WO2025051110A1 - Combinaisons de traitements par inhibiteurs de diacylglycérol kinase (dgk) alpha et d'autres thérapies - Google Patents

Combinaisons de traitements par inhibiteurs de diacylglycérol kinase (dgk) alpha et d'autres thérapies Download PDF

Info

Publication number
WO2025051110A1
WO2025051110A1 PCT/CN2024/116517 CN2024116517W WO2025051110A1 WO 2025051110 A1 WO2025051110 A1 WO 2025051110A1 CN 2024116517 W CN2024116517 W CN 2024116517W WO 2025051110 A1 WO2025051110 A1 WO 2025051110A1
Authority
WO
WIPO (PCT)
Prior art keywords
heterocycloalkyl
compound
alkyl
cycloalkyl
formula
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/CN2024/116517
Other languages
English (en)
Inventor
Deheng SUN
Hongfu LU
Huaxing YU
Man ZHANG
Xiao DING
Feng Ren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
InSilico Medicine IP Ltd
Original Assignee
InSilico Medicine IP Ltd
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 InSilico Medicine IP Ltd filed Critical InSilico Medicine IP Ltd
Publication of WO2025051110A1 publication Critical patent/WO2025051110A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • DAG Diacylglycerol kinases
  • PLCyl T cell receptor
  • PIP2 phosphatidylinositol 4, 5-biphosphate
  • IP3 inositol 1 , 4, 5-triphosphate
  • DAG interacts with other proteins important in TCR signal transduction, such as Protein kinase CO and the Ras activating protein RasGRPI.
  • proteins important in TCR signal transduction such as Protein kinase CO and the Ras activating protein RasGRPI.
  • DGKalpha, DGKdelta, and DGKzeta three isoforms of DGK are known to be present within T cells (DGKalpha, DGKdelta, and DGKzeta) , only two, DGKalpha and DGKzeta, are thought to play an important role in facilitating DAG metabolism downstream of the TCR.
  • DGKalpha and DGKzeta are viewed as targets for cancer immunotherapy (Riese M.J. et al., Front Cell Dev Biol. (2016) 4: 108; Chen, S. S. et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4: 178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686.
  • the present disclosure provides a use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.
  • the present disclosure provides a use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.
  • the present disclosure provides a use of Compound 23 or Compound 13A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent:
  • the present disclosure provides a use of Compound 23 or Compound 13A or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Amino refers to the group -NR a R b , wherein R a and R b are independently selected from groups consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or other suitable organic groups and each of which may be optionally substituted.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • the group may be in either the cis or trans conformation, or alternatively, E or Z conformation about the double bond (s) , and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” , means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkoxy” or “C 1-6 alkoxy” , means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkoxy” where no numerical range is designated. In some embodiments, the alkoxy is a C 1 - 10 alkoxy. In some embodiments, the alkoxy is a C 1-6 alkoxy.
  • the alkoxy is a C 1-5 alkoxy. In some embodiments, the alkoxy is a C 1-4 alkoxy. In some embodiments, the alkyl is a C 1-3 alkoxy. In some embodiments, the alkyl is a C 1-2 alkoxy. In some embodiments, the alkyl is methoxy. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) , bridged or spiro ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with one or more substituents, such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four carbon atoms (C 3 -C 4 fully saturated cycloalkyl or C 3 -C
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more aminos. In some embodiments, the alkyl is substituted with one amino. In some embodiments, the alkyl is substituted with one, two, or three aminos. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens.
  • the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon atoms (C 2 -C 5 fully saturated heterocycloalkyl or C 2 -C 5
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) , bridged or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • partially saturated refers to a radical that includes at least one double or triple bond, and is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four substituents, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with DGKzeta” or, alternatively, “a DGKzeta-mediated disease or disorder” means any disease or other deleterious condition in which DGKzeta, or a mutant thereof, is known or suspected to play a role.
  • Ring A is phenyl or 6-membered heteroaryl
  • n 0-4;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • n 0-8;
  • T is N or CR T ;
  • R T is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • p 0-4;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • Ring A is phenyl. In some embodiments of a compound of Formula (I) , Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) , Ring A is pyridinyl.
  • the compound is of formula selected from: Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) , Formula (Ig) ;
  • n’ is an integer of 0-3, and each of R 1a and R 1b is independently selected from R 1 .
