WO2021258010A1 - Composés oxime utiles comme activateurs de lymphocytes t - Google Patents

Composés oxime utiles comme activateurs de lymphocytes t Download PDF

Info

Publication number
WO2021258010A1
WO2021258010A1 PCT/US2021/038124 US2021038124W WO2021258010A1 WO 2021258010 A1 WO2021258010 A1 WO 2021258010A1 US 2021038124 W US2021038124 W US 2021038124W WO 2021258010 A1 WO2021258010 A1 WO 2021258010A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently selected
cycloalkyl
substituted
compound
Prior art date
Application number
PCT/US2021/038124
Other languages
English (en)
Inventor
Anthony David CASAREZ
Craig Alan Coburn
Terry Allen KELLAR
Daniel John Buzard
Nidhi Arora
Original Assignee
Gossamer Bio Services, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gossamer Bio Services, Inc. filed Critical Gossamer Bio Services, Inc.
Publication of WO2021258010A1 publication Critical patent/WO2021258010A1/fr

Links

Classifications

    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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

Definitions

  • the present invention generally relates to oxime compounds that activate T cells, promote T cell proliferation, and/or exhibit antitumor activity.
  • oxime compounds that activate T cells, promote T cell proliferation, and/or exhibit antitumor activity.
  • oxime 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 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 extraordinar 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.
  • T-cell signaling Mizoguchi et al, Science, 1992, 258, 1795-98
  • suppressive regulatory cells Facciabene et al, Cancer Res, 2012, 72, 2162-71
  • co-opting of endogenous ''immune checkpoints serve to down-modulate the intensity of adaptive immune responses and protect normal tissues from collateral damage, by tumors to evade immune destruction
  • 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).
  • DGK ⁇ and DGK ⁇ 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.
  • SEQ ID NO: 1 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
  • 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 TGF ⁇ , would be significant for the treatment of patients with proliferative disorders, such as cancer, as well as viral infections.
  • 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.
  • compounds having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: X is N or ⁇ CH; Y is N and L is ⁇ CH 2 ⁇ or a bond; or Y is ⁇ CH and L is ⁇ NR′ ⁇ , ⁇ C(O)NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ O ⁇ , or ⁇ S ⁇ ; a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–5 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo,
  • 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 ⁇ 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.
  • 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.
  • 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.
  • Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.
  • DETAILED DESCRIPTION As mentioned above, 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. 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.
  • 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. 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 having the structure of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: X is N or ⁇ CH; Y is N and L is ⁇ CH 2 ⁇ or a bond; or Y is ⁇ CH and L is ⁇ NR′ ⁇ , ⁇ C(O)NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ O ⁇ , or ⁇ S ⁇ ; a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–5 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇
  • 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., ⁇ 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., ⁇ 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.
  • 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.
  • Cycloalkyl 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 C 2 -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.
  • lower haloalkoxy groups include, but are not limited to ⁇ OCF 3 , ⁇ OCH 2 CF 3 , and the like.
  • Hydrodroxyalkyl 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.
  • 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(O) 2 R a or ⁇ S(O) 2 OR 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.
  • the compounds of have the structure of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: L is ⁇ NR′ ⁇ , ⁇ C(O)NH ⁇ , -NHC(O)-, ⁇ O ⁇ , or ⁇ S ⁇ ; a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycl
