediated” or "DGK -modulated” or "DGK-dependent” diseases or disorders means any disease or other deleterious condition in which DGK, or a mutant thereof, is known to play a role.
  • another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which DGK ⁇ , DGK ⁇ , or both DGK ⁇ and DGK ⁇ , or a mutant thereof, are known to play a role.
  • the present application relates to a method of treating or lessening the severity of a disease or condition selected from a viral infection or a proliferative disorder, such as cancer, wherein said method comprises administering to a patient in need thereof a compound of Formula (I), ), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, according to the present application.
  • the term "subject” refers to an animal (e.g., a mammal, such as a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed with a viral infection or proliferative disorder, such as cancer. Diagnosis may be performed by any method or technique known in the art.
  • a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
  • the term "effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent.
  • an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject.
  • the effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.
  • the term "therapeutically effective amount” or “"pharmaceutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor of DGK ⁇ and/or DGK ⁇ or effective to treat or prevent viral infections and proliferative disorders, such as cancer.
  • the terms “modulate”, or “modulating” refer to the ability to increase or decrease the activity of one or more kinases. Accordingly, compounds of the invention can be used in methods of modulating a kinase by contacting the kinase with any one or more of the compounds or compositions described herein.
  • the compounds can act as inhibitors of one or more kinases. In some embodiments, the compounds can act to stimulate the activity of one or more kinases. In further embodiments, the compounds of the invention can be used to modulate activity of a kinase in an individual in need of modulation of the receptor by administering a modulating amount of a compound as described herein. [088] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting the DGK ⁇ and DGK ⁇ enzyme with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having DGK ⁇ and DGK ⁇ , as well as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing DGK ⁇ and DGK ⁇ enzyme.
  • DGK ⁇ and DGK ⁇ inhibitor refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and/or diacylglycerol kinase zeta (DGK ⁇ and DGK ⁇ ) in T cells resulting in T cell stimulation.
  • the DGK ⁇ and DGK ⁇ inhibitor may be a reversible or irreversible DGK ⁇ and DGK ⁇ inhibitor.
  • a "reversible DGK ⁇ and DGK ⁇ inhibitor” is a compound that reversibly inhibits DGK ⁇ and DGK ⁇ enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible DGK ⁇ and DGK ⁇ inhibitor” is a compound that irreversibly destroys DGK ⁇ and DGK ⁇ enzyme activity by forming a covalent bond with the enzyme.
  • the term "cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the compounds of Formula (I) can inhibit activity of diacylglycerol kinase alpha (DGK ⁇ ) and/or diacylglycerol kinase zeta (DGK ⁇ ).
  • the compounds of Formula (I) can be used to inhibit activity of DGK ⁇ and DGK ⁇ in a cell or in an individual in need of modulation of DGK ⁇ and DGK ⁇ by administering an inhibiting amount of a compound of Formula (I) or a salt thereof.
  • the compounds for Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful in treating or preventing any disease or condition associated with DGK target inhibition in T cells. These include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito- urinary infections, systemic infections), and proliferative diseases (e.g., cancer).
  • kinase is DGK. In some embodiments the kinase is DGK ⁇ . In some embodiments the kinase is DGK ⁇ .
  • a DGK dependent condition is a DGK ⁇ dependent condition.
  • the a DGK dependent condition is a DGK ⁇ dependent condition.
  • the DGK dependent condition is an infection.
  • the DGK dependent condition is a a viral infection.
  • the DGK dependent condition is cancer.
  • the invention provides a method of treating a patient suffering from or susceptible to a medical condition that is associated with DGK target inhibition in T cells. A number of medical conditions can be treated.
  • the method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound of Formula (l) and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof.
  • a composition comprising a compound of Formula (l) and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof.
  • the compounds described herein may be used to treat or prevent viral infections and proliferative diseases such as cancer.
  • the present invention further provides methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of DGK ⁇ and DGK ⁇ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof.
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of DGK ⁇ and DGK ⁇ enzyme, such as over expression or abnormal activity.
  • a DGK ⁇ and/or DGK ⁇ associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGK ⁇ and DGK ⁇ enzyme activity.
  • Examples of DGK ⁇ and DGK ⁇ associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.
  • the compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) may be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans.
  • any method of administration may be used to deliver the compound or pharmaceutical composition to the patient.
  • the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered orally.
  • the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered parenterally.
  • Described herein are methods of treating a subject having a proliferative disorder or a viral infection comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof for inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGK ⁇ ).
  • DGKa diacylglycerol kinase alpha
  • DGK ⁇ diacylglycerol kinase zeta
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof for treating a disease or disorder associated with the activity of DGK ⁇ or DGK ⁇ , or both DGK ⁇ and DGK ⁇ .
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof for the treatment of proliferative disorders or viral infections.
  • the proliferative disorder is cancer.
  • the invention provides methods of treating cancer associated with activity or expression, including abnormal activity and/or overexpression, of DGK ⁇ and DGK ⁇ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof.
  • Types of cancers that may be treated with the compound of Formula (I) include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leuk
  • the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, cancer of the head and neck, lymphoma, leukemia, or melanoma.
  • the cancer is colon cancer.
  • the cancer is pancreatic cancer.
  • the cancer is breast cancer.
  • the cancer is prostate cancer.
  • the cancer is ovarian cancer.
  • the cancer is cervical cancer.
  • the cancer is renal cancer.
  • the cancer is renal cancer.
  • the cancer is cancer of the head and neck.
  • the cancer is lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is melanoma.
  • a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof for the treatment of proliferative disorders or viral infections.
  • the proliferative disorder is cancer. In some embodiments, the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.
  • the invention provides methods of treating infections associated with activity or expression, including abnormal activity and/or overexpression, of DGK ⁇ and DGK ⁇ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof.
  • the infections are viral infections.
  • the infections are chronic viral infections.
  • Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CIVIV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV)
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CIVIV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • varicella zoster virus coxsackie virus
  • coxsackie virus e.g., human immunodeficiency virus
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti- viral agents; chemotherapeutics, immuno-oncology agents, or other anti-cancer agents; immune enhancers; immunosuppressants; radiation; anti-tumor and anti-viral vaccines; cytokine therapy (e.g. IL2 and GM-CSF); and/or tyrosine kinase inhibitors can be optionally used in combination with the compounds of Formula (I) for treatment of DGK ⁇ and DGK ⁇ associated diseases, disorders or conditions.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • the combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral mutes, intravenous mutes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-dmg treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-dmg treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • the present invention provides a combined preparation of a compound of Formula (I), and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof; and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple diseases or disorders associated with DGK target inhibition in T cells.
  • T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4- 1BBL, ICOS, ICOS-L, OX40, OX40L, GITR.
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • CTLA-4 e.g., CTLA-4, PD
  • compounds of Formula (I) may be administered in combination with an anti- cancer agent.
  • Anti-cancer agents include, for example, small molecule drugs, antibodies, or other biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, tumor infiltrating lymphocytes, and cytokines.
  • the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.
  • the immuno-oncology agent is an agonist of a stimulatory (including a co- stimulatory) receptor; or an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
  • a stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family which includes B7-l, B7-2, B7-HI (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS- L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • B7-l B7-2, B7-HI (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS- L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT ⁇ R, LIGHT, DcR3, HVEM, VEG1/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin ⁇ /TNF ⁇ , TNFR2, TNF ⁇ , LT ⁇ R, Lymphotoxin ⁇ 1 ⁇ 2, FAS, FASL
  • agents for combination therapies for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • antagonists of KIR such as lirilumab.
  • agents for combination therapies for the treatment of cancer include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG-7155 or FPA-008.
  • agents for combination therapies for the treatment of cancer include agonistic agents that ligate positive co-stimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment, e.g., block inhibitory receptor engagement, such as PD-L1/PD-1 interactions; deplete or inhibit Tregs, such as using an anti-CD25 monoclonal antibody (e.g., daclizumab); or by ex vivo anti-CD25 bead depletion; inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion; and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • agonistic agents that ligate positive co-stimulatory receptors e.g., blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor
  • tumor infiltrating lymphocytes are transferred to a subject in need thereof through adoptive cell transfer.
  • the adoptive cell transfer to the subject in need thereof is of autologous T cells.
  • the adoptive cell transfer to the subject in need thereof is of allogeneic T cells.
  • the adoptive cell transfer to the subject in need thereof is of T cells expressing chimeric antigen receptors (CAR-T cells).
  • the other agents for combination therapies for the treatment of cancer are CAR-T cells, including, but not limited to, KYMRIAH (tisagenlecleucel), YESCARTA (axicabtagene ciloleucel), TECARTUS (brexucabtagene autoleucel), BREYANZI (lisocabtagene maraleucel), and ABECMA (idecabtagene vicleucel).
  • CAR-T cells including, but not limited to, KYMRIAH (tisagenlecleucel), YESCARTA (axicabtagene ciloleucel), TECARTUS (brexucabtagene autoleucel), BREYANZI (lisocabtagene maraleucel), and ABECMA (idecabtagene vicleucel).
  • CTLA-4 antagonists such as an antagonistic CTLA-4 antibody.
  • Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.
  • PD-1 antagonists such as an antagonistic PD-1 antibody.
  • Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MEDI-0680 (AMP-514; WO2012/145493) or pidilizumab (CT-011).
  • OPDIVO nivolumab
  • KEYTRUDA pembrolizumab
  • MEDI-0680 AMP-514; WO2012/145493
  • CT-011 pidilizumab
  • Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fe portion of IgG1, called AMP-224.
  • PD-L1 antagonists such as an antagonistic PD-L1 antibody
  • Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010/077634), durvaluma (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
  • LAG-3 antagonists such as an antagonistic 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).
  • CD137 (4-1BB) agonists such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433).
  • GITR agonists 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).
  • IDO antagonists IDO antagonists.
  • 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).
  • OX40 agonists such as an agonistic OX40 antibody.
  • Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.
  • OX40L antagonists such as an antagonistic OX40L antibody
  • Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).
  • CD40 agonists such as an agonistic CD40 antibody.
  • CD40 antagonists such as an antagonistic CD40 antibody.
  • Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
  • Yet other agents for combination therapies for the treatment of cancer include CD27 agonists, such as an agonistic CD27 antibody.
  • Suitable CD27 antibodies include, for example, varlilumab.
  • agents for combination therapies for the treatment of cancer include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, 5 chlormethine, cyclophosphamide (CYTOXAN), ifosfamide, melphalan, chlorambucil pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • uracil mustard including, without limitation, nitrogen mustards, ethylenimine derivatives, alky
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6- mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formcin, mitomycin-C, L-asparaginase, interferons (especially IFN- ⁇ ), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin
  • daunorubicin
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; haematopoietic growth factors; navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine; antibody therapeutics such as trastuzumab (HERCEPTIN), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF- ⁇ ); and agents that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • epidophyllotoxin an antineoplastic enzyme
  • Yet other agents for combination therapies for the treatment of cancer include anti-cancer vaccines, including dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Yet other agents for combination therapies for the treatment of cancer include signal transduction inhibitors (STI).
  • STI signal transduction inhibitors
  • a "signal transduction inhibitor” is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis.
  • Suitable STI's include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA, SSI-774) and antibodies (Imclone: C225 [Goldstein et al, Clin. Cancer Res, 1995, 1, 1311-1318; and Abgenix: ABX-EGF); (iii) her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L- 744,832 (Kohl et al, Nat.
  • FTI farnesyl transferase inhibitors
  • Akt family kinases or the Akt pathway such as, for example, rapamycin
  • cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01
  • phosphatidyl inositol kinase inhibitors such as, for example, LY294002.
  • suitable agents for use in combination with the compounds of Formula (I) include: dacarbazine (DTIC), optionally, along 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 YERVOYTM.
  • DTIC dacarbazine
  • BCNU carmustine
  • cisplatin the "Dartmouth regimen” which consists of DTIC, BCNU, cisplatin and tamoxifen
  • a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • Compounds of Formula (I) may also be combined with immunotherapy drugs, including cytokines such as inter
  • Compounds of Formula (I) may also be used in combination with vaccine therapy in the treatment of melanoma.
  • Anti-melanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps.
  • Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.
  • Melanomas 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 isolated limb perfusion technique.
  • Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTis), protease inhibitors and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTis non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • Suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivaidine (3TC): abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS- 180194); BCH-I0652, emitricitabine [(-)- FTC]; beta-L-FD4 (also called beta-L-D4C and nan1ed beta-L-2',3'- dicleoxy-5-fluorocytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).
  • ZT zidovudine
  • ddl didanosine
  • ddC zalcitabine
  • stavudine d4T
  • NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721, AG-1549; MKC-442 (l-(ethoxy-methyl)-5- (]-methylethyl)-6- (phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.
  • protease inhibitors examples include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343): amprenavir (141W94); lasinavir (BMS-234475): DMP-450; BMS- 2322623, ABT-378; and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607.
  • the present invention further provides pharmaceutical compositions comprising at least one compound of Formula (I), a pharmaceutically acceptable carrier, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent.
  • a pharmaceutically acceptable carrier optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent.
  • the compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intratarsal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions);
  • kits useful for example, in the treatment or prevention of DGK ⁇ and DGK ⁇ associated diseases or disorders, and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art.
  • reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary.
  • suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures).
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular work-up following the reaction may be employed.
  • route 1 or route 2 will depend on, for example, the various chemical groups present in the specific compounds, availability of the starting materials, stability of starting material and intermediates, and the like, and will be apparent to those of skill in the art of chemical synthesis. Likewise, use and choice of protecting groups will be apparent to those of skill in the art.
  • Scheme 1 General preparation of compounds of formula (I) PREPARATION OF INTERMEDIATES I Oxathiane [0150] (1,4-oxathian-3-yl)methanamine may be prepared according to scheme 2.
  • 2-(bromomethyl) oxirane and 2-chloroethan-1-ol are coupled to form 1-bromo-3-(2-chloroethoxy)propan-2-ol, which is cyclized in the presence of t BuOK to form 2-((2-chloroethoxy)methyl)oxirane.
  • This is converted to the thiirane by treatment with thiourea, and then cyclized to the oxathiane in the presence of ammonium chloride.
  • the chloro group is converted to the azide and reduced to the amine, to provide the intermediate (1,4-oxathian-3-yl)methanamine.
  • 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one may be N- alkylated to introduce R 3 , by treatment with suitable reagents (e.g. R 3 - boronic acid), as shown in scheme 5.
  • suitable reagents e.g. R 3 - boronic acid
  • 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one may be prepared by coupling 4,5- dichloropyridazin-3(2H)-one with (4-phenoxyphenyl)boronic acid, as shown in scheme 6.
  • Scheme 6 4,5-dichloro-2-(4-phenoxyphenyl)pyridazin-3(2H)-one SEPARATION OF ISOMERS [0155]
  • Compounds of formula (I) comprise at least one chiral center.