  • n’ is 1 or 2; each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl; R 2 is C 1 -C 6 alkyl; T is CH; U is N or CH; p is 1 or 2; and each R 4 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (Ib) , p is 1.
  • p is 2.
  • R 4 is halogen such as F.
  • R 4 is C 1 -C 6 alkyl.
  • R 4 is C 1 -C 3 alkyl.
  • R 4 is methyl.
  • R 2 is C 1 -C 3 alkyl.
  • R 2 is methyl.
  • U is N. In some embodiments, U is CH.
  • each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN or -O-heterocycloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 haloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (Ib) , each R 1 is independently -CN or -O-C 1 -C 3 hydroxylalkyl. In some embodiments of a compound of Formula (Ib) , each R 1 is independently -CN or -O-C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (Ib) , each R 1 is independently -CN or -O-CH 2 CH 2 OH. In some embodiments of a compound of Formula (Ib) , at least one R 1 is CN. In some embodiments of a compound of Formula (Ib) , n’ is 1. In some embodiments of a compound of Formula (Ib) , n’ is 2.
  • each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl;
  • R 2 is C 1 -C 6 alkyl;
  • T is CH;
  • U is N or CH;
  • p is 1 or 2;
  • each R 4 is independently halogen or C 1 -C 6 alkyl.
  • p is 1.
  • p is 2.
  • R 4 is halogen such as F.
  • R 4 is C 1 -C 6 alkyl.
  • R 4 is C 1 -C 3 alkyl.
  • R 4 is methyl.
  • R 2 is C 1 -C 3 alkyl.
  • R 2 is methyl.
  • U is N.
  • each R 1a and R 1b are independently -CN or -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (If) , each R 1a and R 1b are independently -CN or -O- C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (If) , each R 1a and R 1b are independently -CN or -O-C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (If) , R 1a is -O-C 1 -C 6 hydroxylalkyl, R 1b is CN.
  • R 1a is -O-C 1 -C 3 hydroxylalkyl
  • R 1b is CN.
  • R 1a is -O-CH 2 CH 2 OH
  • R 1b is CN.
  • each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl;
  • R 2 is C 1 -C 6 alkyl;
  • T is CH;
  • U is N or CH;
  • R 4 is halogen or C 1 -C 6 alkyl.
  • R 4 is halogen such as F.
  • each R 1a and R 1b are independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • each R 1a and R 1b are independently -CN or -O-heterocycloalkyl.
  • each R 1a and R 1b are independently -CN or -O-C 1 -C 6 haloalkyl.
  • each R 1a and R 1b are independently -CN or -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (Ig) , each R 1a and R 1b are independently -CN or -O-C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (Ig) , R 1a is -O-C 1 -C 6 hydroxylalkyl, and R 1b is CN. In some embodiments of a compound of Formula (Ig) , R 1a is -O-C 1 -C 3 hydroxylalkyl, and R 1b is CN. In some embodiments of a compound of Formula (Ig) , R 1a is -O-CH 2 CH 2 OH, and R 1b is CN.
  • R 1a is halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a is halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a is halogen or -CN.
  • R 1a is halogen. In some embodiments of a compound of Formula (If) or (Ig) , R 1a is fluoro or chloro. In some embodiments of a compound of Formula (If) or (Ig) , R 1a is -CN. In some embodiments of a compound of Formula (If) or (Ig) , R 1a is independently halogen, -CN, -OR a , or -NR c R d . In some embodiments of a compound of Formula (If) or (Ig) , R 1a is -CN or -OR a .
  • R 1a is -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a is -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O-C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • R 1a is independently -CN or -NR c R d .
  • -OR a is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a is In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 aminoalkyl.
  • R 1b is halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1b is halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1b is halogen or -CN.
  • R 1b is halogen. In some embodiments of a compound of Formula (If) or (Ig) , R 1b is fluoro or chloro. In some embodiments of a compound of Formula (If) or (Ig) , R 1b is -CN. In some embodiments of a compound of Formula (If) or (Ig) , R 1b is independently halogen, -CN, -OR a , or -NR c R d . In some embodiments of a compound of Formula (If) or (Ig) , R 1b is -CN or -OR a .
