WO2023122772A1 - Dérivés d'oxime utiles comme activateurs de lymphocytes t - Google Patents

Dérivés d'oxime utiles comme activateurs de lymphocytes t Download PDF

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Publication number
WO2023122772A1
WO2023122772A1 PCT/US2022/082307 US2022082307W WO2023122772A1 WO 2023122772 A1 WO2023122772 A1 WO 2023122772A1 US 2022082307 W US2022082307 W US 2022082307W WO 2023122772 A1 WO2023122772 A1 WO 2023122772A1
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compound
pharmaceutically acceptable
isomer
hydrate
solvate
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PCT/US2022/082307
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English (en)
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Anthony David CASAREZ
Craig Alan COBURN
Martin W. Rowbottom
Thomas Aicher
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Gossamer Bio Services, Inc.
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Publication of WO2023122772A1 publication Critical patent/WO2023122772A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention generally relates to compounds that activate T cells, promote T cell proliferation, and/or exhibit antitumor activity.
  • aniline compounds Provided herein are aniline 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.
  • 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.
  • 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 DGKa or DGK ⁇ which show a hyper- responsive T cell phenotype and improved anti-tumor immune activity (Riese et a/, Journal of Biological Chemistry, 2011, 7, 5254-5265; Zha et al, Nature Immunology, 2006, 12, 1343).
  • DGKa and DGK ⁇ are viewed as targets for cancer immunotherapy (Riese et al, Front Cell Dev Biol., 2016, 4, 108; Chen et al.
  • 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 TGFp, would be significant for the treatment of patients with proliferative disorders, such as cancer, as well as viral infections.
  • the present invention fullfils these and other needs as for fully provided in the following disclosure.
  • Described herein are compounds that have activity as inhibitors of one or both of DGKa and DGK ⁇ . Further, the compounds that have activity as inhibitors of one or both of DGKa and DGKrJ 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.
  • a compound having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof, wherein:
  • X 1 is N or CH
  • X 2 is N or CR 2 ;
  • Ar is phenyl or pyridyl
  • R 3 is -L-R 5
  • R 2 is -H or ⁇ CN
  • R 3 is tert-butyl, cyclopropyl, or -CHF?
  • R 4 is -H or -CH 3 ;
  • L is a bond or ⁇ (CH2)n-
  • R 5 is -H, -F, -Ci-4 alkyl, -NH-C(-Gi-G-R 6 .. -O-C(-O)-NH-R 5 f or an optionally substituted heterocycloalkyl;
  • R 6 is H, Ci-4alkyl, or Ci ⁇ haloalkyl; n is 1, 2, or 3.
  • compositions comprising a carrier or excipient and a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof.
  • DGKa diacylglycerol kinase alpha
  • DGK ⁇ J diacylglycerol kinase zeta
  • the diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGKQ dependent condition is a proliferative disorder or a viral infection.
  • the methods of treating the diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGKQ dependent condition condition comprise administering an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof.
  • methods for treating a proliferative disorder or a viral infection, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition, comprising a carrier or excipient and a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof.
  • compounds are provided having one or more of the structures disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof.
  • compounds are provided that have activity as inhibitors of one or both of DGKa and DGKL Further, the compounds that have activity as inhibitors of one or both of DGKa and DGK ⁇ and have selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases.
  • about 100 pL means 95-105 pl. 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.
  • 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.
  • branched lower alkyl groups include, but are not limited to, isopropyl, /so-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • Alkenyl groups include straight and branched chain 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.
  • 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., -CH 2 CH 2 CH 2 -), and butylene (i.e., ⁇ CH 2 CH 2 CH 2 CH 2 ⁇ ).
  • 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., ”0“ 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.
  • Carbocycle refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity.
  • carbocycle includes cycloalkyl as defined above.
  • carbocycle includes aryl as defined above.
  • Cycloalkyl refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloal kyl 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.
  • Representative substituted cycloalkyl groups can be mono-substituted 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, 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).
  • 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 nonaromatic 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 G-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.
  • Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups.
  • a heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring members.
  • a heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely- saturated cyclic group including at least one ring heteroatom.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
  • heterocyclyl includes heteroaryl
  • Heteroaryl refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazo
  • 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.