  • the enzyme assay was performed by diluting enzyme DGK ⁇ (1 ⁇ g/ ⁇ L DGK ⁇ , Carna12-101, SEQ ID NO: 3) or DGK ⁇ (1 ⁇ / ⁇ L DGK ⁇ , Carna 12-110, SEQ ID NO: 4) using 1X assay buffer.
  • OAG 1-oleoyl-2-acetyl-sn-glycerol, 25mg/ml, Avanti 800100O
  • PS (10 mg/ml, Avanti 840032P) were mixed at the ratio of 1:2.
  • a 1X substrate solution was prepared with 1X assay buffer by 100-fold dilution. The substrate solution was sonicated on ice for 1 min.
  • the pure ATP was added to the substrate solution (DGKa:400 ⁇ M).5 ⁇ L of the enzyme solution were added to the 384 well plate, and the plate was spun for 1 min at 1000 rpm and incubated for 30 mins at RT.5 ⁇ L of 1X substrate solution were added to the 384 well plate, the plate was spun and then incubated for 45 mins at RT.10 ⁇ L ADP-Glo detergent was added to stop the assay. After 60 mins at RT, 20 ⁇ L ADP-Glo Detection buffer was added as the final step. Plate was read after 45min incubation at RT.

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Abstract

Disclosed herein are compounds having the structure of Formula (I): Formula (I) or pharmaceutically acceptable salts, solvates, hydrates, isomers, tautomers, racemates, or isotopes thereof, wherein Y, X, R1, L, R2 and (II) are as defined herein. Pharmaceutical compositions comprising them, processes for preparing them and uses of them to treat or prevent diseases, disorders and conditions are also provided. The compounds are inhibitors of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) and are useful in the treatment of diseases, disorders and conditions related to DGKα and / or DGKζ activity. In particular, the compounds are useful for treating viral infections and proliferative disorders, such as cancer.

Description

COMPOUNDS USEFUL AS T CELL ACTIVATORS STATEMENT REGARDING SEQUENCE LISTING [01] The contents of the electronic sequence listing (360474_406WO_SeqListing.xml; Size: 9,950 bytes; and Date of Creation: December 19, 2023) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION [02] The present invention generally relates to compounds that activate T cells, promote T cell proliferation, and/or exhibit antitumor activity. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions comprising at least one compound according to the invention that are useful for the treatment of proliferative disorders, such as cancer, and viral infections. BACKGROUND [03] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al, Science, 2006, 314, 268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considerable plasticity and a memory component. The successful harnessing of all these attributes of the adaptive immune system would make immunotherapy unique among all cancer treatment modalities. However, although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as "self" and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively subvert anti-tumor immunity. These mechanisms include dysfunctional T- cell signaling (Mizoguchi et al, Science, 1992, 258, 1795-98), suppressive regulatory cells (Facciabene et al, Cancer Res, 2012, 72, 2162-71), and the co-opting of endogenous ''immune checkpoints", which serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction (Topalian et al, Curr. Opin. Immunol., 2012, 24, 1-6; Mellman et al, Nature, 2011, 480, 480-489). [04] Diacylglycerol kinases (DGKs) are lipid kinases that mediate the conversion of diacylglycerol to phosphatidic acid thereby terminating T cell functions propagated through the TCR signaling pathway. Thus, DGKs serve as intracellular checkpoints and inhibition of DGKs are expected to enhance T cell signaling pathways and T cell activation. Supporting evidence include knock-out mouse models of either DGKα or DGKζ which show a hyper-responsive T cell phenotype and improved anti-tumor immune activity (Riese et al, Journal of Biological Chemistry, 2011, 7, 5254-5265; Zha et al, Nature Immunology, 2006, 12, 1343). [05] Furthermore, tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients were observed to overexpress DGKα which resulted in inhibited T cell function (Prinz et al, .J immunology, 2012, 12, 5990-6000). Thus, DGKα and DGKζ are viewed as targets for cancer immunotherapy (Riese et al, Front Cell Dev Biol., 2016, 4, 108; Chen et al, Front Cell Dev Biol., 2016, 4, 130; Avila-Flores et al, Immunology and Cell Biology, 2017, 95, 549-563; Noessner, Front Cell Dev Biol., 2017, 5, 16; Krishna, et al, Front Immunology, 2013, 4,178; Jing, et al, Cancer Research, 2017, 77, 5676-5686.) The full length human diacylglycerol kinsase alpha isoform a enzyme is disclosed as SEQ ID NO: 1, and the full length human diacylglycerol kinsase zeta enzyme is disclosed as SEQ ID NO: 2. [06] Accordingly, there remains a need for compounds useful as inhibitors of one or both of DGKα and DGKζ. Additionally, there remains a need for compounds useful as inhibitors of one or both of DGKα and DGKζ that have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases, as well as for related compositions and methods for treating diseases, disorders and conditions that would benefit from such modulation. An agent that is safe and effective in restoring T cell activation, lowering antigen threshold, enhancing anti-tumor functionality, and/or overcoming the suppressive effects of one or more endogenous immune checkpoints, such as PD-1, LAG-3 and TGFβ, would be significant for the treatment of patients with proliferative disorders, such as cancer, as well as viral infections. [07] Described herein are compounds that have activity as inhibitors of one or both of DGKα and DGKζ. Further, the compounds that have activity as inhibitors of one or both of DGKα and DGKζ and have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability. BRIEF SUMMARY [08] In one embodiment, a compound is provided having the structure of Formula (I):
Figure imgf000003_0001
Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a 6-membered aromatic or non-aromatic cycle, wherein Y is N, C or CH; X is -S-, -S(=O)- or -S(=O)2-; R1 is F, Cl or Br; L is -CH2-, -O-, -NR3- or -S(=O)n-L’-; wherein R3 is -H, -C1-5 alkyl, -C3-6 cycloalkyl, -CH2-C3-6 cycloalkyl or -CH2-C3-6 heterocycloalkyl; L’ is a bond, -N(C1-5 alkyl)-, -N(C1-5 haloalkyl)- or -N(C3-6 cycloalkyl)-; and n is 0, 1 or 2; and R2 is a 3–10 membered carbocycle or a 3–10 membered heterocycle, substituted with 0, 1 or 2 substituents independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy. [09] In one embodiment, the compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, is provided wherein X is -S-. [010] In one embodiment, the compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, is provided wherein X is -S(=O)-. [011] In one embodiment, the compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, is provided wherein X is -S(=O)2-. [012] In some embodiments, a pharmaceutical composition is provided comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient. [013] In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, are useful as inhibitors of DGKα or DGKζ, or both DGKα and DGKζ. [014] In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, are useful in therapy. In some embodiments, the therapy is treatment of proliferative disorders, such as cancer and viral infections. [015] In some embodiments, a method of modulating the activity of DGKα or DGKζ, or both DGKα and DGKζ is provided comprising contacting the kinase with an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. [016] In some embodiments, a method for treating a disease or disorder associated with the activity of DGKα or DGKζ, or both DGKα and DGKζ, the method comprising administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. [017] In some embodiments, the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is provided, in the manufacture of a medicament. In some embodiments the medicament is useful for the treatment of proliferative disorders, such as cancer and viral infections. [018] In some embodiments, the compounds of Formula (I) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing viral infections and various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as viral infections and cancer. [019] In some embodiments, processes are provided for the preparation of the compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. [020] In some embodiments, synthetic intermediates useful for the preparation of the compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, are provided. [021] These and other features of the invention will be set forth in expanded form as the disclosure continues. The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting. DETAILED DESCRIPTION [022] Described herein are compounds that have activity as inhibitors of one or both of DGKα and DGKζ. Further, the compounds that have activity as inhibitors of one or both of DGKα and DGKζ and have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases. [023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. [024] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. [025] Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions. [026] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. [027] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 100µL" means "about 100µL" and also "100µL." In some embodiments, about means within 5% of the value. Hence, "about 100 µL" means 95–105 μL. In some embodiments, about means within 4% of the value. In some embodiments, about means within 3% of the value. In some embodiments, about means within 2% of the value. In some embodiments, about means within 1% of the value. Generally, the term "about" includes an amount that would be expected to be within experimental error. COMPOUNDS [028] In one embodiment, a compound is provided having the structure of Formula (I):
Figure imgf000007_0001
Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
Figure imgf000007_0002
a 6-membered aromatic or non-aromatic cycle, wherein Y is N, C or CH; X is -S-, -S(=O)- or -S(=O)2-; R1 is F, Cl or Br; L is -CH2-, -O-, -NR3- or -S(=O)n-L’-; wherein R3 is -H, -C1-5 alkyl, -C3-6 cycloalkyl, -CH2-C3-6 cycloalkyl or -CH2-C3-6 heterocycloalkyl; L’ is a bond, -N(C1-5 alkyl)-, -N(C1-5 haloalkyl)- or -N(C3-6 cycloalkyl)-; and n is 0, 1 or 2; and R2 is a 3–10 membered carbocycle or a 3–10 membered heterocycle, substituted with 0, 1 or 2 substituents independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy. [029] As used herein, "alkyl" means a straight chain or branched saturated hydrocarbon group. "Lower alkyl" means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. [030] "Alkenyl" groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to −CH=CH2, −CH=CH(CH3), −CH=C(CH3)2, −C(CH3)=CH2, −C(CH3)=CH(CH3), −C(CH2CH3)=CH2, −CH=CHCH2CH3, −CH=CH(CH2)2CH3, −CH=CH(CH2)3CH3, −CH=CH(CH2)4CH3, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. [031] "Alkynyl" groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to −C ^CH, −C ^C(CH3), −C ^C(CH2CH3), −CH2C ^CH, −CH2C ^C(CH3), and −CH2C ^C(CH2CH3), among others. [032] As used herein, "alkylene" means a divalent alkyl group. Examples of straight chain lower alkylene groups include, but are not limited to, methylene (i.e., −CH2−), ethylene (i.e., −CH2CH2−), propylene (i.e., −CH2CH2CH2−), and butylene (i.e., −CH2CH2CH2CH2−). As used herein, "heteroalkylene" is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P. [033] "Alkoxy" refers to an alkyl as defined above joined by way of an oxygen atom (i.e., −O−alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like. [034] The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic. Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. [035] "Cycloalkyl" groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Unless specifically indicated to the contrary, the cycloalkyl ring can be substituted. Representative substituted cycloalkyl groups can be mono-substituted, such as, but not limited to, 1-, 2-, 3-, or 4- substituted cyclobutyl, or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, straight or branched chain alkyl groups as defined above, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. [036] "Aryl" groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms "aryl" and "aryl groups" include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Unless specifically indicated to the contrary, aryl can be substituted. [037] "Carbocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like. [038] As used herein, "heterocycle" or "heterocyclyl" groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. A heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. In some embodiments, heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzodioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycle groups within the meaning herein. A heterocycle group designated as a C2-heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms. Unless specifically indicated to the contrary, the heterocycle can be substituted with as many as N substituents wherein N is the size of the heterocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. Representative substituted heterocycle groups can be mono-substituted, such as, but not limited to, 2-, or 3- substituted oxetan-3-yl or 2-, 3-, or 4- substituted tetrahydropyran-4-yl. [039] "Heteroaryl" groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C2-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heteroaryl can be a 5- membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. [040] "Heterocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like. [041] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. [042] "Haloalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, −CF3, −CH2CF3, and the like. [043] "Haloalkoxy" refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to −OCF3, −OCH2CF3, and the like. [044] "Hydroxyalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with −OH. Examples of lower hydroxyalkyl groups include, but are not limited to −CH2OH, −CH2CH2OH, and the like. [045] As used herein, the term "optionally substituted" refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0–25, 0–20, 0–10 or 0–5 substituents. Substituents include, but are not limited to –ORa, −NRaRb, −S(O)2Ra or −S(O)2ORa, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each Ra and Rb is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or Ra and Rb, together with the atom to which they are attached, form a 3–8 membered carbocycle or heterocycle. [046] "Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S). The term also encompasses isomers arising from substitution patterns across double bonds, in particular (E)- and (Z)- isomers, or cis- and trans- isomers. E–Z configuration describes the absolute stereochemistry across double bonds having two, three or four substituents. Following the Cahn-Ingold-Prelog priority rules (CIP rules), each substituent on a double bond is assigned a priority, and the positions of the higher of the two substituents on each carbon determined. If the two groups of higher priority are on the same side of the double bond (cis to each other), the bond is assigned Z ("zusammen", German for "together"). If the two groups of higher priority are on opposite sides of the double bond (trans to each other), the bond is assigned E ("entgegen", German for "opposite"). Each isomer may be isolated separately or exist as mixtures. The mixtures may be predominantly one isomer, e.g.99.9%, or 99% or 90%, predominantly the other isomer, enriched in one or the other of the isomer(e.g. an 80/20 mixture, or a 40/60 mixture), or be approximately equal mixtures. [047] "Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight. [048] "Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%. [049] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out). [050] A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein. [051] A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein. [052] "Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formulas (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formulas (I) includes, but not limited to, compounds of Formulas (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19. [053] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts." [054] The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein). [055] Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), and procaine. [056] Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, βhydroxybutyric, salicylic, -galactaric, and galacturonic acid. [057] Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of the compounds described herein, for example in their purification by recrystallization. [058] In some embodiments, the compounds are pharmaceutically acceptable salts. In some embodiments, the compounds are isomers. In some embodiments, the compounds are racemates. In some embodiments, the compounds are solvates. In some embodiments, the compounds are hydrates. In some embodiments, the compounds are isotopes. [059] In some embodiments, a compound is provided having the structure of Formula (I):
Figure imgf000013_0001
Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
Figure imgf000013_0002
a 6-membered aromatic or non-aromatic cycle, wherein Y is N, C or CH; X is -S-, -S(=O)- or -S(=O)2-; R1 is F, Cl or Br; L is -CH2-, -O-, -NR3- or -S(=O)n-L’-; wherein R3 is -H, -C1-5 alkyl, -C3-6 cycloalkyl, -CH2-C3-6 cycloalkyl or -CH2-C3-6 heterocycloalkyl; L’ is a bond, -N(C1-5 alkyl)-, -N(C1-5 haloalkyl)- or -N(C3-6 cycloalkyl)-; and n is 0, 1 or 2; and R2 is a 3–10 membered carbocycle or a 3–10 membered heterocycle, substituted with 0, 1 or 2 substituents independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy. [060] In some embodiments,
Figure imgf000013_0003
is a 6-membered aromatic cycle. In other embodiments,
Figure imgf000014_0001
is a 6-membered aromatic cycle, wherein Y is CH. In other embodiments,
Figure imgf000014_0002
is phenyl. In other embodiments,
Figure imgf000014_0003
is pyridyl. In some embodiments,
Figure imgf000014_0004
is a 6-membered non-aromatic cycle.