  • R 1b is -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1b is -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O- C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • R 1b is independently -CN or -NR c R d .
  • -OR a is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a is In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (If) or (Ig) , -OR a is -O-C 1 -C 6 aminoalkyl.
  • n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) or (Ia) , wherein n is 0-2. In some embodiments of a compound of Formula (I) or (Ia) , n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia) , n is 2. In some embodiments of a compound of Formula (I) or (Ia) , n is 1. In some embodiments of a compound of Formula (I) or (Ia) , n is 0.
  • n’ is 0, 1, 2, or 3. In some embodiments of a compound of Formula (Ib) - (Ie) , n’ is 0-2. In some embodiments of a compound of Formula (Ib) - (Ie) , n’ is 0 or 1. In some embodiments of a compound of Formula (Ib) - (Ie) , n’ is 2. In some embodiments of a compound of Formula (Ib) - (Ie) , n’ is 1. In some embodiments of a compound of Formula (Ib) - (Ie) , n’ is 0.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen or -CN.
  • each R 1 is independently halogen. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 1 is fluoro or chloro. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 1 is -CN. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 1 is independently halogen, - CN, -OR a , or -NR c R d .
  • each R 1 is independently -CN or -OR a . In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O-C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • each R 1 is independently -CN or -NR c R d .
  • -OR a is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a is In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , -OR a is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , -OR a is -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , -OR a is -O-C 1 -C 6 hydroxylalkyl.
  • -OR a is -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN or -O-heterocycloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 haloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 hydroxylalkyl. In some embodiments, each R 1 is independently -CN or -O-C 1 -C 3 hydroxylalkyl. In some embodiments, each R 1 is independently -CN or -O-CH 2 CH 2 OH. In some embodiments, each R 1 is independently -CN or -O-C 1 -C 6 aminoalkyl. In some embodiments, at least one R 1 is -CN.
  • R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , R 2 is C 1 -C 3 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , R 2 is methyl.
  • U is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , U is CR U .
  • R U is hydrogen, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R U is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R U is hydrogen.
  • a compound of Formula (I) is In some embodiments of a compound of Formula (I) , is In some embodiments of a compound of Formula (I) , is In some embodiments of a compound of Formula (I) , is In some embodiments of a compound of Formula (I) , is in some embodiments of a compound of Formula (I) , is in some embodiments of a compound of Formula (I) , is in some embodiments of a compound of Formula (I) , is
  • each R 3 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 3 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R 3 is independently C 1 -C 6 alkyl.
  • two R 3 on the same or different carbons are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R.
  • two R 3 on different carbons are taken together to form a cycloalkyl optionally substituted with one or more R.
  • m is 0-4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 0. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 1. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 2.
  • m is 3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 4. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 3. In some embodiments of a compound of Formula (I) or (Ia) - (Ie) , m is 5-8.
  • T is N. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , T is CR T .
  • R T is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , R T is hydrogen.
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 4 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 4 is independently halogen or C 1 -C 6 alkyl.
  • each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , each R 4 is methyl. In some embodiments of a compound of Formula (I) or (Ia) - (Ig) , R 4 is F.
  • p is 0-2. In some embodiments of a compound of Formula (I) or (Ia) - (If) , p is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia) - (If) , p is 0. In some embodiments of a compound of Formula (I) or (Ia) - (If) , p is 1. In some embodiments of a compound of Formula (I) or (Ia) - (If) , p is 2.
  • Ring A is phenyl or 6-membered heteroaryl
  • n 0-4;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • Ring B is a bicyclic ring
  • n 0-8;
  • p 0-4;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R a are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R b are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
  • Ring A is phenyl. In some embodiments of a compound of Formula (I-1) , Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I-1) , Ring A is pyridinyl.
  • the compound is of formula selected from: Formula (I-1a) , Formula (I-1b) , Formula (I-1c) , Formula (I-1d) , Formula (I-1e) , Formula (I-1f) ;
  • n’ is an integer of 0-3, each R 1a and R 1b are independently selected from R 1 .
  • n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula (I-1) or (I-1a) , n is 0-2. In some embodiments of a compound of Formula (I-1) or (I-1a) , n is 0 or 1. In some embodiments of a compound of Formula (I-1) or (I-1a) , n is 2. In some embodiments of a compound of Formula (I-1) or (I-1a) , n is 1. In some embodiments of a compound of Formula (I-1) or (I-1a) , n is 0.