  • the compounds have the structure of Formula (II-A): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms,
  • the compounds have the structure of Formula (II-B): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (II-C): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (II-D): (II-D) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from hal
  • the compounds have the structure of Formula (II-E): (II-E) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from hal
  • the compounds have the structure of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: L is ⁇ NR′ ⁇ , ⁇ C(O)NH ⁇ , ⁇ NHC(O) ⁇ , ⁇ O ⁇ , or ⁇ S ⁇ ; a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloal
  • the compounds have the structure of Formula (III-A): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R′ is H, ⁇ C 1-4 alkyl, or ⁇ C 3-6 cycloalkyl; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein: a
  • the compounds have the structure of Formula (III-B): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (III-C): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (III-D): (III-D) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo,
  • the compounds have the structure of Formula (III-E): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • R′ is H. In one embodiment, R′ is ⁇ C 1-4 alkyl. In one embodiment, R′ is methyl. In one embodiment, R′ is ethyl. In one embodiment, R′ is n-propyl or isopropyl. In another embodiment, R′ is t-butyl or iso-butyl. In one embodiment, R′ is ⁇ C 3-6 cycloalkyl. In one embodiment, R′ is cyclopropyl. In one embodiment, R′ is cyclobutyl. In one embodiment, R′ is cyclopentyl. In one embodiment, R′ is cyclohexyl.
  • the compounds have the structure of Formula (IV): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: L is ⁇ CH 2 ⁇ or a bond; a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently
  • the compounds have the structure of Formula (IV-A): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (IV-B): (IV-B) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo,
  • the compounds have the structure of Formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: L is ⁇ CH 2 ⁇ or a bond; a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently
  • the compounds have the structure of Formula (V-A): (V-A) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo,
  • the compounds have the structure of Formula (V-B): or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein: a is 0, 1, or 2; R 1 is an 8–13 membered heteroaryl ring comprising 1–4 N atoms, wherein R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl; R 2 is a 5- or 6-membered aryl or heteroaryl ring comprising 0, 1, or 2 N atoms, wherein R 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halo, ⁇ OH,
  • the compounds have the structure of Formula (II-cis), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein the 1,4-substituents on the cyclohexyl ring are cis: (II-cis).
  • the compounds have the structure of Formula (II-trans), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein the 1,4-substituents on the cyclohexyl ring are trans: (II-trans).
  • the compounds are a mixture of cis and trans isomers. In some embodiments, a is 0 or 1. In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, the oxime is in the (Z) configuration. In some embodiments, the oxime is in the (E) configuration. In some embodiments, the compounds are a mixture of (Z) and (E) isomers. In some embodiments, R 1 is a 9- or 10-membered bicyclic heteroaryl ring comprising 1 or 2 N atoms. In some embodiments, R 1 is a 9- or 10-membered bicyclic heteroaryl ring comprising 1 N atom.
  • R 1 is a 9- or 10-membered bicyclic heteroaryl ring comprising 2 N atoms. In some embodiments, R 1 is a 9-membered bicyclic heteroaryl ring comprising 1 or 2 N atoms. In some embodiments, R 1 is a 10-membered bicyclic heteroaryl ring comprising 1 or 2 N atoms. In some embodiments, R 1 is a 9-membered bicyclic heteroaryl ring comprising 1 N atom. In some embodiments, R 1 is a 10-membered bicyclic heteroaryl ring comprising 1 N atom. In some embodiments, R 1 is a 9-membered bicyclic heteroaryl ring comprising 2 N atoms.
  • R 1 is a 10-membered bicyclic heteroaryl ring comprising 2 N atoms. In some embodiments, the 9- or 10-membered bicyclic heteroaryl ring is a fused bicyclic ring where both rings are aromatic. In some embodiments, R 1 is a 10-membered bicyclic heteroaryl ring comprising 2 or 3 N atoms. In some embodiments, R 1 is a 10-membered bicyclic heteroaryl ring comprising 3 N atoms. In some embodiments, the 9- or 10-membered bicyclic heteroaryl ring is a fused bicyclic ring where both rings are aromatic.