Figure imgf000014_0005
In other embodiments,
Figure imgf000014_0006
is a 6-membered non-aromatic cycle, wherein Y is CH. In other embodiments,
Figure imgf000014_0007
is cyclohexyl. In other embodiments,
Figure imgf000014_0008
is piperidinyl.
Figure imgf000014_0009
[061] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A), Formula (I-B) or Formula (I-C): ,
Figure imgf000015_0001
Formula (I-C) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In other embodiments, the compound of Formula (I) has the structure of Formula (I-A). In other embodiments, the compound of Formula (I) has the structure of Formula (I-B). In other embodiments, the compound of Formula (I) has the structure of Formula (I-C). [062] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-1), Formula (I-A-2) or Formula (I-A-3):
Figure imgf000015_0002
, , Formula (I-A-1) Formula (I-A-2) Formula (I-A-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-1). In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-2). In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-3). [063] In some embodiments, the compound of Formula (I) has the structure of Formula (I-B-1), Formula (I-B-2) or Formula (I-B-3): ,
Figure imgf000016_0001
Formula (I-B-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (I-B-1). In some embodiments, the compound of Formula (I) has the structure of Formula (I-B-2). In some embodiments, the compound of Formula (I) has the structure of Formula (I-B-3). [064] In some embodiments, the compound of Formula (I) has the structure of Formula (I-C-1), Formula (I-C-2) or Formula (I-C-3): Formula (I-C-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (I-C-1). In some embodiments, the compound of Formula (I) has the structure of Formula (I-C-2). In some embodiments, the compound of Formula (I) has the structure of Formula (I-C-3). [065] In some embodiments, the compound of Formula (I) has the structure of Formula (I-D-1) or Formula (I-D-2):
Figure imgf000017_0001
, , Formula (I-D-1) Formula (I-D-2) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof. In some embodiments, the compound of Formula (I) has the structure of Formula (I-D-1). In some embodiments, the compound of Formula (I) has the structure of Formula (I-D-2). [066] In some embodiments, R1 is F. In other embodiments, R1 is Cl. In other embodiments, R1 is Br. [067] In some embodiments, L is -CH2-. In some embodiments, L is -O-. In other embodiments, L is -NR3- . In other embodiments, L is -NH-. In other embodiments, L is -N-C1-5 alkyl-. In other embodiments, L is -N- C3-6 cycloalkyl. In other embodiments, L is -N-CH2-C3-6 cycloalkyl. In other embodiments, L is -N-CH2-C3- 6 heterocycloalkyl. [068] In some embodiments, L is -S(=O)n-L’-. In other embodiments, L is -S(=O)2-L’- and L’ is a bond. In other embodiments, L is -S(=O)2-N(C1-5 alkyl)-, -S(=O)2-N(C1-5 haloalkyl)- or -S(=O)2-N(C3-6 cycloalkyl)-. [069] In some embodiments, R2 is a 5- or 6-membered carbocycle. In other embodiments, R2 is a 5- membered carbocycle. In other embodiments, R2 is a 6-membered carbocycle. In some embodiments, R2 is a 5- or 6-membered heterocycle. In other embodiments, R2 is a 5-membered heterocycle In other embodiments, R2 is a 6-membered heterocycle In other embodiments, R2 cyclohexyl, phenyl or pyridyl. In other embodiments, R2 cyclohexyl. In other embodiments, R2 phenyl. In other embodiments, R2 pyridyl. [070] In other embodiments, R2 is unsubstituted. In other embodiments, R2 is substituted with one substituent selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy. In other embodiments, R2 is substituted with two substituents each independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy. [071] In one embodiment, a compound of Formula (I) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 1. Table 1: Compounds of Formula (I) Cmpd Structure Name
Figure imgf000018_0001
Cmpd Structure Name
Figure imgf000019_0001
Cmpd Structure Name
Figure imgf000020_0001
Cmpd Structure Name
Figure imgf000021_0001
Cmpd Structure Name (S)-4-chloro-2-(1-((5- (difluoromethoxy)pyridin-2- 16B yl)sulfonyl)piperidin-4-yl)-5-(((4,4- dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (R)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(4-(4- 17 fluorophenoxy)phenyl)pyridazin- 3(2H)-one (S)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(4-(4- 18 fluorophenoxy)phenyl)pyridazin- 3(2H)-one 4-chloro-2-(1-((5-chloropyridin-2- yl)sulfonyl)piperidin-4-yl)-5-(((4,4- 19 dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (S)-4-((4-(5-chloro-4-(((4,4-dioxido- 1,4-oxathian-3-yl)methyl)amino)-6- 20 oxopyridazin-1(6H)-yl)piperidin-1- yl)sulfonyl)benzonitrile (R)-4-((4-(5-chloro-4-(((4,4-dioxido- 1,4-oxathian-3-yl)methyl)amino)-6- 21 oxopyridazin-1(6H)-yl)piperidin-1- yl)sulfonyl)benzonitrile Cmpd Structure Name
Figure imgf000023_0001
Cmpd Structure Name 4-chloro-2-((1r,4R)-4-((4- chlorophenyl)(oxetan-3- 29 yl)amino)cyclohexyl)-5-((((R)-4,4- dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 4-chloro-2-((1r,4S)-4-((4- chlorophenyl)(oxetan-3- 30 yl)amino)cyclohexyl)-5-((((S)-4,4- dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 2-((1R,4R)-4-((((R)-1,4-dioxan-2- yl)methyl)(4- (trifluoromethoxy)phenyl)amino)cycl 31 ohexyl)-4-chloro-5-((((R)-4,4-dioxido- 1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 2-((1S,4R)-4-((((S)-1,4-dioxan-2- yl)methyl)(4- (trifluoromethyl)phenyl)amino)cyclo 32 hexyl)-4-chloro-5-((((R)-4,4-dioxido- 1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 2-((1R,4R)-4-((((R)-1,4-dioxan-2- yl)methyl)(4- (trifluoromethyl)phenyl)amino)cyclo 33 hexyl)-4-chloro-5-((((R)-4,4-dioxido- 1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 2-((1S,4S)-4-((((S)-1,4-dioxan-2- yl)methyl)(4- (trifluoromethoxy)phenyl)amino)cycl 34 ohexyl)-4-chloro-5-((((S)-4,4-dioxido- 1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one Cmpd Structure Name 4-chloro-2-((1r,4R)-4-(3- chlorophenoxy)cyclohexyl)-5-((((R)- 35 4,4-dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 4-chloro-2-((1r,4S)-4-(3- chlorophenoxy)cyclohexyl)-5-((((S)- 36 4,4-dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one 4-chloro-5-((((R)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 37 ((1r,4R)-4-(3- (trifluoromethyl)phenoxy)cyclohexyl) pyridazin-3(2H)-one 4-chloro-5-((((S)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 38 ((1r,4S)-4-(3- (trifluoromethyl)phenoxy)cyclohexyl) pyridazin-3(2H)-one 4-chloro-5-((((R)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 39 ((1r,4R)-4-(pyridin-2- yloxy)cyclohexyl)pyridazin-3(2H)-one 4-chloro-5-((((S)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 40 ((1r,4S)-4-(pyridin-2- yloxy)cyclohexyl)pyridazin-3(2H)-one 4-chloro-5-((((R)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 41 ((1r,4R)-4-((5-fluoropyridin-2- yl)oxy)cyclohexyl)pyridazin-3(2H)- one 4-chloro-5-((((S)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 42 ((1r,4S)-4-((5-fluoropyridin-2- yl)oxy)cyclohexyl)pyridazin-3(2H)- one Cmpd Structure Name 4-chloro-5-((((R)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 43 ((1r,4R)-4-((5-isopropylpyridin-2- yl)oxy)cyclohexyl)pyridazin-3(2H)- one 4-chloro-5-((((S)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2- 44 ((1r,4S)-4-((5-isopropylpyridin-2- yl)oxy)cyclohexyl)pyridazin-3(2H)- one 2-(1-((4-bromophenyl) sulfonyl)piperidin-4-yl)-4-chloro-5- 45 (((4,4-dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (R)-4-chloro-2-(1-((2- (difluoromethoxy)-5-ethylphenyl) 46 sulfonyl)piperidin-4-yl)-5-(((4,4- dioxido-1,4-oxathian-3-yl)methyl) amino)pyridazin-3(2H)-one (R)-4-chloro-2-(1-((6-chloropyridin-2- yl)sulfonyl)piperidin-4-yl)-5-(((4,4- 47 dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (S)-4-chloro-2-(1-((6-chloropyridin-2- yl)sulfonyl)piperidin-4-yl)-5-(((4,4- 48 dioxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (R)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(1-((5- 49 methoxy-6-methylpyridin-2- yl)sulfonyl)piperidin-4-yl)pyridazin- 3(2H)-one Cmpd Structure Name
Figure imgf000027_0001
Cmpd Structure Name (R)-4-(5-chloro-4-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-6- 56 oxopyridazin-1(6H)-yl)-N-(4- cyanophenyl)-N- cyclopropylpiperidine-1-sulfonamide (R)-4-chloro-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)-2-(6-(4- 57 (trifluoromethoxy)phenoxy)pyridin-3- yl)pyridazin-3(2H)-one [072] Representative compounds of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-A-1), Formula (I-A-2), Formula (I-A-3), Formula (I-B-1), Formula (I-B-2), Formula (I-B-3), Formula (I-C-1), Formula (I-C-2) or Formula (I-C-3) as applicable, include the compounds having the structure of those described in the Examples below, as well as pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.”, “Cmpd. No.” or “No.” PHARMACEUTICAL COMPOSITIONS [073] In certain embodiment, also disclosed herein are pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof. In some embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. [074] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013. [075] In other embodiments, there are provided methods of making a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation. [076] As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. [077] The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired. [078] The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred. [079] Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference. INHIBITING DGK ACTIVITY AND TREATING DISEASES ASSOCIATED WITH DGKΑ AND/OR DGKΖ [080] In certain embodiments, described herein, are methods for inhibiting the activity of at least one diacylglycerol kinase comprising contacting the diacylglycerol kinase with a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof. In some embodiments, the diacylglycerol kinase is diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGKζ). In certain embodiments, methods of treating a subject having a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ are disclosed, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof. [081] As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration. [082] As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed. The terms cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development: and/or (c) relieving the disease-state, i.e., causing regression of the disease state. [083] As used herein, the term "DGK-mediated" or "DGK -modulated" or "DGK-dependent" diseases or disorders means any disease or other deleterious condition in which DGK, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which DGKα, DGKζ, or both DGKα and DGKζ, or a mutant thereof, are known to play a role. Specifically, the present application relates to a method of treating or lessening the severity of a disease or condition selected from a viral infection or a proliferative disorder, such as cancer, wherein said method comprises administering to a patient in need thereof a compound of Formula (I), ), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, according to the present application. [084] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a viral infection or proliferative disorder, such as cancer. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. [085] As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure. [086] As used herein, the term "therapeutically effective amount" or “"pharmaceutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor of DGKα and/or DGKζ or effective to treat or prevent viral infections and proliferative disorders, such as cancer. [087] As used herein, the terms "modulate", or "modulating" refer to the ability to increase or decrease the activity of one or more kinases. Accordingly, compounds of the invention can be used in methods of modulating a kinase by contacting the kinase with any one or more of the compounds or compositions described herein. In some embodiments, the compounds can act as inhibitors of one or more kinases. In some embodiments, the compounds can act to stimulate the activity of one or more kinases. In further embodiments, the compounds of the invention can be used to modulate activity of a kinase in an individual in need of modulation of the receptor by administering a modulating amount of a compound as described herein. [088] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the DGKα and DGKζ enzyme with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having DGKα and DGKζ, as well as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing DGKα and DGKζ enzyme. [089] The term "DGKα and DGKζ inhibitor" refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and/or diacylglycerol kinase zeta (DGKα and DGKζ) in T cells resulting in T cell stimulation. The DGKα and DGKζ inhibitor may be a reversible or irreversible DGKα and DGKζ inhibitor. A "reversible DGKα and DGKζ inhibitor" is a compound that reversibly inhibits DGKα and DGKζ enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible DGKα and DGKζ inhibitor" is a compound that irreversibly destroys DGKα and DGKζ enzyme activity by forming a covalent bond with the enzyme. [090] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. [091] The compounds of Formula (I) can inhibit activity of diacylglycerol kinase alpha (DGKα) and/or diacylglycerol kinase zeta (DGKαζ). For example, the compounds of Formula (I) can be used to inhibit activity of DGKα and DGKζ in a cell or in an individual in need of modulation of DGKα and DGKζ by administering an inhibiting amount of a compound of Formula (I) or a salt thereof. [092] The compounds for Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful in treating or preventing any disease or condition associated with DGK target inhibition in T cells. These include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito- urinary infections, systemic infections), and proliferative diseases (e.g., cancer). [093] In some embodiments, are methods of inhibiting a kinase comprising contacting the kinase with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. In some embodiments the kinase is DGK. In some embodiments the kinase is DGKα. In some embodiments the kinase is DGKζ. [094] In some embodiments, are methods for treating a DGK dependent condition, comprising administering to a subject in need thereof, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. In some embodiments, the a DGK dependent condition is a DGKα dependent condition. In some embodiments, the a DGK dependent condition is a DGKζ dependent condition. In some embodiments the DGK dependent condition is an infection. In some embodiments the DGK dependent condition is a a viral infection. In some embodiments the DGK dependent condition is cancer. [095] In some embodiments are uses of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof in the manufacture of a medicament. [096] In some embodiments the medicament is for the treatment of cancer. In some embodiments the medicament is for the treatment of an autoimmune disease. [097] In some aspects, the invention provides a method of treating a patient suffering from or