  • Heterocycles I kyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle.
  • heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like.
  • Halo or "halogen” refers to fluorine, chlorine, bromine and iodine.
  • Halo refers to -OH.
  • Haloaikyi refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloaikyi groups include, but are not limited to, “CFs, -CH2CF3, 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.
  • Hydroalkyl 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.
  • 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 ⁇ -OR a , ⁇ NR a R b , ⁇ S(0)2R a or -S(0)20R a , halogen, cyano, alkyl, haloaikyi, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R 3 and R b is, independently, H, alkyl, haloaikyi, 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 particular form is meant to indicate an assumed stereochemistry or isomeric form unless it is specifically indicated that the particular stereochemistry or isomeric form has been definitively determined.
  • 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.
  • 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 ("zusammeri', 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”).
  • 1,4-disubstitued cyclohexanes may exist as cis and trans isomers. 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. Assignment of cis or trans is illustrated in the figure below.
  • 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%.
  • 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 Sight 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.
  • a solvent other that water for example, methanol or ethanol can form an “alcoholate", which can again be stoichiometric or non-stoichiometric.
  • 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.
  • Isotope refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of structure (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.
  • 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.
  • an isotope of a compound having the structure (I) includes, but not limited to, compounds of structure (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.
  • acids in their anionic form and cations
  • 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, I nt. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).
  • 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.
  • 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
  • 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.
  • 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 compounds are tautomers.
  • a "tautomer” refers to a proton shift from one atom of molecule to another atom of the same molecule.
  • the compounds presented herein may exist as tautomers.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements, where tautomerization is possible, a chemical equilibrium of the tautomers will exist.
  • compounds of structure (I) may include tautomers.
  • the present disclosure provides compounds compound having activity as inhibitors of one or both of DGKa and DGK ⁇ . Accordingly, one embodiment provides a compound having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof, wherein:
  • X 1 is N or CH
  • X 2 is N or CR 2 ;
  • Ar is phenyl or pyridyl
  • R 3 is -L-R 5
  • R 2 is -H or ⁇ CN
  • R 3 is tert-butyl, cyclopropyl, or -CHF?
  • R 4 is -H or “CH3;
  • L is a bond or -(CHzJrr-
  • R 6 is H, C ⁇ alkyl, or Ci ⁇ haloalkyl; n is 1, 2, or 3.
  • R 6 is
  • R 2 is H.
  • R 2 is -CN.
  • Representative compounds having the structure of Formula (I), include, but are not limited to, any one of the compounds listed in Table 1 below, or pharmaceutically acceptable salt, solvate, hydrate, isomer, or isotope thereof.
  • representative compounds are identified herein by their respective “Compound Number”, or “Example Number” which is sometimes abbreviated as “Compound No.”, “Cmpd. No.”, “No.”, “Example No.”, “Eg. No.”, or “Ex”, and the like.
  • compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof.
  • the 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 which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound 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, in some such embodiments, 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. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • 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 noninflammatory 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, suspending or dispersing agents, sweeteners, or waters of hydration.
  • 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, suspending 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.
  • 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, isotope, or composition thereof.
  • the diacylglycerol kinase is diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGK0-
  • DGKa diacylglycerol kinase alpha
  • DGK0 diacylglycerol kinase zeta
  • methods of treating a subject having a disease or disorder associated with the activity of DGKa, DGK ⁇ , or both DGKa and DGK ⁇ are disclosed, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, 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:
  • 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 DGKa, DGKij, or both DGKa 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 structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, 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.
  • an 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.
  • 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 DGKa and/or DGKij 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.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the DGKa and DGK ⁇ enzyme with a compound of Structure (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having DGKa and DGK ⁇ , as well as, for example, introducing a compound of structure (I) into a sample containing a cellular or purified preparation containing DGKa and DGK ⁇ enzyme.
  • DGKa and DGKC inhibitor refers to an agent capable of inhibiting the activity of diacylglycerol kinase alpha and/or diacylglycerol kinase zeta (DGKa and DGKiQ in T cells resulting in T cell stimulation.
  • the DGKa and DGK ⁇ inhibitor may be a reversible or irreversible DGKa and DGK ⁇ inhibitor.