  • R 1 is a 13-membered tricyclic heteroaryl ring comprising 2, 3 or 4 N atoms. In some embodiments, R 1 is a 13-membered tricyclic heteroaryl ring comprising 2 N atoms. In some embodiments, R 1 is a 13-membered tricyclic heteroaryl ring comprising 3 N atoms. In some embodiments, R 1 is a 13-membered tricyclic heteroaryl ring comprising 4 N atoms. In some embodiments, the 13-membered tricyclic heteroaryl ring is a fused tricyclic ring where all rings are aromatic.
  • R 1 is substituted with 3 or 4 substituents, each individually selected from oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, and ⁇ C 1-4 alkyl ⁇ OH. In some embodiments, R 1 is substituted with 3 substituents. In some embodiments, R 1 is substituted with 4 substituents.
  • R 1 is: , In some embodiments, R 1 is: wherein R 1 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl.
  • substituents independently selected from ⁇ OH, oxo, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl.
  • R 1 is substituted with 1, 2 or 3 substituents, each individually selected from ⁇ OH, halo, ⁇ CN, ⁇ NO 2 , ⁇ C 1-4 alkyl, ⁇ C 1-4 haloalkyl, ⁇ O ⁇ C 1-4 alkyl, ⁇ C 1-4 alkyl ⁇ OH, ⁇ C 1-4 alkenyl, and ⁇ C 3-6 cycloalkyl.
  • R 1 is substituted with 1 or 2 substituents.
  • R 1 is substituted with 2 or 3 substituents.
  • R 1 is substituted with 1 substituent.
  • R 1 is substituted with 2 substituents.
  • R 1 is substituted with 3 substituents.
  • R 2 is a 6-membered aryl or heteroaryl ring comprising 0, 1 or 2 N atoms. In some embodiments, R 2 is a 6-membered aryl ring. In some embodiments, R 2 is a 6- membered heteroaryl ring comprising 1 or 2 N atoms. In some embodiments, R 2 is a 6- membered heteroaryl ring comprising 1 N atom. In some embodiments, R 2 is a 6-membered heteroaryl ring comprising 2 N atoms. In some embodiments, R 2 is unsubstituted phenyl or unsubstituted pyridyl. In some embodiments, R 2 is unsubstituted phenyl.
  • R 2 is unsubstituted pyridyl. In some embodiments, R 2 is substituted phenyl. In some embodiments, R 2 is substituted pyridyl. In some embodiments, R 3 is cyclopropyl or cyclobutyl. In some embodiments, R 3 is cyclopropyl or cyclobutyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopropyl and a is 1. In some embodiments, R 3 is cyclobutyl and a is 1.
  • R 3 is a 3–6 membered heterocycle comprising 1 or 2 O atoms. In some embodiments, R 3 is a 3–6 membered heterocycle comprising 1 O atom. In some embodiments, R 3 is a 3–6 membered heterocycle comprising 2 O atoms. In some embodiments, R 3 is a 3-membered heterocycle comprising 1 or 2 O atoms. In some embodiments, R 3 is a 3- membered heterocycle comprising 1 O atom. In some embodiments, R 3 is a 3-membered heterocycle comprising 2 O atoms. In some embodiments, R 3 is a 4-membered heterocycle comprising 1 or 2 O atoms.
  • R 3 is a 4-membered heterocycle comprising 1 atom. In some embodiments, R 3 is a 4-membered heterocycle comprising 2 O atoms. In some embodiments, R 3 is a 5-membered heterocycle comprising 1 or 2 O atoms. In some embodiments, R 3 is a 5-membered heterocycle comprising 1 O atom. In some embodiments, R 3 is a 5-membered heterocycle comprising 2 O atoms. In some embodiments, R 3 is a 6-membered heterocycle comprising 1 or 2 O atoms. In some embodiments, R 3 is a 6-membered heterocycle comprising 1 O atom. In some embodiments, R 3 is a 6-membered heterocycle comprising 2 O atoms.
  • R 3 is unsubstituted. In some embodiments, R 3 is substituted.
  • Representative compounds of Formula (I), and Formulas (II) through (IV) as applicable include the compounds having the structure of those listed in Table 1 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.” Table 1: Compounds of Formula (I)
  • 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.
  • 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 (E)- or (Z)- to the below examples depends upon the nature of substituents X and R 2 .
  • "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.
  • salts formed between acids in their anionic form and cations are referred to as “acid addition salts”.
  • salts formed between bases in the cationic form and anions are referred to as “base addition salts.”
  • 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.
  • Pharmaceutical Compositions 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.
  • 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.