susceptible to a medical condition that is associated with DGK target inhibition in T cells. A number of medical conditions can be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound of Formula (l) and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof. For example, the compounds described herein may be used to treat or prevent viral infections and proliferative diseases such as cancer. [098] The present invention further provides methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of DGKα and DGKζ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of DGKα and DGKζ enzyme, such as over expression or abnormal activity. A DGKα and/or DGKζ associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGKα and DGKζ enzyme activity. Examples of DGKα and DGKζ associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C. [099] The compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) may be administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered orally. In other embodiments, the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered parenterally. [0100] Described herein are methods of treating a subject having a proliferative disorder or a viral infection comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof. [0101] Also described herein, are uses of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, for inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKζ). [0102] Also described herein, are uses of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, for treating a disease or disorder associated with the activity of DGKα or DGKζ, or both DGKα and DGKζ. [0103] Also described herein, are uses of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, for the treatment of proliferative disorders or viral infections. CANCER [0104] In some embodiments, the proliferative disorder is cancer. Thus, in some aspects, the invention provides methods of treating cancer associated with activity or expression, including abnormal activity and/or overexpression, of DGKα and DGKζ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof. [0105] Types of cancers that may be treated with the compound of Formula (I) include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma. [0106] In some embodiments, the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, cancer of the head and neck, lymphoma, leukemia, or melanoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is cancer of the head and neck. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is melanoma. [0107] Also described herein, are uses of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, for the treatment of proliferative disorders or viral infections. [0108] In some embodiments, the proliferative disorder is cancer. In some embodiments, the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma. [0109] Also described herein, are uses of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof, for the manufacture of a medicament. INFECTIONS [0110] In other aspects, the invention provides methods of treating infections associated with activity or expression, including abnormal activity and/or overexpression, of DGKα and DGKζ in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of Formula (I) or a pharmaceutical composition thereof. In some embodiemnts, the infections are viral infections. In some embodiemnts, the infections are chronic viral infections. [0111] Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CIVIV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV) Notably, parasitic infections (e.g., malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents. COMBINATION THERAPY [0112] One or more additional pharmaceutical agents or treatment methods such as, for example, anti- viral agents; chemotherapeutics, immuno-oncology agents, or other anti-cancer agents; immune enhancers; immunosuppressants; radiation; anti-tumor and anti-viral vaccines; cytokine therapy (e.g. IL2 and GM-CSF); and/or tyrosine kinase inhibitors can be optionally used in combination with the compounds of Formula (I) for treatment of DGKα and DGKζ associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. [0113] The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral mutes, intravenous mutes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-dmg treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-dmg treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. [0114] In some aspects, the present invention provides a combined preparation of a compound of Formula (I), and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof; and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple diseases or disorders associated with DGK target inhibition in T cells. [0115] In one aspect, T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4- 1BBL, ICOS, ICOS-L, OX40, OX40L, GITR. GITRL, CD70, CD27, CD40, DR3 and CD28H. COMBINATION WITH ANTI-CANCER AGENTS [0116] In another aspect, compounds of Formula (I) may be administered in combination with an anti- cancer agent. Anti-cancer agents include, for example, small molecule drugs, antibodies, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, tumor infiltrating lymphocytes, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. [0117] In one aspect the immuno-oncology agent is an agonist of a stimulatory (including a co- stimulatory) receptor; or an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators). Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co- inhibitory receptors is the B7 family, which includes B7-l, B7-2, B7-HI (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS- L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to costimulatory or coinhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEG1/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α 1β2, FAS, FASL, RELT, DR6, TROY, NGFR. [0118] Yet other agents for combination therapies for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, antagonists of KIR, such as lirilumab. [0119] Yet other agents for combination therapies for the treatment of cancer include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG-7155 or FPA-008. [0120] Yet other agents for combination therapies for the treatment of cancer include agonistic agents that ligate positive co-stimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment, e.g., block inhibitory receptor engagement, such as PD-L1/PD-1 interactions; deplete or inhibit Tregs, such as using an anti-CD25 monoclonal antibody (e.g., daclizumab); or by ex vivo anti-CD25 bead depletion; inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion; and agents that trigger innate immune activation and/or inflammation at tumor sites. [0121] Yet other agents for combination therapies for the treatment of cancer include tumor infiltrating lymphocytes. In one embodiment, the tumor infiltrating lymphocytes are transferred to a subject in need thereof through adoptive cell transfer. In one embodiment, the adoptive cell transfer to the subject in need thereof is of autologous T cells. In another embodiment, the adoptive cell transfer to the subject in need thereof is of allogeneic T cells. In one embodiment, the adoptive cell transfer to the subject in need thereof is of T cells expressing chimeric antigen receptors (CAR-T cells). In one embodiment, the other agents for combination therapies for the treatment of cancer are CAR-T cells, including, but not limited to, KYMRIAH (tisagenlecleucel), YESCARTA (axicabtagene ciloleucel), TECARTUS (brexucabtagene autoleucel), BREYANZI (lisocabtagene maraleucel), and ABECMA (idecabtagene vicleucel). [0122] Yet other agents for combination therapies for the treatment of cancer include CTLA-4 antagonists such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. [0123] Yet other agents for combination therapies for the treatment of cancer include PD-1 antagonists, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MEDI-0680 (AMP-514; WO2012/145493) or pidilizumab (CT-011). Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fe portion of IgG1, called AMP-224. [0124] Yet other agents for combination therapies for the treatment of cancer include PD-L1 antagonists, such as an antagonistic PD-L1 antibody Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010/077634), durvaluma (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174). [0125] Yet other agents for combination therapies for the treatment of cancer include LAG-3 antagonists, such as an antagonistic 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). [0126] Yet other agents for combination therapies for the treatment of cancer include CD137 (4-1BB) agonists, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433). [0127] Yet other agents for combination therapies for the treatment of cancer include GITR agonists 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). Yet other agents for combination therapies for the treatment of cancer include IDO antagonists. 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). [0128] Yet other agents for combination therapies for the treatment of cancer include OX40 agonists, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. [0129] Yet other agents for combination therapies for the treatment of cancer include OX40L antagonists, such as an antagonistic OX40L antibody Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879). [0130] Yet other agents for combination therapies for the treatment of cancer include CD40 agonists, such as an agonistic CD40 antibody. [0131] Yet other agents for combination therapies for the treatment of cancer include CD40 antagonists, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. [0132] Yet other agents for combination therapies for the treatment of cancer include CD27 agonists, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab. [0133] Yet other agents for combination therapies for the treatment of cancer include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, 5 chlormethine, cyclophosphamide (CYTOXAN), ifosfamide, melphalan, chlorambucil pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. Suitable chemotherapeutic or other anti-cancer agents further include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6- mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine. Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formcin, mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide, and teniposide. Suitable chemotherapeutic or other anti-cancer agents further include, for example, epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; haematopoietic growth factors; navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine; antibody therapeutics such as trastuzumab (HERCEPTIN), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF-β); and agents that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4. [0134] Yet other agents for combination therapies for the treatment of cancer include anti-cancer vaccines, including dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. [0135] Yet other agents for combination therapies for the treatment of cancer include signal transduction inhibitors (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis. Suitable STI's include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA, SSI-774) and antibodies (Imclone: C225 [Goldstein et al, Clin. Cancer Res, 1995, 1, 1311-1318; and Abgenix: ABX-EGF); (iii) her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L- 744,832 (Kohl et al, Nat. Med., 1995, 1(8), 792-797); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin; (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01; and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002. [0136] In the treatment of melanoma, suitable agents for use in combination with the compounds of Formula (I) include: dacarbazine (DTIC), optionally, along 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 YERVOYTM. Compounds of Formula (I) may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma. [0137] Compounds of Formula (I) may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells. [0138] Melanomas 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 isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects. COMBINATION WITH ANTI-VIRAL AGENTS Suitable antiviral agents contemplated for use in combination with the compound of Formula (I) include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTis), protease inhibitors and other antiviral drugs. [0139] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivaidine (3TC): abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS- 180194); BCH-I0652, emitricitabine [(-)- FTC]; beta-L-FD4 (also called beta-L-D4C and nan1ed beta-L-2',3'- dicleoxy-5-fluorocytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). [0140] Examples of suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721, AG-1549; MKC-442 (l-(ethoxy-methyl)-5- (]-methylethyl)-6- (phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. [0141] Examples of suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343): amprenavir (141W94); lasinavir (BMS-234475): DMP-450; BMS- 2322623, ABT-378; and AG-1549. [0142] Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. [0143] The present invention further provides pharmaceutical compositions comprising at least one compound of Formula (I), a pharmaceutically acceptable carrier, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent. ROUTES OF ADMINISTRATION [0144] The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intratarsal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. KITS [0145] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of DGKα and DGKζ associated diseases or disorders, and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. COMPOUND SYNTHESIS [0146] Compounds having the structure of Formulas (I) can be synthesized using standard synthetic techniques known to those of skill in the art. For example, compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in Scheme 1. [0147] Modifications to these methods will be apparent to one skilled in the art. To this end, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed. [0148] Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared. GENERAL SCHEME [0149] Compounds of formula (I) are generally prepared from aminomethyl oxathiane and 5-chloro-4-R1- 2-substituted pyridazinones, via either of two routes, as shown in scheme 1. Route 1 couples the oxathiane and pyridazinone first, followed by oxidation of the oxathiane; while route 2 oxidizes the oxathiane first and then couples with the pyridazinone. Preference for route 1 or route 2 will depend on, for example, the various chemical groups present in the specific compounds, availability of the starting materials, stability of starting material and intermediates, and the like, and will be apparent to those of skill in the art of chemical synthesis. Likewise, use and choice of protecting groups will be apparent to those of skill in the art. Scheme 1: General preparation of compounds of formula (I)
Figure imgf000044_0001