  • a “reversible DGKa and DGK ⁇ inhibitor” is a compound that reversibly inhibits DGKa and DGK ⁇ enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible DGKa and DGK£ inhibitor” is a compound that irreversibly destroys DGKa and DGK/J enzyme activity by forming a covalent bond with the enzyme.
  • 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 structure (I) can inhibit activity of diacylglycerol kinase alpha (DGKa) and/or diacylglycerol kinase zeta (DGKaQ.
  • DGKa diacylglycerol kinase alpha
  • DGKaQ diacylglycerol kinase zeta
  • the compounds of structure (I) can be used to inhibit activity of DGKa and DGK ⁇ in a cell or in an individual in need of modulation of DGKa and DGKC by administering an inhibiting amount of a compound of structure (I) or a salt thereof.
  • the compounds of structure (I) and pharmaceutical compositions comprising at least one compound of structure (I) are useful in treating or preventing any disease or condition associated with DGK target inhibition in T cells.
  • diseases or condition associated with DGK target inhibition in T cells include viral and other infections (e.g., skin infections, Gl infection, urinary tract infections, genito- urinary infections, systemic infections), and proliferative diseases (e.g., cancer).
  • a kinase comprising contacting the kinase with an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof, or composition thereof, for the treatment of proliferative disorders or viral infections.
  • the kinase is DGK. In some embodiments the kinase is DGKa. In some embodiments the kinase is DGKC
  • DGK dependent condition is a DGKa dependent condition.
  • DGK dependent condition is a DGK ⁇ dependent condition.
  • the DGK dependent condition is an infection.
  • the DGK dependent condition is a viral infection.
  • the DGK dependent condition is cancer.
  • [112] are uses of a compound of structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, isotope, or pharmaceutical composition thereof in the manufacture of a medicament.
  • the medicament is for the treatment of cancer. In some embodiments the medicament is for the treatment of an autoimmune disease.
  • 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 structure (I) 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 DGKa and DGKC 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 Structure (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 DGKa and DGKij enzyme, such as over expression or abnormal activity.
  • a DGKa and/or DGK ⁇ associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating DGKa and DGK ⁇ enzyme activity.
  • Examples of DGKa and DGK ⁇ associated diseases include cancer and viral infections such as HIV infection, hepatitis B, and hepatitis C.
  • the compounds of structure (I) and pharmaceutical compositions comprising at least one compound of structure (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 structure (I) or pharmaceutical composition comprising at least one compound of structure (I) is administered orally. In other embodiments, the compound of structure (I) or pharmaceutical composition comprising at least one compound of structure (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, isotope, or composition thereof.
  • methods for treating a proliferative disorder or a viral infection, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition, comprising a carrier or excipient and a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof.
  • a compound of structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, 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 structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, 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 (DGKC).
  • DGKa diacylglycerol kinase alpha
  • DGKC diacylglycerol kinase zeta
  • a compound of structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, isotope, or composition thereof for treating a disease or disorder associated with the activity of DGKa or DGK ⁇ , or both DGKa and DGK ⁇
  • a compound of structure (I), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, isotope, or composition thereof for treating a disease or disorder associated with the activity of DGKa or DGK/J, or both DGKa and DGK ⁇ (.
  • the proliferative disorder is cancer.
  • the invention provides methods of treating cancer associated with activity or expression, including abnormal activity and/or overexpression, of DGKa 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 structure (I) or a pharmaceutical composition thereof.
  • Types of cancers that may be treated with the compound of structure (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. [128] In one embodiment, are provided uses of a compound of structure (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof, or composition thereof, for the treatment of proliferative disorders.
  • the proliferative disorder is cancer.
  • 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 DGKa 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 structure (! 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 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 structure (I) for treatment of DGKa 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 pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer or isotope thereof, with at least one pharmaceutically acceptable carrier, diluent, or excipient further comprises a second therapeutic agent.
  • 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.)
  • 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.