  • 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 ⁇ 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.
  • the diacylglycerol kinase is diacylglycerol kinase alpha (DGKa) or diacylglycerol kinase zeta (DGK ⁇ ).
  • 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 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.
  • 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.
  • a 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.
  • 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.
  • 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.
  • the compounds can act to stimulate the activity of one or more kinases.
  • 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.
  • 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 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.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
  • the kinase is DGK.
  • the kinase is DGK ⁇ .
  • 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.
  • 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 ⁇ .
  • 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.
  • 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. 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. 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.
  • 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)
  • parasitic infections e.g., malaria
  • 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 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.)
  • 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., immune checkpoint inhibitors
  • 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 B7-1, 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.
  • 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).
  • 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).
  • 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.
  • 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
  • alkylating agents 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.
  • 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 inhibitor
  • 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 da
  • 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
  • agents for combination therapies for the treatment of cancer include anti-cancer vaccines, including dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • agents for combination therapies for the treatment of cancer include signal transduction inhibitors (STI).
  • STI signal transduction inhibitors
  • 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
  • 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.
  • NRTIs examples 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
  • lamivaidine
  • NNRTIs examples 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.
  • Routes of Administration 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
  • 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.
  • kits can also be included in the kit.
  • Compound Synthesis 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 Schemes 1–7. 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.
  • 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.
  • conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed.
  • Amide 2-B can be transformed into ketone 2-C with an appropriately metallated aryl species, either commercially available or through preparation by one skilled in the art.
  • the Boc- protecting group on 2-C can be removed by treatment with HCl or an alternative acid e.g. TFA, providing amine 2-D as a protonated salt or free base following neutralization.
  • Amide 2-E can be produced by subjecting 2-D to an appropriate coupling reagent and necessary Ar 2 -carboxylic acid. Oxime formation utilizing reagent 1-C, described in scheme 1, or a commercially available alkoxyamine can be facilitated by the use of acid, though can also be performed under neutral or basic conditions that one skilled in the art would find applicable.
  • Scheme 3 Preparation of cyclohexylamines (L is -CONH-, X is CH and Y is CH)
  • examples embodied by compounds of structure 2-F can also be prepared by means illustrated in scheme 3.
  • Intermediate 2-C can be condensed with the appropriate alkoxyamine 1-C, either prepared or commercially available, with concomitant deprotection of the Boc-protecting group, or via a 2-step fashion where oxime formation precedes deprotection in a separate vessel.
  • Amine 3-B can be subjected to R 1 -carboxylic acid and an appropriate coupling agent to result in 2-F.