  • n’ is an integer of 0-2. In some embodiments of a compound of Formula (I-1b) - (I-1e) , n’ is 0 or 1. In some embodiments of a compound of Formula (I-1b) - (I-1e) , n’ is 2. In some embodiments of a compound of Formula (I-1b) - (I-1e) , n’ is 1. In some embodiments of a compound of Formula (I-1b) - (I-1e) , n’ is 0.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently halogen or -CN. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 1 is independently halogen. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 1 is fluoro or chloro. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 1 is -CN.
  • each R 1 is independently halogen, -CN, -OR a , or -NR c R d . In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 1 is independently -CN or -OR a . In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 1 is independently -CN or -NR c R d .
  • -OR a is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, -O-C 1 -C 6 aminoalkyl.
  • -OR a is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a is In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , -OR a is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , -OR a is -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , -OR a is -O-C 1 -C 6 hydroxylalkyl.
  • -OR a is -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN, -O-heterocycloalkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • each R 1 is independently -CN or -O-heterocycloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 haloalkyl.
  • each R 1 is independently -CN or -O-C 1 -C 6 hydroxylalkyl. In some embodiments, each R 1 is independently -CN or -O-C 1 -C 6 aminoalkyl. In some embodiments, at least one R 1 is -CN.
  • R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , R 2 is C 1 -C 6 alkyl.
  • U is N. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , U is CR U .
  • R U is hydrogen or -CN.
  • R U is -CN.
  • a compound of Formula (I-1) is In some embodiments of a compound of Formula (I-1) , is In some embodiments of a compound of Formula (I-1) , is In some embodiments of a compound of Formula (I-1) , In some embodiments of a compound of Formula (I-1) , is
  • Ring B is a bicyclic heterocycloalkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , Ring B is a bicyclic 6-to 10-membered heterocycloalkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , Ring B is a bicyclic 6-to 10-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of N, O, and S.
  • Ring B is a bicyclic 6-to 10-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of N and O.
  • Ring B is a bridged bicyclic ring.
  • Ring B is 3, 8-diazabicyclo [3.2.1] octane or 2, 5-diazabicyclo [2.2.2] octane.
  • Ring B is 3, 8-diazabicyclo [3.2.1] octane or 2, 5-diazabicyclo [2.2.2] octane.
  • each R 3 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 3 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R 3 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 3 is independently methyl or ethyl.
  • m is 0-4. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 0-3. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 0-2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 1.
  • m is 2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 3. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 4. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , m is 5-8
  • each R 4 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , each R 4 is methyl. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , R 4 is F.
  • p is 0-2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , p is 1 or 2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , p is 2. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , p is 1. In some embodiments of a compound of Formula (I-1) or (I-1a) - (I-1f) , p is 0.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  • each R is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or C 1 -C 6 alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.
  • one or more of R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R d .
  • the abundance of deuterium in each of R, R 1 , R 2 , R 3 , R 4 , R U , R T , R a , R b , R c , and R d is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more 1 H of Ring A or Ring B are replaced with one or more deuteriums.
  • the compound of Formula (I) disclosed herein is one of the compounds in Table 1.
  • W’ is N or CR 1b’ ;
  • R 2’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • Ring B’ is a heterocycloalkyl
  • R 3’ on the same or different carbons are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R’;
  • n’ is an integer of 0-6;
  • X’ is N or CR X’ ;
  • Y’ is N or CR Y’ ;
  • Z’ is N or CR Z’ ;
  • R 4’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a’ ;
  • each R a’ is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R’;
  • R a’ are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R’;
  • each R b’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R’;
  • R b’ are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R’;
  • R c’ and R d’ are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R’;
  • R c’ and R d’ are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R’;
  • R 1a’ is halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a’ is halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a’ is independently halogen, -CN, -OR a’ , or -NR c’ R d’ .
  • R 1a’ is -CN or -OR a’ .
  • R 1a’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O-C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • R 1a’ is independently -CN or -NR c’ R d’ .