PREPARATION OF INTERMEDIATES I Oxathiane [0150] (1,4-oxathian-3-yl)methanamine may be prepared according to scheme 2. 2-(bromomethyl) oxirane and 2-chloroethan-1-ol are coupled to form 1-bromo-3-(2-chloroethoxy)propan-2-ol, which is cyclized in the presence of tBuOK to form 2-((2-chloroethoxy)methyl)oxirane. This is converted to the thiirane by treatment with thiourea, and then cyclized to the oxathiane in the presence of ammonium chloride. The chloro group is converted to the azide and reduced to the amine, to provide the intermediate (1,4-oxathian-3-yl)methanamine. Scheme 2: (1,4-oxathian-3-yl)methanamine
Figure imgf000044_0002
[0151] 3-(aminomethyl)-1,4-oxathiane 4,4-dioxide may be prepared according to scheme 3. (1,4- oxathian-3-yl)methanamine is treated with a suitable oxidizing agent, such as m-CPBA, using protecting groups (e.g. boc), as appropriate, to afford the sulfone. Scheme 3: 3-(aminomethyl)-1,4-oxathiane 4,4-dioxide II 5-chloro-4-R1-2-substituted pyridazinones
Figure imgf000045_0001
[0152] 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one may be prepared by coupling 4,5- dichloro-2-(4-oxocyclohexyl)pyridazin-3(2H)-one with an optionally substituted aniline, as shown in scheme 4. Scheme 4: 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one
Figure imgf000045_0002
[0153] 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one may be N- alkylated to introduce R3, by treatment with suitable reagents (e.g. R3 - boronic acid), as shown in scheme 5. Scheme 5: N-alkylation of 4,5-dichloro-2-(4-(phenylamino)cyclohexyl)pyridazin-3(2H)-one
Figure imgf000045_0003
[0154] 4,5-dichloro-2-(4-phenoxyphenyl)pyridazin-3(2H)-one may be prepared by coupling 4,5- dichloropyridazin-3(2H)-one with (4-phenoxyphenyl)boronic acid, as shown in scheme 6. Scheme 6: 4,5-dichloro-2-(4-phenoxyphenyl)pyridazin-3(2H)-one
Figure imgf000045_0004
SEPARATION OF ISOMERS [0155] Compounds of formula (I) comprise at least one chiral center. The synthetic routes described herein afford a racemic mixture of products which may be used as the racemate or separated as shown in scheme 7, using standard techniques, well known to those of skill in the art, such as chiral chromatography. Alternatively, the syntheses may be carried out using chiral starting materials to produce single isomers. Furthermore, other isomers may be present, such as, but not limited to cis- / trans- isomers or other chiral centers. Such compounds may also be used as mixtures or separated into individual compounds. Scheme 7: Separation of (R)- and (S)- isomers
Figure imgf000046_0001
EXAMPLES [0156] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. I Preparation of Synthetic Intermediates EXAMPLE 1 Synthesis of 4-oxathian-3-ylmethanamine hydrochloride STEP 1: 1-bromo-3-(2-chloroethoxy)propan-2-ol A solution of 2-chloroethanol (161 g, 2.00 mol) in DCM (60 mL) was cooled to -4 °C. While maintaining the temperature, BF3•Et2O (1 mL) and 2-(bromomethyl)oxirane (54.8 g, 400.1 mmol) were added sequentially over 35 mins. The resulting clear solution was stirred at 0 °C for 3 h and then gently warmed to rt. The solvent was removed under pressure to afford the title compound (80.0 g, 92%) as a light yellow oil. NMR (300 MHz, Chloroform-d) δ 4.00 (p, J = 5.3 Hz, 1H), 3.82-3.74 (m, 2H), 3.66 (qdd, J = 5.0, 3.2, 1.8 Hz, 4H), 3.59-3.44 (m, 2H), 2.83 (s, 1H) STEP 2: 2-(2-chloroethoxymethyl)oxirane A solution of 1-bromo-3-(2-chloroethoxy)propan-2-ol (80.0 g, 367.8 mmol) in THF (160 mL) was cooled to 0 °C and t-BuOK (1 M, 368 mL) was added dropwise. The mixture was then stirred for 1 h at 0 °C, warmed to rt and filtered. The filtrate was concentrated, dissolved in ether (500 mL), washed with water (200 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound (20.0 g, 40%) as a colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 4.06-3.96 (m, 1H), 3.84-3.77 (m, 2H), 3.73-3.63 (m, 4H), 3.50-3.40 (m, 2H) STEP 3: 2-(2-chloroethoxymethyl)thiirane A solution of 2-(2-chloroethoxymethyl)oxirane (10.0 g, 73.2 mmol) and thiourea (11.0 g, 146.4 mmol) in methanol (250 mL) with molecular sieves (4Å, 7 g) was heated to 70 °C for 30 min. The mixture was then cooled to rt, concentrated, dissolved in ether (300 mL), filtered and the filtrate evaporated onto silica gel and purified by column chromatography to yield the title compound (7.0 g, 56%) as a colorless oil. GCMS (EI, m/z): 152.0, 154.0 STEP 4: 3-(azidomethyl)-1,4-oxathiane 2-(2-chloroethoxymethyl)thiirane (7.0 g, 49.8 mmol), sodium azide (9.7 g, 149.3 mmol) and ammonium chloride (7.9 g, 149.3 mmol) in methanol (100 mL) was heated for 3 h at 70 °C. The mixture was then cooled to rt, filtered and the filtrate concentrated under reduced pressure. Water (200 mL) was added, and the aqueous layer extracted with ether (2 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound (1.4 g, 16%) as a yellow oil. NMR (400 MHz, DMSO-d6) δ 3.88 (dd, J = 11.9, 2.8 Hz, 1H), 3.81-3.76 (m, 2H), 3.74-3.52 (m, 4H), 2.92- 2.75 (m, 2H) STEP 5: 1,4-oxathian-3-ylmethanamine A solution of 3-(azidomethyl)-1,4-oxathiane (1.4 g, 8.8 mmol) and triphenylphosphine (6.9 g, 26.4 mmol) in THF (10 mL) and water (2 mL) was stirred for 16 h at rt. The mixture was then concentrated to afford 1,4-oxathian-3-ylmethanamine (2.0 g, crude) as a yellow solid which was used without further purification. LCMS (ES, m/z): 134.2 [M+H]+ STEP 6: tert-butyl N-(1,4-oxathian-3-ylmethyl)carbamate A solution of tert-butoxycarbonyl tert-butyl carbonate (3.28 g, 15.01 mmol), 1,4-oxathian-3- ylmethanamine (2.0 g) and TEA (2.2 g, 22.52 mmol) in DCM (20 mL) was stirred for 16 h at rt. The mixture was then concentrated onto silica gel and purified by column chromatography to afford the title compound (1.5 g, 73%, two steps) as a yellow oil LCMS (ES, m/z): 178.2 [M+H-Bu]+ STEP 7: 1,4-oxathian-3-ylmethanamine hydrochloride A solution of tert-butyl N-(1,4-oxathian-3-ylmethyl)carbamate (1.5 g, 6.43 mmol) and HCl (4 M in ethyl acetate, 16.1 mL) in ethyl acetate (20 mL) was stirred for 2 h at rt. The mixture was then concentrated to afford the title compound (1 g, 83%) as an off-white solid. LCMS (ES, m/z): 134.0 [M-HCl +H]+ EXAMPLE 2 Synthesis of (4,4-dioxo-1,4-oxathian-3-yl)methanamine hydrochloride
Figure imgf000048_0001
STEP 1: tert-butyl N-[(4,4-dioxo-1,4-oxathian-3-yl)methyl]carbamate A solution of tert-butyl N-(1,4-oxathian-3-ylmethyl)carbamate (9.00 g, 38.5 mmol), m-CPBA (13.3 g, 77.1 mmol) in DCM (50 mL) was stirred for 1 h at rt. The mixture was quenched with NH4Cl (satd, aq, 50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound as a white solid (9.0 g). LCMS (ES, m/z): 266.1 [M+H]+ STEP 2: (4,4-dioxo-1,4-oxathian-3-yl)methanamine hydrochloride A mixture of tert-butyl N-[(4,4-dioxo-1,4-oxathian-3-yl)methyl]carbamate (9.00 g, 33.9 mmol) and HCl (4 M in ethyl acetate, 84.8 mL) in ethyl acetate (40 mL) was stirred for 2 h at rt. The reaction was concentrated to afford the title compound (6.30 g, 92%) as a white solid. LCMS (ES, m/z): 166.1 [M-HCl+H]+ EXAMPLE 3 Synthesis of 4-chloro-5-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-2-(4-piperidyl)pyridazin-3-one hydrochloride
Figure imgf000049_0001
STEP 1: tert-butyl 4-[5-chloro-4-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-6-oxo-pyridazin-1- yl]piperidine-1-carboxylate A solution of (4,4-dioxo-1,4-oxathian-3-yl)methanamine hydrochloride (1.13 g, 5.60 mmol), tert-butyl 4- (4,5-dichloro-6-oxo-pyridazin-1-yl)piperidine-1-carboxylate (1.50 g, 4.31 mmol) and DIEA (1.67 g, 12.9 mmol) in n-BuOH (20 mL) was heated to 100 °C for 48 h, whereupon it was cooled to rt and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to afford the title compound as a light-yellow solid (1.1 g, 54%). LCMS (ES, m/z): 477.2, 479.20 [M+H]+ STEP 2: 4-chloro-5-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-2-(piperidin-4-yl)pyridazin-3(2H)-one hydrochloride To a solution of tert-butyl 4-[5-chloro-4-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-6-oxo-pyridazin-1- yl]piperidine-1-carboxylate (1.1 g, 2.31 mmol) in ethyl acetate (10 mL) were added HCl (4M in ethyl acetate, 3.0 mL). The resulting solution was stirred for 2 h at rt, whereupon it was concentrated under reduced pressure to afford the title compound as a white solid (900 mg, 94%). LCMS (ES, m/z): 377.1, 379.1 [M-HCl+H]+ EXAMPLE 4 Synthesis of 4,5-dichloro-2-[4-(4-fluorophenoxy)phenyl]pyridazin-3-one
Figure imgf000050_0001
Cu(OAc)2 (2.5 g, 13.8 mmol) was added to a solution of 4,5-dichloro-1H-pyridazin-6-one (760 mg, 4.61 mmol), [4-(4-fluorophenoxy)phenyl]boronic acid (1.6 g, 6.91 mmol), and pyridine (1.1 g, 13.8 mmol) in DCM (20 mL) and the mixture stirred under oxygen atmosphere. After 16 h, the solution was filtered through a pad of celite, diluted with water and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, concentrated and purified by column chromatography to afford the title compound (600 mg, 32%) as a yellow solid. LCMS (ES, m/z): 350.9, 352.9[M+H]+ EXAMPLE 5 Synthesis of Cis-4-[cyclopropyl-[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile
Figure imgf000050_0002
STEP 1: cis-4-[[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile; and trans-4-[[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile Acetic acid (1.3 mL) was added to a solution of 4,5-dichloro-2-(4-oxocyclohexyl)pyridazin-3-one (3.0 g, 11.5 mmol) and 4-aminobenzonitrile (1.63 g, 13.8 mmol) in DCM (55 mL) and stirred for 0.5 h at 0 °C. STAB (7.31 g, 34.5 mmol) was then added and the mixture was then warmed to rt. After 4 h it was diluted with NaHCO3 (satd, aq, 60 mL) and extracted with DCM (3 x 60 mL). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford: cis-4-[[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile (670 mg, 15%) and trans-4-[[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile (620 mg, 14%) as a yellow oil. LCMS (ES, m/z): 363.05, 362.05 [M+H]+ STEP 2: Cis-4-[cyclopropyl-[4-(4,5-dichloro-6-oxo-pyridazin-1-yl)cyclohexyl]amino]benzonitrile Sodium cyanoborohydride (224.9 mg, 3.58 mmol) was added to a solution of cis-4-[[4-(4,5-dichloro-6-oxo- pyridazin-1-yl)cyclohexyl]amino]benzonitrile (650 mg, 1.79 mmol) and (1-ethoxy cyclopropoxy)-trimethyl- silane (935.77 mg, 5.37 mmol) in acetic acid (7 mL). After heating for 2 h at 50 °C, the mixture was cooled to rt, quenched with NaHCO3 (satd, aq, 30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound (320 mg, 38%) as a light-yellow solid. LCMS (ES, m/z): 403.15, 405.15 [M+H]+. II Preparation of Compounds of Formula (I), wherein X is S EXAMPLE 6 Synthesis of 4-(((1s,4s)-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin- 1(6H)-yl)cyclohexyl)(cyclopropyl)amino)benzonitrile (compound 6)
Figure imgf000051_0001
TEA (210.8 mg, 2.08 mmol) was added to a solution of cis-4-[cyclopropyl-[4-(4,5-dichloro-6-oxo-pyridazin- 1-yl)cyclohexyl]amino]benzonitrile (280 mg, 694.27 μmol) and 1,4-oxathian-3-ylmethanamine hydrochloride (235.60 mg, 1.39 mmol) in ethanol (3 mL). After heating at 80 °C for 24 h, it was cooled to rt, concentrated in vacuo and purified by reverse phase column chromatography to afford the title compound (150 mg38%) as a yellow solid. LCMS (ES, m/z): 500.2, 502.2 [M+H]+ EXAMPLE 7 Synthesis of 4-(4-(((1,4-oxathian-3-yl)methyl)amino)-5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-cyano-2- fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide
Figure imgf000052_0001
A solution of N-(4-cyano-2-fluoro-phenyl)-4-(4,5-dichloro-6-oxo-pyridazin-1-yl)-N- (difluoromethyl)piperidine-1-sulfonamide (670 mg, 1.35 mmol), 1,4-oxathian-3-ylmethanamine (458 mg, 2.70 mmol) and DIPEA (546 mg, 5.40 mmol) in ethanol (4 mL) was heated at 80 °C for 24 h. The mixture was cooled to rt and purified directly by reverse flash chromatography to afford the title compound (600 mg, 70%) as a yellow solid. LCMS (ES, m/z): 593.0, 594.0 [M+H]+ EXAMPLE 8 Synthesis of (4-chloro-2-[4-(4-fluorophenoxy)phenyl]-5-[[(3S)-1,4-oxathian-3-yl]methylamino] pyridazin-3-one (Compound 8A)
Figure imgf000052_0002
4-chloro-2-[4-(4-fluorophenoxy)phenyl]-5-[[(3R)-1,4-oxathian-3-yl]methylamino] pyridazin-3-one (Compound 8B)
Figure imgf000052_0003
A solution of of 1,4-oxathian-3-ylmethanamine (483 mg, 2.85 mmol), 4,5-dichloro-2-[4-(4- fluorophenoxy)phenyl]pyridazin-3-one hydrochloride (500 mg, 1.42 mmol) and TEA (720 mg, 7.12 mmol) in ethanol (10 mL) was heated for 16 h at 80 °C. The mixture was cooled to rt, concentrated and purified by reverse flash chromatography to afford the racemate, which was further separated by chiral-prep-HPLC. 4-chloro-2-[4-(4-fluorophenoxy)phenyl]-5-[[(3S)-1,4-oxathian-3-yl]methylamino]pyridazin-3-one (compound 8A, 32.8 mg, 5.1%) as an off-white solid. NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.27 (t, J = 8.7 Hz, 2H), 7.17 -7.12(m, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.95 (t, J = 6.4 Hz, 1H), 4.00-3.66 (m, 5H), 3.61-3.51 (m, 1H), 2.92-2.85 (m, 1H), 2.50-2.46 (m, 2H) LCMS (ES, m/z): 448.1, 450.1 [M+H]+ 4-chloro-2-[4-(4-fluorophenoxy)phenyl]-5-[[(3R)-1,4-oxathian-3-yl]methylamino]pyridazin-3-one (compound 8B, 30.6 mg, 4.7%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.55-7.44 (m, 2H), 7.30-7.23 (m, 2H), 7.27-7.10 (m, 2H), 7.10- 7.00 (m, 2H), 6.95 (t, J = 6.4 Hz, 1H), 3.95-3.94 (m, 1H), 3.91-3.66 (m, 4H), 3.61-3.51 (m, 1H), 2.94-2.84 (m, 2H), 2.50-2.44 (m, 1H) LCMS (ES, m/z):448.1, 450.1 [M+H]+ III Preparation of Compounds of Formula (I), wherein X is S=O EXAMPLE 9 Synthesis of 4-chloro-2-(4-(4-fluorophenoxy)phenyl)-5-((((3R,4S)-4-oxido-1,4-oxathian-3-yl)methyl)amino)pyridazin- 3(2H)-one (compound 9A) 4-chloro-2-(4-(4-fluorophenoxy)phenyl)-5-((((3R,4R)-4-oxido-1,4-oxathian-3- yl)methyl)amino)pyridazin-3(2H)-one (compound 9B)
Figure imgf000054_0001
4-chloro-2-(4-(4-fluorophenoxy)phenyl)-5-((((3S,4S)-4-oxido-1,4-oxathian-3-yl)methyl)amino)pyridazin- 3(2H)-one (compound 9C)
Figure imgf000054_0002
4-chloro-2-(4-(4-fluorophenoxy)phenyl)-5-((((3S,4R)-4-oxido-1,4-oxathian-3-yl)methyl)amino)pyridazin- 3(2H)-one (compound 9D)
Figure imgf000054_0003
A mixture of 5-(((1,4-oxathian-3-yl)methyl)amino)-4-chloro-2-(4-(4-fluorophenoxy)phenyl) pyridazin- 3(2H)-one (240 mg, 536 μmol) and m-chloroperoxybenzoic acid (102 mg, 589 μmol) in DCM (5 mL) was stirred for 2 h at 0 °C, whereupon the solvent was removed in vacuo and the crude residue was purified by reverse flash chromatography to afford a mixture of products (200 mg). The mixture of diastereomers was further purified by chiral-prep-HPLC to afford: (compound 9A, 36.7 mg, 15%) as a white solid. (compound 9B, 2.2 mg, 1%) as a white solid.
Figure imgf000055_0001
8.14 (s, 1H), 7.56-7.42 (m, 2H), 7.35-7.24 (m, 2H), 7.19-7.13 (m, 2H), 7.10- 7.00 (m, 3H), 4.26-3.98 (m, 2H), 3.83-3.68 (m, 3H), 3.61 (dd, J = 13.0, 5.7 Hz, 1H), 3.32-3.27 (m, 1H), 2.98 (br s, 1H), 2.75 (dd, J = 13.7, 5.1 Hz, 1H). LCMS (ES, m/z): 464.1 [M+H]+ (compound 9C, 11.5 mg, 5%) as a white solid. (compound 9D, 20.9 mg, 8%) as a white solid. EXAMPLE 10 Compounds 10A, 10B, 10C and 10D were prepared according to similar procedures as described above and according to the scheme below.