  • Scheme 5 Preparation of piperidines (L is a bond, X is N and Y is CH) Piperidines embodied by compounds of structure 5-F can be generated is through the steps illustrated in scheme 5.
  • Commercially available 5-A can be combined with the appropriate metallated-aryl species R 2 -M, either prepared or purchased, to result in alcohol 5-B.
  • Oxidation with the appropriate reagent converts alcohol 5-B to ketone 5-C, which can be condensed with an alkoxyamine, either prepared by methods described in scheme 1 or purchased, to arrive at oxime 5-D.
  • Protecting group removal is affected by HCl or an appropriate acid e.g. TFA, resulting in amine 5-E as an ammonium salt or free base upon neutralization.
  • conversion of 5-C to 5-E by assumed intermediate 5-D can be performed in a 2-step single vessel procedure by combining the alkoxyamine and acid together with 5-C. The order of steps in this single pot transformation are assumed, though does not preclude deprotection of 5-C first followed by condensation of the alkoxyamine.
  • Scheme 7 Preparation of aminopiperidines (L is -CONH-, X is CH and Y is N)
  • Aminopiperidines of formula (I) and embodied by 7-E can be prepared according to Scheme 7.
  • R 2 aldehyde is condensed with 7-A to afford 7-B.
  • Treatment with N- chlorosuccinimide provides intermediate 7-C which is then reacted with N-Boc protected 4- aminopiperidine.
  • the protecting group is removed (e.g.by treatment with acid), and the free amine 7-D is reacted with R 1 -carboxylic acid and an appropriate coupling reagent to form the amide 7-E.
  • tert-butyl 4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylate To a solution of bromo(2-pyridyl)magnesium (0.25 M in THF, 41 mL) at 0 °C, was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.38 mmol) in THF (3 mL). After 21 h at rt, NH 4 Cl (aq, saturated) was added followed by ether, and the layers were separated. The aqueous layer was extracted with ether (3x), then the combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated in vacuo.
  • tert-butyl 4-picolinoylpiperidine-1-carboxylate To a vial charged with NaHCO 3 (1.44 g, 17.1 mmol) and DMP (1.89 g, 4.45 mmol) was added a solution of tert-butyl 4-(hydroxy(pyridin-2-yl)methyl)piperidine-1-carboxylate (1.0 g, 3.42 mmol) After stirring for 23 h at rt, Na 2 SO 3 (1 M, 10 mL) was added and it was stirred for an additional 1 h, whereupon it was diluted with DCM/water and the layers were separated.
  • tert-butyl (E/Z)-4-(((cyclopropylmethoxy)imino)(pyridin-2-yl)methyl)piperidine-1- carboxylate To a solution of tert-butyl 4-picolinoylpiperidine-1-carboxylate (397 mg, 1.37 mmol) in ethanol (6.9 mL) was added O-(cyclopropylmethyl)hydroxylamine hydrochloride (588 mg, 1.38 mmol). After 3 h, more O-(cyclopropylmethyl)-hydroxylamine hydrochloride (170 mg, 397 mmol) was introduced.
  • trans -4-aminocyclohexyl) (pyridin-2-yl) methanone A solution of trans-tert-butyl N-[4-(pyridine-2-carbonyl) cyclohexyl] carbamate (580 mg, 1.91 mmol) in 1,4-dioxane/HCl (4 M in dioxane, 10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step. LCMS (ES, m/z): 205 [M+H] + . STEP 3.
  • trans-2-methyl-N-[4-(pyridine-2-carbonyl) cyclohexyl]-1H-indole-3-carboxamide A solution of HBTU (1.62 g, 4.28 mmol) and 2-methyl-1H-indole-3-carboxylic acid (750 mg, 4.28 mmol) in DMA (4 mL) was stirred for 0.5 h at room temperature, To the above mixture were added trans-(4-aminocyclohexyl)-(2-pyridyl)methanone HCl (350 mg, 1.71 mmol) and N,N-diethylethanamine (865 mg, 8.55 mmol, 1.19 mL). The mixture was stirred for 16 h at room temperature.
  • tert-butyl 4-(hydroxy(phenyl)methyl)piperidine-1-carboxylate A solution of phenylmagnesium bromide (3 M, 3.44 mL, 10.32 mmol) was diluted with THF (8 mL) and cooled 0 °C, whereupon a solution of tert-butyl 4-formylpiperidine-1- carboxylate (2 g, 9.38 mmol) in THF (3 mL) was added, drop-wise. After 1 h, the mixture was quenched with NH4Cl (aq), then diluted with ether and separated the layers.
  • tert-butyl 4-benzoylpiperidine-1-carboxylate 1.2 g, 4.1 mmol
  • K 2 CO 3 573 mg, 4.15 mmol
  • O-(cyclopropylmethyl)hydroxylamine hydrochloride 533 mg, 4.31 mmol).
  • trans-(4-aminocyclohexyl)(1-methyl-1H-pyrazol-5-yl)methanone O-((2- (trifluoromethyl)cyclopropyl)methyl) oxime hydrochloride
  • intermediate D 60.6 mg, 390 ⁇ mol
  • HCl HCl
  • the mixture was stirred for 3 h at room temperature.