  • the present invention provides a combined preparation of a compound of structure (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 Structure (I) and one or more of:
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3 Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 284, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4;
  • 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, 0X40, OX40L, GITR. GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • compounds of structure (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 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-I, 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-I 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/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT ⁇ R, LIGHT, DcR3, HVEM, VEG1/TL1A, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFP, TNFR2, TNFo, LTpR, Lymphotoxin a lp2, FAS, FAS, FA
  • 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 Nl ⁇ 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-tum
  • 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;
  • PD-1 receptor 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 IgGl, called AMP-224,
  • PD- L1 antagonists such as an antagonistic PD-L1 antibody
  • Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; W02010/077634), durvaluma (MEDI4736), BMS-936559 (W02007/005874), and MSB0010718C (WO2013/79174).
  • LAGS antibodies include, for example, BMS-986016 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (W008/132601, 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 (W006/105021, W009/009116) and MK-4166 (WO11/028683),
  • IDO antagonists include, for example, INCB-024360 (W02006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, BMS-986205, or NLG-919 (W009/73620, WO09/1156652, WO11/56652, WO12/142237).
  • 0X40 agonists such as an agonistic 0X40 antibody.
  • Suitable 0X40 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.
  • CD27 agonists such as an agonistic CD27 antibody.
  • Suitable CD27 antibodies include, for example, varlilumab.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • 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.
  • 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-a), 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-10 or TG F-
  • anticancer vaccines including epidophyllotoxin, including a tumor
  • STI signal transduction inhibitors
  • bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC);
  • epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA, SSI-774) and antibodies (Imclone: C225 [Goldstein et c?/, Clin. Cancer Res, 1995, 1, 1311-1318; and Abgenix: ABX-EGF);
  • 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);
  • FTI farnesyl transferase inhibitors
  • inhibitors of 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 structure (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 Structure (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.
  • Compounds of structure (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 antivirus 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 structure (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.
  • Suitable antiviral agents contemplated for use in combination with the compound of structure (I) include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTis), protease inhibitors and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTis nonnucleoside 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-10652, emitricitabine [(-)- FTC]; beta-L-FD4 (also called beta-L-D4C and nanled 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
  • lamivaidine 3TC:
  • NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, LJ- 90152); efavirenz (DMP-266); PNU-142721, AG-1549; MKC-442 (l-(ethoxy-methyl)-5- (]- methylethyl)-6-(phenylmethyl)-(2,4(lH,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.
  • 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 structure (I), 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); 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.
  • the invention provides an oral pharmaceutical composition
  • kits useful for example, in the treatment or prevention of DGKa and DGKxj 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 structure (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.
  • 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.
  • (methylamino)cyclohexane-l-carboxamide may be prepared from (/?)-cydohex-3-ene-l- carboxyiic acid or (S)-cyclohex-3-ene-l-carboxylic acid, according to scheme 1 or scheme 2 using suitable protecting groups ("PG 1 ", "PG 2 "),
  • Methylation of the hydroxy group may be achieved by treatment with methyl iodide, as shown in scheme 4. R 3 -aryl is then introduced.
  • 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.
  • 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.
  • 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-lnterscience. (2006). All starting materials and reagents are commercially available or readily prepared.
  • Phenyl lithium (1.9 M, 12.83 mL) was added dropwise at to a stirred mixture of tert-butyl ((lR,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-(methoxy(methyl) carbamoyl)cyclohexyl)(methyl)carbamate (3.5 g, 8.13 mmol) in THF (35 mL) at -78 °C. The reaction was stirred for 0.5 h at -78 °C, quenched with NH4CI (satd, aq, 50 mL) at -78 °C and then extracted with ethyl acetate (3 x 50 mL).