Figure imgf000055_0002
4-(5-chloro-4-((((3R)-4-oxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano-2- fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 10A)
Figure imgf000055_0003
1H NMR (400 MHz, DMSO-d6) δ 8.23-8.07 (m, 1H), 8.02 (s, 1H), 7.96-7.80 (m, 2H), 7.49 (t, J = 59.2 Hz, 1H), 6.90 (t, J = 6.2 Hz, 1H), 5.02-4.92 (m, 1H), 4.17-3.97 (m, 1H), 3.90-3.66 (m, 5H), 3.66-3.48 (m, 1H), 3.45- 3.35 (m, 1H), 3.21-3.08 (m, 3H), 2.97-2.80 (m, 2H), 1.91-1.71 (m, 4H). (ES, m/z): 609.1, 611.2 [M+H]+ 4-(5-chloro-4-((((3R,4S)-4-oxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano- 2-fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 10B)
Figure imgf000056_0001
1H NMR (400 MHz, DMSO-d6) δ 8.23 - 8.10 (m, 1H), 8.04 (s, 1H), 7.91-7.79 (m, 2H), 7.49 (t, J = 59.2 Hz, 1H), 6.88 (t, J = 6.3 Hz, 1H), 5.01 - 4.88 (m, 1H), 4.24-4.02 (m, 2H), 3.83 - 3.63 (m, 5H), 3.63 - 3.50 (m, 1H), 3.32 - 3.28 (m, 1H), 3.20-3.03 (m, 2H), 3.00-2.90 (m, 1H), 2.77-2.69 (m, 1H), 1.91-1.71 (m, 4H). (ES, m/z): 609.1, 611.2 [M+H]+ 4-(5-chloro-4-((((3S,4R)-4-oxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano- 2-fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 10C)
Figure imgf000056_0002
(m, 2H), 7.49 (t, J = 59.3 Hz, 1H), 6.88 (t, J = 6.3 Hz, 1H), 5.09-4.82 (m, 1H), 4.26-4.03 (m, 2H), 3.83-3.67 (m, 5H), 3.65-3.49 (m, 1H), 3.33- 3.27 (m, 1H), 3.21-3.02 (m, 2H), 3.00-2.87 (m, 1H), 2.81-2.67 (m, 1H), 1.91-1.72 (m, 4H). (ES, m/z): 609.1, 611.2 [M+H]+ 4-(5-chloro-4-((((3S,4S)-4-oxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano- 2-fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 10D) , . . , , . , , . . (m, 2H), 7.49 (t, J = 59.2 Hz, 1H), 6.90 (t, J = 6.2 Hz, 1H), 5.07-4.85 (m, 1H), 4.16-3.93 (m, 1H), 3.91-3.61 (m, 5H), 3.61-3.47 (m, 1H), 3.45- 3.34 (m, 1H), 3.23-3.07 (m, 3H), 3.01-2.80 (m, 2H), 1.98-1.76 (m, 4H). (ES, m/z): 609.1, 611.2 [M+H]+ IV Preparation of Compounds of Formula (I), wherein X is S(=O)2 EXAMPLE 11 Sy thesis of 4-((cis-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)- yl)cyclohexyl)(cyclopropyl)amino)benzonitrile (compound 11)
Figure imgf000057_0001
Potassium peroxomonosulfate (oxone, 552.5 mg, 900 μmol) was added to 4-((cis-4-(4-(((1,4-oxathian-3- yl)methyl)amino)-5-chloro-6-oxopyridazin-1(6H)-yl)cyclohexyl)(cyclopropyl)amino)benzonitrile (150 mg, 300 μmol) in water (2 mL) and methanol (6 mL). After stirring for 2 h, it was concentrated and purified by reverse phase column chromatography to yield the title compound (2.2 mg, 1.4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.78-6.60 (m, 1H), 4.90-4.79 (m, 1H), 4.24-3.94 (m, 3H), 3.93-3.64 (m, 4H), 3.49-3.40 (m, 3H), 2.49-2.42 (m, 1H), 2.39- 2.23 (m, 2H), 2.13-1.98 (m, 2H), 1.98-1.81 (m, 2H), 1.72-1.60 (m, 2H), 0.96-0.86 (m, 2H), 0.63-0.47 (m, 2H) LCMS (ES, m/z): 532.1, 534.1 [M+H]+ EXAMPLE 12 Synthesis of (R)-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano- 2-fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 12A) and (S)-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano- 2-fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 12B)
Figure imgf000058_0001
3-chlorobenzenecarboperoxoic acid (157 mg, 910 μmol) was added to a solution of 4-[5-chloro-4-(1,4- oxathian-3-ylmethylamino)-6-oxo-pyridazin-1-yl]-N-(4-cyano-2-fluoro-phenyl)-N- (difluoromethyl)piperidine-1-sulfonamide (270 mg, 455 μmol) in DCM (2 mL) and the resulting mixture stirred for 2 h at 25 °C, then concentrated and purified by prep-HPLC to afford the racemate, which was separated by chiral-rep-HPLC to afford: (R)-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano-2- fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (compound 12A, 57.0 mg, 20%) as a white solid.
Figure imgf000058_0002
8.12 (m, 1H), 7.99 (s, 1H), 7.92-7.83 (m, 2H), 7.70-7.28 (m, 1H), 6.77- 6.69 (m, 1H), 5.01-4.91 (m, 1H), 4.10-3.97 (m, 3H), 3.91-3.77 (m, 2H), 3.77-3.64 (m, 3H), 3.52-3.41 (m, 2H), 3.32-3.24 (m, 1H), 3.19-3.08 (m, 2H), 1.89-1.77 (m, 4H) LCMS (ES, m/z): 625.1, 636.1 [M+H]+ and (S)-4-(5-chloro-4-(((4,4-dioxido-1,4-oxathian-3-yl)methyl)amino)-6-oxopyridazin-1(6H)-yl)-N-(4-cyano-2- fluorophenyl)-N-(difluoromethyl)piperidine-1-sulfonamide (60 mg), which was further purified by prep- HPLC (compound 12B, 45.7 mg, 16%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 9.5 Hz, 1H), 7.98 (s, 1H), 7.92-7.83 (m, 2H), 7.63-7.34 (m, 1H), 6.74-6.69 (m,1H), 4.97-4.93(m, 1H), 4.09-4.03 (m, 1H), 4.01-3.97 (m,2H), 3.89-3.77 (m, 2H), 3.75-3.64 (m, 3H), 3.52-3.43 (m, 2H), 3.32-3.24 (m,1H), 3.21-3.10 (m,2H), 1.90-1.78 (m,4H) LCMS (ES, m/z): 625.1, 626.1 [M+H]+ EXAMPLE 13 Synthesis of cis-4-chloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]-5-[[(3R)-4,4-dioxo-1,4-oxathian- 3-yl]methylamino]pyridazin-3-one (compound 13A)
Figure imgf000059_0001
cis-4-chloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]-5-[[(3S)-4,4-dioxo-1,4-oxathian- 3-yl]methylamino]pyridazin-3-one (compound 13B)
Figure imgf000059_0002
STEP 1: 1-(fluoromethoxy)-4-nitro-benzene 4-nitrophenol (3.00 g, 21.5 mmol), fluoroiodomethane (6.9 g, 43.1 mmol) and potassium hydroxide (17.9 g, 43.1 mmol) in acetonitrile (30 mL)/water (10 mL) were stirred at rt for 3 h. The mixture was then extracted with DCM (3 x 50 mL) and the combined organic extracts were washed with brine (150 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound as a light-yellow solid (1.7 g, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.39-8.21 (m, 2H), 7.40-7.30 (m, 2H), 6.02 (d, J = 53.1 Hz, 2H) STEP 2: 4-(fluoromethoxy)aniline 1-(fluoromethoxy)-4-nitro-benzene (1.60 g, 9.35 mmol) and Pd/C (10%, 1.60 g) in ethanol (25 mL) were stirred for 1 h at rt under a hydrogen atmosphere. The solids were removed by filtration and the filtrate concentrated to afford the title compound as a yellow oil (1.2 g, 89% ). LCMS (ES, m/z): 142.1 [M+H]+ STEP 3: cis-4,5-dichloro-2-[4-[4-(fluoromethoxy)anilino]cyclohexyl]pyridazin-3-one and trans-4,5-dichloro- 2-[4-[4-(fluoromethoxy)anilino]cyclohexyl]pyridazin-3-one Acetic acid (827 mg, 13.7 mmol) was added to 4,5-dichloro-2-(4-oxocyclohexyl)pyridazin-3-one (1.20 g, 4.60 mmol), 4-(fluoromethoxy)aniline (648 mg, 4.60 mmol) in DCM (30 mL) and the resulting mixture stirred for 0.5 h. STAB (5.67 g, 13.7 mmol) was then added in portions and the mixture stirred for 2 h at rt, then poured into NaHCO3 (satd, aq, 30 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by column chromatography to afford the title compound as a yellow solid (1.4 g, 78%) LCMS (ES, m/z): 386.0, 388.0 [M+H]+ STEP 4: cis-4,5-dichloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]pyridazin-3-one A solution of cis-4,5-dichloro-2-[4-[4-(fluoromethoxy)anilino]cyclohexyl]pyridazin-3-one (700 mg, 1.81 mmol), (1-ethoxycyclopropoxy)-trimethyl-silane (947 mg, 5.44 mmol) and sodium cyanoborohydride (227 mg, 3.62 mmol) in acetic acid (7 mL) was heated for 1 h at 50 °C. The mixture was cooled to rt, poured into NaHCO3 (satd, aq, 20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4, concentrated and purified by column chromatography to yield the title compound as a yellow solid (370 mg, 47%). LCMS (ES, m/z): 426.1, 428.1 [M+H]+ STEP 5: cis-4-chloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]-5-[[(3R)-4,4-dioxo-1,4- oxathian-3-yl]methylamino]pyridazin-3-one (13A); and cis-4-chloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]-5-[[(3S)-4,4-dioxo-1,4-oxathian-3- yl]methylamino]pyridazin-3-one (13B) A solution of cis-4,5-dichloro-2-[4-[N-cyclopropyl-4-(fluoromethoxy)anilino]cyclohexyl]pyridazin-3-one (600 mg, 1.41 mmol), (4,4-dioxo-1,4-oxathian-3-yl)methanamine hydrochloride (851 mg, 4.22 mmol) and TEA (996 mg, 9.85 mmol) in ethanol (3 mL) was heated at 80 °C for 20 h. The mixture was cooled to rt, concentrated in vacuo and purified by reverse phase column chromatography to afford the racemate. The racemate was further purified by chiral prep HPLC to afford two products: Compound 13A (34.1 mg, 4.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.11-6.96 (m, 4H), 6.67 (t, J = 6.4 Hz, 1H), 5.85 (s, 1H), 5.72 (s, 1H), 4.84-4.72 (m, 1H), 4.11-3.93 (m, 3H), 3.90-3.61 (m, 3H), 3.54-3.42 (m, 2H), 3.41-3.34 (m, 2H), 2.36- 2.21 (m, 1H), 2.15-1.96 (m, 4H), 1.68-1.48 (m, 4H), 0.70-0.54 (m, 2H), 0.40-0.29 (m, 2H) LCMS (ES, m/z): 555.2, 557.2 [M+H]+ Compound 13B (21.6 mg, 2.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.11-7.02 (m, 2H), 7.01-6.96 (m, 2H), 6.67 (t, J = 6.4 Hz, 1H), 5.85 (s, 1H), 5.72 (s, 1H), 4.84-4.72 (m, 1H), 4.11-4.03 (m, 1H), 4.00 (t, J = 5.2 Hz, 2H), 3.90-3.77 (m, 2H), 3.76-3.61 (m, 1H), 3.54-3.42 (m, 2H), 3.41-3.36 (m, 1H), 3.31-3.26 (m, 1H), 2.36-2.21 (m, 1H), 2.15-1.96 (m, 4H), 1.68-1.48 (m, 4H), 0.70-00.54 (m, 2H), 0.40-0.29 (m, 2H) LCMS (ES, m/z): 555.2, 557.2 [M+H]+ EXAMPLE 14 Synthesis of 4-chloro-2-((1r,4R)-4-(cyclopropyl(4-(hydroxymethyl)phenyl)amino)cyclohexyl)-5-((((R)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)pyridazin-3(2H)-one (compound 14A)
Figure imgf000062_0001
4-chloro-2-((1r,4S)-4-(cyclopropyl(4-(hydroxymethyl)phenyl)amino)cyclohexyl)-5-((((S)-4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)pyridazin-3(2H)-one (compound 14B)
Figure imgf000062_0002
STEP 1: Cis-4,5-dichloro-2-[4-[4-[[1,1-dimethylethyl(dimethyl)silyl]oxymethyl]anilino]cyclohexyl] pyridazin-3-one; and trans-4,5-dichloro-2-[4-[4-[[1,1-dimethylethyl(dimethyl)silyl]oxymethyl]anilino]cyclohexyl] pyridazin-3- one 4,5-dichloro-2-(4-oxocyclohexyl)pyridazin-3-one (7.00 g, 26.8 mmol), 4-[[tert-butyl(dimethyl) silyl]oxymethyl]aniline (6.36 g, 26.8 mmol) and acetic acid (1 mL) in DCM (40 mL) were stirred for 0.5 h. STAB (33.0 g, 80.4 mmol) was then added and the mixture was stirred for 1 h, whereupon it was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated onto silica gel and purified by column chromatography. The first eluting isomer afforded the cis-diastereomer as a yellow solid (5.1 g, 35%). The second eluting isomer afforded trans-diastereomer as a yellow solid (3.2 g, 22%). LCMS (ES, m/z): 482.2, 484.2 [M+H]+ STEP 2: Trans-4,5-dichloro-2-[4-[N-cyclopropyl-4-[[1,1-dimethylethyl(dimethyl)silyl]oxymethyl] anilino]cyclohexyl]pyridazin-3-one trans-4,5-dichloro-2-[4-[4-[[1,1-dimethylethyl(dimethyl)silyl]oxymethyl]anilino] cyclohexyl] pyridazin-3- one (3.20 g, 6.63 mmol), cyclopropylboronic acid (1.14 g, 13.2 mmol), copper acetate (1.20 g, 6.63 mmol), 2-(2-pyridyl)pyridine (1.04 g, 6.63 mmol) and sodium carbonate (1.41 g, 13.2 mmol) in DCE (60 mL) were heated to 70 °C for 2 h under an oxygen atmosphere. The mixture was cooled to rt then partitioned between water (50 mL) and DCM (3 x 40 mL). The combined organic extracts were washed with brine (1 x 40 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound as a yellow solid (1.8 g, 47%). LCMS (ES, m/z): 522.3, 524.3 [M+H]+ STEP 3: Trans-4-chloro-2-[4-[N-cyclopropyl-4-[[1,1-dimethylethyl(dimethyl)silyl]oxymethyl] anilino]cyclohexyl]-5-[[(3R)-4,4-dioxo-1,4-oxathian-3-yl]methylamino]pyridazin-3-one trans-4,5-dichloro-2-[4-[N-cyclopropyl-4-[[1,1-dimethylethyl(dimethyl)silyl] oxymethyl] anilino]cyclohexyl]pyridazin-3-one (1.60 g, 3.06 mmol), (4,4-dioxo-1,4-oxathian-3-yl)methanamine hydrochloride (1.24 g, 6.12 mmol) and TEA (1.24 g, 12.2 mmol) in ethanol (15 mL) were heated to 80 °C for 3 h. The resulting solution was cooled to rt, concentrated and purified by reverse phase column chromatography to afford the title compound as a yellow solid (870 mg, 39%). LCMS (ES, m/z): 651.4, 653.4 [M+H]+ STEP 4: 4-chloro-2-[4-[N-cyclopropyl-4-(hydroxymethyl)anilino]cyclohexyl]-5-[[(3R)-4,4-dioxo-1,4- oxathian-3-yl]methylamino]pyridazin-3-one (14A); and 4-chloro-2-[4-[N-cyclopropyl-4-(hydroxymethyl)anilino]cyclohexyl]-5-[[(3S)-4,4-dioxo-1,4-oxathian-3- yl]methylamino]pyridazin-3-one (14B) To a solution of trans-4-chloro-2-[4-[N-cyclopropyl-4-[[1,1-dimethylethyl(dimethyl) silyl]oxymethyl]anilino]cyclohexyl]-5-[[(3R)-4,4-dioxo-1,4-oxathian-3-yl]methylamino]pyridazin-3-one (860 mg, 1.32 mmol) in THF (4.70 mL) was added TBAF (1 M in THF, 6.60 mL) portion-wise. The resulting solution was stirred for 1 h, concentrated onto silica gel and purified by column chromatography to afford the racemate which was separated by chiral prep-HPLC to afford: Compound 14A (27.3 mg, 27%) as white solid . 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.67 (t, J = 6.4 Hz, 1H), 4.92 (t, J = 5.7 Hz, 1H), 4.78-4.67 (m, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.10-3.95 (m, 3H), 3.88-3.76 (m, 2H), 3.68 (dt, J = 14.8, 7.4 Hz, 1H), 3.48-3.40 (m, 3H), 3.30-3.28 (m, 1H), 2.35 (t, J = 5.0 Hz, 1H), 1.88-1.69 (m, 8H), 0.86-0.76 (m, 2H), 0.41-0.30 (m, 2H) LCMS (ES, m/z): 537.2, 539.2 [M+H]+ Compound 14B (27.7 mg, 28%) as a white solid . NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.67 (t, J = 6.4 Hz, 1H), 4.92 (t, J = 5.7 Hz, 1H), 4.78-4.67 (m, 1H), 4.37 (d, J = 5.7 Hz, 2H), 4.10-3.95 (m, 3H), 3.88-3.76 (m, 2H), 3.68 (dt, J = 14.8, 7.4 Hz, 1H), 3.48-3.40 (m, 3H), 3.30-3.28 (m, 1H), 2.35 (t, J = 5.0 Hz, 1H), 1.88-1.69 (m, 8H), 0.86-0.76 (m, 2H), 0.41-0.30 (m, 2H). LCMS (ES, m/z): 537.25, 539.20 [M+H]+ EXAMPLE 15 Synthesis of 4-chloro-5-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-2-[1-[4-(oxetan-3- yl)phenyl]sulfonyl-4-piperidyl]pyridazin-3-one (compound 15)