  • the crude product was purified by reversed phase chromatography (Column: XBridge Shield RP18 OBD Column, 5 ⁇ m, 30 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: ⁇ CH 3 CN (10% to 40% in 7 min); Flow rate: 40 mL/min; Detector: UV 254 nm).
  • the collected fractions were lyophilized to afford the title compound as a light yellow solid (25.9 mg, 9 %).
  • EXAMPLE 2 trans-2-methyl-N-(4-((E/Z)-(1-methyl-1H-pyrazol-3-yl)(((2-(trifluoromethyl)cyclopropyl) methoxy)imino)methyl)cyclohexyl)-1H-indole-3-carboxamide (compound 2) STEP 1. (2-(trifluoromethyl)cyclopropyl)methanol To a mixture of 3-bromo-1-methyl-pyrazole (1.69 g, 10.48 mmol) in THF (50 mL) was added n-BuLi (2.5 M in THF, 3.49 mmol, 4.2 mL) dropwise at -78 °C.
  • the mixture was stirred for 4 h at room temperature.
  • the reaction was purified by reversed phase chromatography (Column: XBridge Prep OBD C18 Column, 19 x 250 mm, 5 um; Mobile Phase, A: water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O) and B: ACN (56% to 76% in 7 min); Detector: 220 nm) to afford the title compounds.
  • the first eluting isomer (RT1: 5.9) was lyophilized to afford the title compound (15.7 mg, 39.4 ⁇ mol, 3.9% yield, 99% purity) as a white solid.
  • the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (column, C18 silica gel; mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: ACN (0% to 55% in 30 min); Detector: UV 254 nm). The collected fraction was concentrated to give trans-tert-butyl N-[4-(pyridazine-3- carbonyl)cyclohexyl]carbamate (1.1 g, 3.60 mmol, 29% yield) as a yellow solid.
  • the crude product was purified by reversed phase chromatography (Column: XBridge C18 OBD Prep Column, 100 ⁇ , 10 ⁇ m, 19 mm x 250 mm; Mobile Phase, A: H 2 O (0.05% TFA) and B: ACN (48% to 72% in 7 min); Detector: 220 nm.
  • the collected fraction was lyophilized to afford the title compound (19.3 mg, 44.5 ⁇ mol, 16% yield, 99.5% purity) as a yellow solid.
  • the crude product was purified by reversed phase chromatography (Column: Xselect CSH OBD Column, 30 x150 mm, 5 um; Mobile Phase, A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O) and B: ACN (47% to 67% in 7 min); Detector: 220 nm).
  • the collected fractions were lyophilized to afford N-[4-[(N-(1,4-dioxan-2-ylmethoxy)-C-phenyl-carbonimidoyl]cyclohexyl]-2-methyl-1H- indole-3-carboxamide (12.6 mg, 25.8 ⁇ mol, 6.2% yield, 97.2% purity) as a yellow solid.
  • the crude product was purified by reversed phase chromatography (Column: Xselect CSH OBD Column, 30 x 150 mm, 5 um; Mobile phase, A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O) and B: ACN (60% to 80% in 7 min); Detector: 220 nm).
  • the collected fraction was lyophilized to afford the title compound (29 mg, 57.01 ⁇ mol, 11.42% yield, 98.4% purity) as a yellow solid.
  • the crude product was purified by pre-Achiral SFC (Column: DAICEL DCpak P4VP, 20mm x 250mm,5um; Mobile Phase, A: CO 2 and B: MeOH (0.5% 2M NH 3 -MeOH) (hold 30% in 6 min); Flow rate: 50 mL/min; Detector: 254 nm).
  • the crude product was purified by reversed phase chromatography (Column: C18, 30 x 250, 5 um; Mobile Phase, A: Water (0.05%TFA) and B: ACN (0% to 60% in 30min); Detector: 254 nm).
  • the product fractions were lyophilized to give 5-methyl-7-nitro-8-[4-[(E/Z)- N-(oxetan-3-yloxy)-C-phenyl-carbonimidoyl]-1-piperidyl]-6-oxo-3,4,7,8-tetrahydro-1,5- naphthyridine-2-carbonitrile (22.9 mg, 45 ⁇ mol, 5.9% yield, 96.8% purity) as a light-yellow solid.
  • reaction was stirred for 2 h at 30 °C, filtered and purified by reversed phase HPLC (30 x 150 mm, 5 um, C18 column, 19-39% ACN/water, 0.1% formic acid modifier, 19 mL/min), affording the title compound (10.2 mg, 12%) as a white solid.
  • the suspension was filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by reversed phase chromatography (Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile Phase, A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .H 2 O) and B: ACN (40-60% in 7 min); Detector: UV 254 nm).
  • EXAMPLE 76 (Z or E)-8-(4-(((cyclopropylmethoxy)imino)(pyridin-2-yl)methyl)piperidin-1-yl)-7- (hydroxymethyl)-5-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-2-carbonitrile.
  • BIOLOGICAL ASSAYS EXAMPLE 111 DGK ⁇ and DGK ⁇ 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%,CaCl2 1 ⁇ M, MgCl210mM, DTT 2mM).
  • 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.
  • Hc High control
  • Lc Low Control
  • A denotes an IC 50 of less than 10nM
  • B denotes an IC 50 of from 10 nM to less than 100 nM
  • C denotes an IC 50 of from 100 nM to less than 1000 nM
  • D denotes an IC 50 of 1000 nM or more.