  • STEP 10 (15,2R,5S)-5-[(E)-N-(l,l-dimethylethoxy)-C-phenyl-carbonimidoyl]-2- (methylamino)cyclohexanol
  • STEP 2 Mixture of (lR,3S,6S)-methyl 7-oxa-bicyclo[4.1.0]heptane-3-carboxylate and (lS,3S,6R)-methyl 7-oxa-bicyclo[4.1.0]heptane-3-carboxylate
  • STEP 3 Mixture of (lS,3R,4R)-methyl 4-azido-3-hydroxycydohexanecarboxylate and (lS,3S,4S)-methyl 4-azido-3-hydroxycyclohexanecarboxylate
  • STEP 4 Mixture of (lS,3R,4R)-methyl 4-amino-3-hydroxycyclohexanecarboxylate and (lS,3S,4S)-methyl 4-amino-3-hydroxycyclohexanecarboxylate
  • STEP 8 1,1-dimethylethyl N-[(lR,2R,4S)-2-[l,l-dimethylethyl(dimethyl)silyl]oxy-4- [methoxy(methyl)carbamoyl]cyclohexyl]carbamate
  • reaction mixture was stirred at 0 °C for 0.5 h and then maintaining the temperature, iodomethane (11.24 g, 79.21 mmol, 4.93 mL) was added dropwise. The reaction mixture was then warmed gently to rt and spun for 3 h. Once complete, the reaction mixture was poured into ice-water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (800 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography (PE/EtOAc, 3:1) to afford the title compound (10.0 g79%) as a yellow oil. LCMS (ES, m/z): 431.30 [M+H] + .
  • STEP 14 (5S)-8-[[(lR,2R,4S)-4-[(Z)-N-(l,l-dimethylethoxy)-C-phenyl-carbonimidoyl]-2- hydroxy-cyclohexyl]-methyl-amino]-5-methyl-6-oxo-l,5-naphthyridine-2,7-dicarbonitrile and
  • reaction mixture was purified by reserve phase column chromatography to afford the mixture of E- and Z- isomers which were separated by SFC to afford: (5S)-8-[[(lR,2R,4S)-4-[(Z)-N-(l,l-dimethylethoxy)-C-phenyl-carbonimidoyl]-2-hydroxy- cyclohexyl]-methyl-amino]-5-methyl-6-oxo-l,5-naphthyridine-2,7-dicarbonitrile as a yellow solid (compound 2A, 49.4 mg, 42%).
  • Compound 5 was prepared according to the scheme above and analogous procedures as compound 1, using 4-fluorophenyl lithium in place of phenyl lithium and 8-chloro-5-methyl- 6-oxo-5,6-dihydro-l,5-naphthyridine-2-carbonitrile in place of 8-chloro-5-methyl-6-oxo-5,6- dihydro-l,5-naphthyridine-2,7-dicarbonitrile.
  • STEP 4 8-(((lR,2S,4R)-4-((tert-butoxyimino)(4-fiuorophenyl)methyi)-2-((tert- butyldimethylsilyl)oxy)cyclohexy!(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-l,5- naphthyridine-2,7-dicarbonitrile
  • STEP 5 8-(((lR,2S,4R)-4-((Z)-(tert-butoxyimino)(4-fluorophenyl)methyl)-2-hydroxy cyclohexyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7-dicarbonitrile and
  • Compound 9 was prepared from 1,1-dimethylethyl N-[(lR,2R,4S)-2-[l,l- dimethylethyl(dimethyl)silyl]oxy-4-(6-fluoropyridine-3-carbonyl)cyclohexyl]-N- methylcarbamate, using the appropriate starting materials and according to synthetic procedures as described herein.
  • Hydroxylamine hydrochloride (8.54 g, 122.86 mmol) and sodium acetate (15.12 g, 184.28 mmol) were added to a solution of 1,1-dimethylethyl N-[(lR,2R,4S)-4-benzoyl-2-[l,l- dimethylethyl(dimethyl)silyl]oxy-cyclohexylj-N-methyl-carbamate (5.50 g, 12.3 mmol) in ethanol (26 mL) and water (13 mL) and the mixture stirred for 16h at 80 °C. After cooling to rt, the ethanol was removed under reduced pressure.
  • Compound 10 was prepared from tert-butyl ((lR,2R,4S)-2-((tert-butyldimethylsilyl)oxy)-4- ((Z)-(cyclopropoxyimino)(phenyl)methyl)cyclohexyl)(methyl)carbamate using the appropriate starting materials and according to synthetic procedures as described herein.
  • STEP 6 Synthesis of 8-(((lR,2R,4S)-4-((Z)-(tert-butoxyimino)(4-fluorophenyl)methyl)-2" methoxy cyclohexyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydro-l,5-naphthyridine-2,7- dicarbonitrile
  • tert-butyl ((lR,2S,4S)-2-((tert-butyldimethyls!lyl)oxy)-4-(methoxy(methyl)carbamoyl) cyclohexyl)carbamate was prepared as describe din example 2.