Figure imgf000065_0001
STEP 1: 2-[1-(4-bromophenyl)sulfonyl-4-piperidyl]-4-chloro-5-[(4,4-dioxo-1,4-oxathian-3- yl)methylamino]pyridazin-3-one A solution of 4-chloro-5-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-2-(4-piperidyl)pyridazin-3-one hydrochloride (900 mg, 2.18 mmol), 4-bromobenzenesulfonyl chloride (834 mg, 3.27 mmol) and N,N- diethylethanamine (661 mg, 6.53 mmol) in ACN (5 mL) was heated to 80 °C for 0.5 h. The reaction was then cooled to rt and quenched with water (5 mL). The solid was collected by filtration and dried in a vacuum oven to give the title compound as a light-yellow solid (800 mg, 62%). LCMS (ES, m/z): 594.9, 596.9, 598.9 [M+H]+ STEP 2: 4-chloro-5-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-2-[1-[4-(oxetan-3-yl)phenyl]sulfonyl-4- piperidyl]pyridazin-3-one 2-[1-(4-bromophenyl)sulfonyl-4-piperidyl]-4-chloro-5-[(4,4-dioxo-1,4-oxathian-3- yl)methylamino]pyridazin-3-one (400 mg, 671 μmol), 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2- dioxaborolane (494 mg, 2.68 mmol), Pd(dppf)Cl2•CH2Cl2 (49.1 mg, 67.1 μmol) and potassium carbonate (185 mg, 1.34 mmol) in dioxane (5 mL)/water (0.5 mL) were heated to 100 °C for 3 h. The mixture was cooled to rt, concentrated, purified by prep TLC and further separated by Achiral SFC to afford the title compound as a white solid (13.8 mg, 3.5%). 11H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 6.71 (t, J = 6.5 Hz, 1H), 4.99 (dd, J = 8.3, 6.0 Hz, 2H), 4.72– 4.63 (m, 3H), 4.48-4.34 (m, 1H), 4.12-3.95 (m, 3H), 3.90- 3.63 (m, 5H), 3.51-3.44 (m, 2H), 3.33-3.27 (m, 1H), 2.49-2.41 (m, 2H), 1.89-1.79 (m, 4H) LCMS (ES, m/z): 573.1, 575.1 [M+H]+ EXAMPLE 16 Synthesis of (R)-4-chloro-2-(1-((5-(difluoromethoxy)pyridin-2-yl)sulfonyl)piperidin-4-yl)-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)pyridazin-3(2H)-one (compound 16A)
Figure imgf000066_0001
(S)-4-chloro-2-(1-((5-(difluoromethoxy)pyridin-2-yl)sulfonyl)piperidin-4-yl)-5-(((4,4-dioxido-1,4- oxathian-3-yl)methyl)amino)pyridazin-3(2H)-one (compound 16B)
Figure imgf000066_0002
STEP 1: 2-bromo-5-(difluoromethoxy)pyridine A mixture of 6-bromopyridin-3-ol (6.00 g, 34.5 mmol), sodium 2-chloro-2,2-difluoroacetate (10 g, 65.6 mmol) and cesium carbonate (16.0 g, 49.1 mmol) in DMF (60 mL) was heated to 80 °C for 3 h. The mixture was cooled to rt and filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound as a yellow oil (3.3 g, 43%). LCMS (ES, m/z): 224.0, 226.0 [M+H]+ STEP 2: 2-benzylsulfanyl-5-(difluoromethoxy)pyridine 2-bromo-5-(difluoromethoxy)pyridine (3.20 g, 14.3 mmol), BnSH (1.77 g, 14.3 mmol), Pd2(dba)3 (657 mg, 717 μmol), XantPhos (830 mg, 1.43 mmol) and DIPEA (3.70 g, 28.6 mmol) in toluene (30 mL) were heated to 110 °C for 16 h. The mixture was cooled to rt and partitioned between water (100 mL) and ethyl acetate (2 x 100 mL). The organic extracts were dried over Na2SO4, concentrated onto silica gel and purified by column chromatography to afford the title compound as a light-yellow oil (3.1 g, 81%). LCMS (ES, m/z): 268.2 [M+H]+ STEP 3: 5-(difluoromethoxy)pyridine-2-sulfonyl chloride NCS (401 mg, 3.00 mmol) was added to a mixture of 2-benzylsulfanyl-5-(difluoromethoxy) pyridine (0.20 g, 748 μmol) in acetic acid (3 mL)/water (1 mL). The resulting mixture was stirred for 1 h, diluted with saturated NaHCO3 (satd, aq, 100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by column chromatography to afford the title compound (160 mg, 88%). LCMS (ES, m/z): 244.0, 246.0 [M+H]+ STEP 4: 4-chloro-2-[1-[[5-(difluoromethoxy)-2-pyridyl]sulfonyl]-4-piperidyl]-5-[[(3R)-4,4-dioxo-1,4- oxathian-3-yl]methylamino]pyridazin-3-one; and 4-chloro-2-[1-[[5-(difluoromethoxy)-2-pyridyl]sulfonyl]-4-piperidyl]-5-[[(3S)-4,4-dioxo-1,4-oxathian-3- yl]methylamino]pyridazin-3-one TEA (97 mg, 958 μmol) was added to 4-chloro-5-[(4,4-dioxo-1,4-oxathian-3-yl)methylamino]-2-(4- piperidyl)pyridazin-3-one hydrochloride (0.08 g, 193 μmol) and 5-(difluoromethoxy)pyridine-2-sulfonyl chloride (140 mg, 574 μmol) in acetonitrile (8 mL). After stirring for 2 h, the mixture was concentrated, purified by reverse flash chromatography and separated by chiral prep-HPLC to afford: Compound 16A (21.4 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.7 Hz, 1H), 8.04 (dd, J = 8.7, 0.6 Hz, 1H), 7.98-7.92 (m, 2H), 7.50 (t, J = 72.6 Hz, 1H), 6.71 (t, J = 6.4 Hz, 1H), 4.82-4.74 (m, J 1H), 4.12-3.96 (m, 3H), 3.90-3.78 (m, J 4H), 3.70 (dt, J = 14.8, 7.4 Hz, 1H), 3.53-3.42 (m, 2H), 3.31-3.28 (m, J 1H), 2.94-2.83 (m, 2H), 1.89-1.74 (m, J 4H) LCMS (ES, m/z): 584.1, 586.1 [M+H]+ Compound 16B (19 mg, 17%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.97-7.93 (m, 2H), 7.50 (t, J = 72.6 Hz, 1H), 6.71 (t, J = 6.4 Hz, 1H), 4.82-4.74 (m, 1H)J , 4.12-3.97 (m, 3H), 3.88-3.77 (m, 4H), 3.70 (dt, J = 14.7, 7.3 Hz, 1H), 3.53-3.42 (m, J 2H), 3.31-3.29 (m, 1H), 2.93-2.83 (m, 2H), 1.89-1.74 (m, J 4H) LCMS (ES, m/z): 584.1, 586.1 [M+H]+ EXAMPLES 17 - 57 Compounds 17 - 57, were prepared according to the methods and procedures described herein. 1H NMR: 3300MHz; 4400MHz; MS = LCSM [M+1]+
Figure imgf000068_0001
Figure imgf000069_0001
Eg Structure MS 1H NMR 24 25 26 27 28 29 30
Figure imgf000070_0001
Eg Structure MS 1H NMR (4DMSO-d6) δ 7.95 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 9.3 Hz, 2H), 6.71 (t, J = 6.2 Hz, 1H), 4.85-4.75 (m, 1H), 4.12-4.05 31 651.1 (m, 1H), 4.03-3.95 (m, 2H), 3.83-3.65 (m, 8H), 3.65-3.48 (m, 4H), 3.36-3.22 (m, 3H), 3.20-3.10 (m, 1H), 1.96-1.65 (m, 8H). (4Methanol-d4) δ 8.04 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.24- 32 635.2 4.07 (m, 3H), 4.05-3.92 (m, 2H), 3.89-3.61 (m, 8H), 3.53-3.34 (m, 5H), 3.30-3.20 (m, 2H), 2.08-1.93 (m, 6H), 1.90-1.77 (m, 2H). (4Methanol-d4) δ 8.04 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.24- 33 635.2 4.07 (m, 3H), 4.05-3.97 (m, 2H), 3.89-3.55 (m, 8H), 3.53-3.34 (m, 5H), 3.30-3.20 (m, 2H), 2.08-1.93 (m, 6H), 1.90-1.77 (m, 2H). (3DMSO-d6) δ 7.95 (s, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 9.3 Hz, 2H), 6.72-6.65 34 651.2 (m, 1H), 4.85-4.75 (m, 1H), 4.20-3.95 (m, 3H), 3.85-3.44 (m, 13H), 3.29-3.12 (m, 3H), 2.00-1.58 (m, 8H). (3DMSO-d6) δ 7.96 (s, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.99-6.93 (m, 2H), 6.77 (t, J = 6.1 Hz, 1H), 4.86-4.73 (m, 1H), 4.50-4.38 (m, 1H), 4.10-3.96 (m, 35 502.1 3H), 3.89-3.78 (m, 2H), 3.75-3.62 (m, 1H), 3.52-3.42 (m, 2H), 3.33-3.25 (m,1H), 2.21- 2.08 (m, 2H), 1.95-1.74 (m, 4H), 1.61-1.45 (m, 2H). (3DMSO-d6) δ 7.96 (s, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 6.77 (t, J = 6.3 Hz, 1H), 4.86- 4.73 (m, 1H), 4.50-4.38 (m, 1H), 4.10-3.96 36 502.1 (m, 3H), 3.89-3.78 (m, 2H), 3.75-3.62 (m, 1H), 3.52-3.42 (m, 2H), 3.33-3.25 (m,1H), 2.21-2.08 (m, 2H), 1.95-1.74 (m, 4H), 1.61- 1.45 (m, 2H). Eg Structure MS 1H NMR δ 7.96 , 7.51 J = 7.8 37 38 39 40
Figure imgf000072_0001
1.70 (m, 4H), 1.65-1.51 (m, 2H). (4DMSO-d6) δ 8.14 (d, J = 3.2 Hz, 1H), 7.97 41 42
Figure imgf000072_0002
, , 1.52 (m, 2H). Eg Structure MS 1H NMR (4DMSO-d6) δ 8.02 (d, J = 2.5 Hz, 1H), 7.97
Figure imgf000073_0001
Eg Structure MS 1H NMR (3DMSO-d6) δ 7.95 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.71 (t, J = 6.3 Hz, 1H), 4.79 (p, J = 5.2 Hz, 1H), 4.17- 49 562.0 3.91 (m, 6H), 3.87-3.79 (m, 4H), 3.75-3.65 (m,1H), 3.54-3.41 (m, 2H), 3.33-3.27 (m, 1H), 2.95-2.75 (m, 2H), 2.46 (s, 3H), 1.87- 1.75 (m, 4H). (3DMSO-d6) δ 7.95 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.71 (t, J = 6.3 Hz, 1H), 4.79 (p, J = 5.9 Hz, 1H), 4.17- 50 562.1 3.91 (m, 6H), 3.87-3.79 (m, 4H), 3.75-3.65 (m,1H), 3.54-3.41 (m, 2H), 3.33-3.27 (m, 1H), 2.95-2.75 (m, 2H), 2.46 (s, 3H), 1.87- 1.75 (m, 4H). (3DMSO-d6) δ 8.70 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.2, 2.3 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 6.3 Hz, 1H), 51 560.1 4.85-4.71 (m, 1H), 4.07-3.96 (m, 3H), 3.87- 3.63 (m, 5H), 3.48-3.42 (m, 2H), 3.33-3.25 (m, 1H), 3.10-3.05 (m, 1H), 2.91-2.84 (m, 2H), 1.79 (br s, 4H), 1.28-1.26 (m, 6H). (3DMSO-d6) δ 8.70 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.2, 2.3 Hz, 1H), 7.95 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 6.74-6.69 (m, 1H), 4.85- 52 560.1 4.71 (m, 1H), 4.07-3.96 (m, 3H), 3.87-3.63 (m, 5H), 3.48-3.42 (m, 2H), 3.33-3.25 (m, 1H), 3.10-3.05 (m, 1H), 2.91-2.84 (m, 2H), 1.79 (br s, 4H), 1.28-1.26 (m, 6H). (3DMSO-d6) δ 7.98 (s, 1H), 7.52-7.35 (m, 4H), 7.35-7.19 (m, 1H), 6.81-6.65 (m, 1H), 4.42-4.25 (m, 1H), 4.18-3.93 (m, 3H), 3.92- 53 572.1 3.75 (m, 2H), 3.75-3.60 (m, 3H), 3.54-3.41 (m, 2H), 3.30-3.20 (m, 1H), 3.20-3.08 (m, 1H), 3.08-2.94 (m, 2H), 1.82-1.67 (m, 4H), 0.88-0.70 (m, 2H), 0.65-0.51 (m, 2H). (3DMSO-d6) δ 7.98 (s, 1H), 7.46-7.35 (m, 4H), 7.34-7.20 (m, 1H), 6.78-6.64 (m, 1H), 4.95-4.70 (m, 1H), 4.19-3.92 (m, 3H), 3.91- 3.76 (m, 2H), 3.76-3.58 (m, 3H), 3.55-3.48 54 572.1 (m, 2H), 3.32-3.22 (m, 1H), 3.20-3.08 (m, 1H), 3.08-2.92 (m, 2H), 1.84-1.60 (m, 4H), 0.79 (td, J = 7.1, 4.9 Hz, 2H), 0.68-0.48 (m, 2H). Eg Structure MS 1H NMR
Figure imgf000075_0001
, . IV BIOLOGICAL ASSAYS EXAMPLE 58 DGKα and DGKζ biochemical assays Compounds of the present invention were prepared into 10 mM DMSO solution and 10 nL of stock was transferred into 384 plates (Optiplate 384 plate) using Echo550. DMSO was used as high control, and ATP substrate buffer was used as a low control. A 1x enzyme assay buffer was prepared (Hepes, pH 7.025mM, BSA 0.05%, Triton-X1000.002%,CaCl21μM, MgCl210mM, DTT 2mM). The enzyme assay was performed by diluting enzyme DGKα (1μg/μL DGKα, Carna12-101, SEQ ID NO: 3) or DGKζ (1μ/μL DGKζ, Carna 12-110, SEQ ID NO: 4) using 1X assay buffer. OAG (1-oleoyl-2-acetyl-sn-glycerol, 25mg/ml, Avanti 800100O) and PS (10 mg/ml, Avanti 840032P) were mixed at the ratio of 1:2. A 1X substrate solution was prepared with 1X assay buffer by 100-fold dilution. The substrate solution was sonicated on ice for 1 min. The pure ATP was added to the substrate solution (DGKa:400 μM).5 μL of the enzyme solution were added to the 384 well plate, and the plate was spun for 1 min at 1000 rpm and incubated for 30 mins at RT.5 μL of 1X substrate solution were added to the 384 well plate, the plate was spun and then incubated for 45 mins at RT.10 μL ADP-Glo detergent was added to stop the assay. After 60 mins at RT, 20 μL ADP-Glo Detection buffer was added as the final step. Plate was read after 45min incubation at RT. Data analysis was performed by calculating the % Inhibition using following the formula: ^^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ % ^^ ^^ℎ ^^ ^^ ^^ ^^ ^^ ^^ ^^ = .100 ^^ ^^ − ^^ ^^ High control (Hc): DMSO/DGKα(DGKζ)/Substrate/ATP/ADP-Glo Low Control (Lc): ATP/ADP-Glo The activity of the compounds of the invention are presented according to the following ranges: "A" denotes an IC50 of less than 10nM; "B" denotes an IC50 of from 10 nM to less than 100 nM; "C" denotes an IC50 of from 100 nM to less than 1000 nM; and "D" denotes an IC50 of 1000 nM or more. IC50 (nM) Compound
Figure imgf000076_0001
8A 8B 9A 9B 9C 9D 10A 10B 10C 10D 11 D C 12A D D 12B D B 13A D D 13B D B 14A D D 14B D C D DA D CB D B D B D D D C D D D C D D D C D D D B D B D C D B D B D D D D D B D B D D D B D D D B D D D C D D D C D D D B 45 D B 46 D B 47 D D 48 D C 49 D D 50 D D 51 D B 52 D D 53 D C 54 D B 55 D A 56 D D 57 D B [0157] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. [0158] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure. [0159] This application claims the benefit of priority to U.S. Application No.63/476,909, filed December 22, 2022, which application is hereby incorporated by reference in its entirety.