Abstract

Sont divulgués des composés oxime ayant la structure de formule (I) : ou un sel, solvate, hydrate, isomère, tautomère, racémate ou isotope pharmaceutiquement acceptable de celui-ci, R1, R2, R3, A, L, X et Y étant tels que définis dans la description. Des compositions pharmaceutiques les comprenant, des procédés de préparation de celles-ci et des utilisations de celles-ci pour traiter ou prévenir des maladies, des troubles et des états pathologiques sont également prévus. Les composés sont des inhibiteurs de la diacylglycérol kinase alpha (DGKα) et/ou de la diacylglycérol kinase zêta (DGKζ) 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. En particulier, les composés sont utiles pour le traitement d'infections virales et de troubles prolifératifs, tels que le cancer.
PCT/US2021/038124 2020-06-19 2021-06-18 Composés oxime utiles comme activateurs de lymphocytes t WO2021258010A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063041771P 2020-06-19 2020-06-19
US63/041,771 2020-06-19

Publications (1)

Publication Number Publication Date
WO2021258010A1 true WO2021258010A1 (fr) 2021-12-23

Family

ID=77051127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/038124 WO2021258010A1 (fr) 2020-06-19 2021-06-18 Composés oxime utiles comme activateurs de lymphocytes t

Country Status (1)

Country Link
WO (1) WO2021258010A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022271659A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271684A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271650A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2023122772A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles comme activateurs de lymphocytes t
WO2023122777A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles en tant qu'activateurs de lymphocytes t
WO2023150186A1 (fr) * 2022-02-01 2023-08-10 Arvinas Operations, Inc. Composés de ciblage de dgk et utilisations associées
WO2023165528A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de la diacylglycérol kinase (dgk) alpha et leurs utilisations
WO2023186060A1 (fr) * 2022-03-31 2023-10-05 InventisBio Co., Ltd. Inhibiteurs de kinase, leurs procédés de préparation et leurs utilisations
WO2023184327A1 (fr) * 2022-03-31 2023-10-05 InventisBio Co., Ltd. Inhibiteurs de kinase, leurs procédés de préparation et leurs utilisations
US11845723B2 (en) 2019-12-24 2023-12-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
US11932634B2 (en) 2021-06-23 2024-03-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
WO2006105021A2 (fr) 2005-03-25 2006-10-05 Tolerrx, Inc. Molecules de liaison gitr et leurs utilisations
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
WO2007075598A2 (fr) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles en tant que modulateurs d'indoleamine 2,3-dioxygenase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008132601A1 (fr) 2007-04-30 2008-11-06 Immutep Anticorps monoclonal anti-lag-3 cytotoxique et son utilisation dans le traitement ou la prévention d'un rejet du greffon d'organe et de maladies auto-immunes
WO2009009116A2 (fr) 2007-07-12 2009-01-15 Tolerx, Inc. Thérapies combinées utilisant des molécules de liaison au gitr
WO2009044273A2 (fr) 2007-10-05 2009-04-09 Immutep Utilisation d'une protéine lag-3 recombinée ou de dérivés de celle-ci pour produire une réponse immunitaire des monocytes
WO2009073620A2 (fr) 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2009156652A1 (fr) 2008-05-29 2009-12-30 Saint-Gobain Centre De Recherches Et D'etudes Europeen Structure en nid d'abeille a base de titanate d'aluminium
WO2010019570A2 (fr) 2008-08-11 2010-02-18 Medarex, Inc. Anticorps humains qui se lient au gène 3 d'activation des lymphocytes (lag-3), et leurs utilisations
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011028683A1 (fr) 2009-09-03 2011-03-10 Schering Corporation Anticorps anti-gitr
WO2011056652A1 (fr) 2009-10-28 2011-05-12 Newlink Genetics Dérivés imidazole comme inhibiteurs de l'ido
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013079174A1 (fr) 2011-11-28 2013-06-06 Merck Patent Gmbh Anticorps anti-pd-l1 et utilisations associées
WO2014008218A1 (fr) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimisation d'anticorps se liant à la protéine lag-3 exprimée par le gène 3 d'activation des lymphocytes, et leurs utilisations
WO2020006016A1 (fr) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Composés de naphtyridinone utiles en tant qu'activateurs de lymphocytes t
WO2020006018A1 (fr) * 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Composés de naphtyridinone substitués utiles en tant qu'activateurs de lymphocytes t