  • Compound 12D was then prepared according to similar procedures as described for compound 12A and was isolated as an off-white solid (12.3 mg, 11%).
  • STEP 6 8-(((lR,2R,4S)"4"((Z)-(tert-Butoxyimino)(phenyl)methyl)-2-((tert-butyldimethylsilyl) oxy)cyclohexyl)(methyl)amino)-5-methyl-6-oxo-5,6-dihydropyrido[3,2-djpyrimidine-2- carbonitrile
  • STEP 7 8-(((lR,2R,4S)-4-((Z)-(tert-butoxyimino)(phenyl)methyl)-2-hydroxycyclohexyl) (methyl)amino)-5-methyl-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidine-2-carbonitrile
  • carbonitrile 50 mg, 82.9 pmol
  • STEP 5 6-chloro-4-(((lR,2R,4S)-4-((Z)-((difluoromethoxy)imino)(phenyl)methyl)-2- hydroxycyclohexyl)(methyl)amino)-l-methylpyrido[3,2-d]pyrimidin-2(lH)-one 4,6-dichloro-l-methylpyrido[3,2-d]pyrimidin-2(lH)-one was coupled with (Z)-((lS,3R,4R)-3- hydroxy-4-(methylamino)cyclohexyl)(phenyl)methanone O-difluoromethyl oxime according to procedures described herein, to afford the title compound.
  • STEP 6 4-(((lR,2R,4S)-4-((Z)-((difluoromethoxy)imino)(phenyl)methyl)-2- hydroxycyclohexyl)(methyl)amino)-l-methyl-2-oxo-l,2-dihydropyrido[3,2-d]pyrimidine-6- carbonitrile
  • the enzyme assay was performed by diluting enzyme DGKa (Ipg/pL DGKa, Carnal2-101, SEQ ID NO: 3) or DGK ⁇ (Ip/pL DGKC Carna 12-110, SEQ ID NO: 4) using IX assay buffer.
  • OAG l-oleoyl-2-acetyl-sn-glycerol, 25mg/ml, Avanti 8001000
  • PS (10 mg/ml, Avanti 840032P) were mixed at the ratio of 1:2.
  • a IX substrate solution was prepared with IX 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 pM).
  • He High control
  • Lc Low Control
  • a 10- point concentration curve of test compounds were prepared by performing 3-fold serial dilutions of the compounds, starting at a concentration of 3000 nM (3000, 1000, 333.3, 111.1, 37, 12.3, 4.1, 1.4, 0.45, and 0.15 nM). Serial dilution of compounds was added to cells and the plate was pre-incubated for 60 mins at 37°C with 5% CO?. Treated cells were then stimulated with anti-CD3/CD28 antibodies for additional 6 h at 37°C with 5% CO?. The concentrations of anti-CD3 and anti-CD28 antibodies were 0.5 pg/mL each, diluted in RPMI1640 medium with 10% FBS.
  • A denotes an IC 50 or EC 5 o of less than lOnM
  • B denotes an ICso or ECso of from 10 nM to less than 100 nM;

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Abstract

L'invention concerne des composés ayant la structure de formule (I) : (I) ou un sel pharmaceutiquement acceptable, solvate, hydrate, isomère, ou un isotope de ceux-ci, Ar, X1, X2, R1, R2, R3 et R4 étant tels que définis dans la description. L'invention concerne également des compositions pharmaceutiques contenant de tels composés, ainsi que les composés eux-mêmes. L'invention concerne également des procédés, les composés étant des inhibiteurs de l'une parmi la diacylglycérol kinase alpha (DGKα) et la diacylglycérol kinase zêta (DGKζ) ou des deux et sont utiles dans le traitement de maladies, de troubles et d'états pathologiques liés à l'activité de la DGKα et/ou de la DGKζ. Plus particulièrement, l'invention concerne des méthodes de traitement d'une infection proliférative ou virale par administration à un sujet qui en a besoin d'une quantité efficace de la composition pharmaceutique contenant les composés ayant la structure de formule (I).
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