Claims

CLAIMS 1. A compound having the structure of Formula (I):
Figure imgf000079_0001
Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:
Figure imgf000079_0002
a 6-membered aromatic or non-aromatic cycle, wherein Y is N, C or CH; X is -S-, -S(=O)- or -S(=O)2-; R1 is F, Cl or Br; L is -CH2-, -O-, -NR3- or -S(=O)n-L’-; wherein R3 is -H, -C1-5 alkyl, -C3-6 cycloalkyl, -CH2-C3-6 cycloalkyl or -CH2-C3-6 heterocycloalkyl; L’ is a bond, -N(C1-5 alkyl)-, -N(C1-5 haloalkyl)- or -N(C3-6 cycloalkyl)-; and n is 0, 1 or 2; and R2 is a 3–10 membered carbocycle or a 3–10 membered heterocycle, substituted with 0, 1 or 2 substituents independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein
Figure imgf000079_0003
3. The compound of claim 1, having the structure of Formula (I-A), Formula (I-B) or Formula (I-C): Formula (I-C) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
4. The compound of claim 1, having the structure of Formula (I-A-1), Formula (I-A-2) or Formula (I-A- ,
Figure imgf000080_0001
Formula (I-A-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
5. The compound of claim 1, having the structure of Formula (I-B-1), Formula (I-B-2) or Formula (I-B- 3): ,
Figure imgf000081_0001
Formula (I-B-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
6. The compound of claim 3, having the structure of Formula (I-C-1), Formula (I-C-2) or Formula (I-C- ,
Figure imgf000081_0002
Formula (I-C-3) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
7. The compound of claim 1, having the structure of Formula (I-D-1) or Formula (I-D-2):
Figure imgf000082_0001
, , Formula (I-D-1) Formula (I-D-2) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is F.
9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is Cl.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-.
11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -NR3-.
12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -S(=O)n-L’-.
13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -S(=O)2-L’- and L’ is a bond.
14. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -S(=O)2-N(C1-5 alkyl)-, -S(=O)2-N(C1-5 haloalkyl)- or -S(=O)2-N(C3-6 cycloalkyl)-.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 is a 5- or 6-membered carbocycle .
16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 is a 5- or 6-membered heterocycle .
17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 cyclohexyl, phenyl or pyridyl.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 is unsubstituted.
19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 is substituted with one substituent selected from, halo, - CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy.
20. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, tautomer, racemate, or isotope thereof, wherein R2 is substituted with two substituents each independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy.
21. A compound having a structure listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
22. A pharmaceutical composition comprising a compound having the structure of Formula (I):
Figure imgf000084_0001
Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate or isotope thereof, wherein:
Figure imgf000084_0002
a 6-membered aromatic or non-aromatic cycle, wherein Y is N, C or CH; X is -S-, -S(=O)- or -S(=O)2-; R1 is F, Cl or Br; L is -CH2-, -O-, -NR3- or -S(=O)n-L’-; wherein R3 is -H, -C1-5 alkyl, -C3-6 cycloalkyl, -CH2-C3-6 cycloalkyl or -CH2-C3-6 heterocycloalkyl; L’ is a bond, -N(C1-5 alkyl)-, -N(C1-5 haloalkyl)- or -N(C3-6 cycloalkyl)-; and n is 0, 1 or 2; and R2 is a 3–10 membered carbocycle or a 3–10 membered heterocycle, substituted with 0, 1 or 2 substituents independently selected from, halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxy, C1-4 haloalkyl or C1-4 haloalkoxy.
23. A pharmaceutical composition comprising a compound of any one of claims 1–21, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof.
24. The pharmaceutical composition of claim 22 or 23, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.
25. A pharmaceutical composition comprising: an anti-cancer agent; and a therapeutically effective amount of a compound having the structure of Formula (I).
26. A pharmaceutical composition comprising: an anti-cancer agent; and a therapeutically effective amount of the compound any one of claims 1–21.
27. The pharmaceutical composition of claim 25 or 26, wherein the anti-cancer is a biologic immune- oncology agent.
28. The pharmaceutical composition of claim 27, wherein the biologic immune-oncology agent is a cancer vaccine, an antibody, a tumor infiltrating lymphocyte, or a cytokine.
29. A method for inhibiting the activity of at least one diacylglycerol kinase comprising contacting the diacylglycerol kinase with a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or composition thereof.
30. A method for inhibiting the activity of at least one diacylglycerol kinase comprising contacting the diacylglycerol kinase with a compound of any one of claims 1–21.
31. The method of claim 29 or 30, wherein the diacylglycerol kinase is diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGKζ).
32. A method of treating a subject having a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I).
33. A method of treating a subject having a disease or disorder associated with the activity of DGKα, DGKζ, or both DGKα and DGKζ comprising administering to the subject in need thereof a therapeutically effective amount of the compound any one of claims 1–21.
34. A method of treating a subject having a proliferative disorder or a viral infection comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the structure of Formula (I).
35. A method of treating a subject having a proliferative disorder or a viral infection comprising administering to the subject in need thereof a therapeutically effective amount of the compound any one of claims 1–21.
36. The method of claim 34 or 35, wherein the proliferative disorder is cancer.
37. The method of claim 36, wherein the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, or melanoma.
38. A method of treating a subject having a proliferative disorder comprising administering to the subject in need thereof: a therapeutically effective amount of an anti-cancer agent; and a therapeutically effective amount of a compound having the structure of Formula (I).
39. A method of treating a subject having a proliferative disorder comprising administering to the subject in need thereof a therapeutically effective amount of an anti-cancer agent; and a therapeutically effective amount of the compound any one of claims 1–21.
40. The method of claim 38 or 39, wherein the proliferative disorder is cancer.
41. The method of claim 40, wherein the cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia, or melanoma.
42. The method of any one of claims 38–41, wherein the anti-cancer agent is a biologic immune- oncology agent.
43. The method of claim 42, wherein the biologic immune-oncology agent is a cancer vaccine, an antibody, a tumor infiltrating lymphocyte, or a cytokine.
44. Use of a compound having the structure of Formula (I), for inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKζ).
45. Use of a compound according to any one of claims 1–21, for inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKa) and diacylglycerol kinase zeta (DGKζ).
46. Use of a compound having the structure of Formula (I), for treating a disease or disorder associated with the activity of DGKα or DGKζ, or both DGKα and DGKζ.
47. Use of a compound according to any one of claims 1–21, for treating a disease or disorder associated with the activity of DGKα or DGKζ, or both DGKα and DGKζ.
48. Use of a compound having the structure of Formula (I), for the treatment of proliferative disorders or viral infections.
49. Use of a compound according to any one of claims 1–21, for the treatment of proliferative disorders or viral infections.
50. The use of claim 48 or 49, wherein the proliferative disorder is cancer.
51. The use of claim 50, wherein said cancer is cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.
52. Use of a compound having the structure of Formula (I), for the manufacture of a medicament.
53. Use of a compound according to any one of claims 1–21, for the manufacture of a medicament.
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Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029879A2 (en) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anti-ox40l antibodies
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
WO2006122150A1 (en) 2005-05-10 2006-11-16 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007075598A2 (en) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008036653A2 (en) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008036642A2 (en) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2009009116A2 (en) 2007-07-12 2009-01-15 Tolerx, Inc. Combination therapies employing gitr binding molecules
WO2009044273A2 (en) 2007-10-05 2009-04-09 Immutep Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response
WO2009073620A2 (en) 2007-11-30 2009-06-11 Newlink Genetics Ido inhibitors
WO2009156652A1 (en) 2008-05-29 2009-12-30 Saint-Gobain Centre De Recherches Et D'etudes Europeen Cellular structure containing aluminium titanate
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
WO2011056652A1 (en) 2009-10-28 2011-05-12 Newlink Genetics Imidazole derivatives as ido inhibitors
WO2012032433A1 (en) 2010-09-09 2012-03-15 Pfizer Inc. 4-1bb binding molecules
WO2012142237A1 (en) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2017210685A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Pyradazinone derivatives and the compositions and methods of treatment regarding the same
WO2021105115A1 (en) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation
WO2021133750A1 (en) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted bicyclic piperidine derivatives useful as t cell activators
WO2023122778A1 (en) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029879A2 (en) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anti-ox40l antibodies
WO2006105021A2 (en) 2005-03-25 2006-10-05 Tolerrx, Inc. Gitr binding molecules and uses therefor
WO2006122150A1 (en) 2005-05-10 2006-11-16 Incyte Corporation Modulators of indoleamine 2,3-dioxygenase and methods of using the same
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007075598A2 (en) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008036653A2 (en) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008036642A2 (en) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008132601A1 (en) 2007-04-30 2008-11-06 Immutep Cytotoxic anti-lag-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
WO2009009116A2 (en) 2007-07-12 2009-01-15 Tolerx, Inc. Combination therapies employing gitr binding molecules
WO2009044273A2 (en) 2007-10-05 2009-04-09 Immutep Use of recombinant lag-3 or the derivatives thereof for eliciting monocyte immune response
WO2009073620A2 (en) 2007-11-30 2009-06-11 Newlink Genetics Ido inhibitors
WO2009156652A1 (en) 2008-05-29 2009-12-30 Saint-Gobain Centre De Recherches Et D'etudes Europeen Cellular structure containing aluminium titanate
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
WO2011056652A1 (en) 2009-10-28 2011-05-12 Newlink Genetics Imidazole derivatives as ido inhibitors
WO2012032433A1 (en) 2010-09-09 2012-03-15 Pfizer Inc. 4-1bb binding molecules
WO2012142237A1 (en) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
WO2012145493A1 (en) 2011-04-20 2012-10-26 Amplimmune, Inc. Antibodies and other molecules that bind b7-h1 and pd-1
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2017210685A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Pyradazinone derivatives and the compositions and methods of treatment regarding the same
WO2021105115A1 (en) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Substituted aminoquinolones as dgkalpha inhibitors for immune activation
WO2021133750A1 (en) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted bicyclic piperidine derivatives useful as t cell activators
WO2023122778A1 (en) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPENCOTT WILLIAMS & WILKINS
"The United States Pharmacopeia: The National Formulary", 2013, JOHN WILEY AND SONS, INC
AVILA-FLORES ET AL., IMMUNOLOGY AND CELL BIOLOGY, vol. 95, 2017, pages 549 - 563
FACCIABENE ET AL., CANCER RES, vol. 72, 2012, pages 2162 - 71
GOLDSTEIN ET AL., CLIN. CANCER RES, vol. 1, 1995, pages 1311 - 1318
JING ET AL., CANCER RESEARCH, vol. 77, 2017, pages 5676 - 5686
KOHL ET AL., NAT. MED., vol. 1, no. 8, 1995, pages 792 - 797
KRISHNA ET AL., FRONT IMMUNOLOGY, vol. 4, 2013, pages 178
LIT ET AL.: "Salt Selection for Basic Drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
MELLMAN ET AL., NATURE, vol. 480, 2011, pages 480 - 489
MIZOGUCHI ET AL., SCIENCE, vol. 258, 1992, pages 1795 - 98
NOESSNER, FRONT CELL DEV BIOL., vol. 5, 2017, pages 16
PETER G. M. WUTSTHEODORA W. GREEN: "Protecting Groups in Organic Synthesis", 2006, WILEY-INTERSCIENCE
PRINZ ET AL., J IMMUNOLOGY, vol. 12, 2012, pages 5990 - 6000
RIESE ET AL., FRONT CELL DEV BIOL., vol. 4, 2016, pages 130
RIESE ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 7, 2011, pages 5254 - 5265
SJOBLOM ET AL., SCIENCE, vol. 314, 2006, pages 268 - 74
TOPALIAN ET AL., CURR. OPIN. IMMUNOL., vol. 24, 2012, pages 1 - 6
ZHA ET AL., NATURE IMMUNOLOGY, vol. 12, 2006, pages 1343

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