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
WO2006105021A2 (fr) 2005-03-25 2006-10-05 Tolerrx, Inc. Molecules de liaison gitr et leurs utilisations
WO2006122150A1 (fr) 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
WO2007075598A2 (fr) 2005-12-20 2007-07-05 Incyte Corporation N-hydroxyamidinoheterocycles en tant que modulateurs d'indoleamine 2,3-dioxygenase
WO2008036642A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
WO2008036653A2 (fr) 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles modulateurs de l'indoléamine 2,3-dioxygénase
WO2008132601A1 (fr) 2007-04-30 2008-11-06 Immutep Anticorps monoclonal anti-lag-3 cytotoxique et son utilisation dans le traitement ou la prévention d'un rejet du greffon d'organe et de maladies auto-immunes
WO2009009116A2 (fr) 2007-07-12 2009-01-15 Tolerx, Inc. Thérapies combinées utilisant des molécules de liaison au gitr
WO2009044273A2 (fr) 2007-10-05 2009-04-09 Immutep Utilisation d'une protéine lag-3 recombinée ou de dérivés de celle-ci pour produire une réponse immunitaire des monocytes
WO2009073620A2 (fr) 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2009156652A1 (fr) 2008-05-29 2009-12-30 Saint-Gobain Centre De Recherches Et D'etudes Europeen Structure en nid d'abeille a base de titanate d'aluminium
WO2010019570A2 (fr) 2008-08-11 2010-02-18 Medarex, Inc. Anticorps humains qui se lient au gène 3 d'activation des lymphocytes (lag-3), et leurs utilisations
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011028683A1 (fr) 2009-09-03 2011-03-10 Schering Corporation Anticorps anti-gitr
WO2011056652A1 (fr) 2009-10-28 2011-05-12 Newlink Genetics Dérivés imidazole comme inhibiteurs de l'ido
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
WO2012142237A1 (fr) 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
WO2013079174A1 (fr) 2011-11-28 2013-06-06 Merck Patent Gmbh Anticorps anti-pd-l1 et utilisations associées
WO2014008218A1 (fr) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimisation d'anticorps se liant à la protéine lag-3 exprimée par le gène 3 d'activation des lymphocytes, et leurs utilisations
WO2020006016A1 (fr) 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Composés de naphtyridinone utiles en tant qu'activateurs de lymphocytes t
WO2020006018A1 (fr) * 2018-06-27 2020-01-02 Bristol-Myers Squibb Company Composés de naphtyridinone substitués utiles en tant qu'activateurs de lymphocytes t

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", vol. 36, 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

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845723B2 (en) 2019-12-24 2023-12-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
WO2022271684A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
WO2022271650A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2022271659A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés modulant les diacylglycérol kinases
US11976072B2 (en) 2021-06-23 2024-05-07 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
US11932634B2 (en) 2021-06-23 2024-03-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
US11926628B2 (en) 2021-06-23 2024-03-12 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2023122772A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles comme activateurs de lymphocytes t
WO2023122777A1 (fr) * 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Dérivés d'oxime utiles en tant qu'activateurs de lymphocytes t
WO2023150186A1 (fr) * 2022-02-01 2023-08-10 Arvinas Operations, Inc. Composés de ciblage de dgk et utilisations associées
WO2023165528A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de la diacylglycérol kinase (dgk) alpha et leurs utilisations
WO2023184327A1 (fr) * 2022-03-31 2023-10-05 InventisBio Co., Ltd. Inhibiteurs de kinase, leurs procédés de préparation et leurs utilisations
WO2023186060A1 (fr) * 2022-03-31 2023-10-05 InventisBio Co., Ltd. Inhibiteurs de kinase, leurs procédés de préparation et leurs utilisations

Similar Documents

Publication Publication Date Title
WO2021258010A1 (fr) Composés oxime utiles comme activateurs de lymphocytes t
US11337970B2 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11866430B2 (en) Naphthyridinone compounds useful as T cell activators
US11548870B2 (en) Compounds useful as inhibitors of helios protein
US10544099B2 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11584747B2 (en) Substituted pyridopyrimidinonyl compounds useful as T cell activators
US20230086933A1 (en) Substituted heteroaryl compounds useful as t cell activators
KR20190003687A (ko) 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
WO2022133083A1 (fr) Composés utiles en tant qu'activateurs de lymphocytes t
CA3162992A1 (fr) Composes de quinolinonyle piperazine substitues utiles en tant qu'activateurs de lymphocytes t
KR20190003685A (ko) 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
KR20190004743A (ko) 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
US11649212B2 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074824A1 (fr) Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation
WO2023122772A1 (fr) Dérivés d'oxime utiles comme activateurs de lymphocytes t
TWI836159B (zh) 可作為helios蛋白質抑制劑之化合物
WO2023122777A1 (fr) Dérivés d'oxime utiles en tant qu'activateurs de lymphocytes t
WO2023122778A1 (fr) Dérivés de pyridazinone utiles en tant qu'activateurs de lymphocytes t
AU2022253450A1 (en) Pyridinyl substituted oxoisoindoline compounds for the treatment of cancer
WO2023150186A1 (fr) Composés de ciblage de dgk et utilisations associées

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21746208

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21746208

Country of ref document: EP

Kind code of ref document: A1