  • -OR a’ is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a’ is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a’ is In some embodiments of a compound of Formula (II) , -OR a’ is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , -OR a’ is -O-C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , -OR a’ is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (II) , -OR a’ is -O-C 1 -C 3 hydroxylalkyl.
  • -OR a’ is -O-CH 2 CH 2 OH. In some embodiments of a compound of Formula (II) , -OR a’ is -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -OR a’ , -NR c’ R d’ , or heterocycloalkyl. In some embodiments of a compound of Formula (II) , R 1a’ is -OR a’ . In some embodiments of a compound of Formula (II) , R 1a’ is -O-heterocycloalkyl, -O-C 1 -C 6 hydroxylalkyl, -NH-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -O-heterocycloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (II) , R 1a’ is -O-heterocycloalkyl. In some embodiments of a compound of Formula (II) , R 1a’ is -O-5-6 membered heterocycloalkyl. In some embodiments of a compound of Formula (II) , R 1a’ is -O-C 1 -C 6 hydroxylalkyl.
  • R 1a’ is -O-C 1 -C 3 hydroxylalkyl. In some embodiments of a compound of Formula (II) , R 1a’ is -O-CH 2 CH 2 OH. In some embodiments of a compound of Formula (II) , R 1a’ is -O-C 1 -C 6 aminoalkyl.
  • W is N. In some embodiments of a compound of Formula (II) , W is CR 1b’ .
  • each R 1b’ is independently hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 1b’ is independently hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R 1b’ is independently hydrogen, halogen, or -CN.
  • each R 1b’ is independently hydrogen or halogen.
  • each R 1b’ is independently hydrogen or -CN.
  • the compound is of a formula selected from: Formula (IIa) , Formula (IIb) , or Formula (IIc) .
  • R 1a’ is halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a’ is halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1a’ is independently halogen, -CN, -OR a’ , or -NR c’ R d’ .
  • R 1a’ is -CN or -OR a’ .
  • R 1a’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O-C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • R 1a’ is independently -CN or -NR c’ R d’ .
  • -OR a’ is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a’ is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a’ is In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 haloalkyl.
  • -OR a’ is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -OR a’ , -NR c’ R d’ , or heterocycloalkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -OR a’ .
  • R 1a’ is -O-heterocycloalkyl, -O-C 1 -C 6 hydroxylalkyl, -NH-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -O-heterocycloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -O-heterocycloalkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -O-C 1 -C 3 hydroxylalkyl.
  • R 1a’ is -O-CH 2 CH 2 OH. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -O-C 1 -C 6 aminoalkyl.
  • R 1b’ is hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R 1b’ is hydrogen, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 1b’ is halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 1b’ is hydrogen, halogen, or -CN. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is halogen or -CN. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is hydrogen or -CN. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is -CN.
  • R 1b’ is hydrogen or halogen. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is halogen. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is Cl.
  • R 1b’ is halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1b’ is halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1b’ is halogen or -CN.
  • R 1b’ is halogen. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is fluoro or chloro. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1b’ is -CN.
  • R 1b’ is independently halogen, -CN, -OR a’ , or -NR c’ R d’ .
  • R 1b’ is -CN or -OR a’ .
  • R 1b’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • R 1b’ is -CN, -O-heterocycloalkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 3 haloalkyl, -O-C 1 -C 3 hydroxylalkyl, or -O-C 1 -C 3 aminoalkyl.
  • R 1b’ is independently -CN or -NR c’ R d’ .
  • -OR a’ is -O-heterocycloalkyl, -O-C 1 -C 6 alkyl, -O-C 1 -C 6 haloalkyl, -O-C 1 -C 6 hydroxylalkyl, or -O-C 1 -C 6 aminoalkyl.
  • -OR a’ is -O-heterocycloalkyl, wherein the heterocycloalkyl is a 5 or 6 membered ring.
  • -OR a’ is In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 haloalkyl.
  • -OR a’ is -O-C 1 -C 6 hydroxylalkyl. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , -OR a’ is -O-C 1 -C 6 aminoalkyl.
  • R 1a’ is -O-C 1 -C 6 hydroxylalkyl and R 1b’ is CN.
  • R 1a’ is -O-C 1 -C 3 hydroxylalkyl and R 1b’ is CN.
  • R 1a’ is -O-CH 2 CH 2 OH and R 1b’ is CN.
  • R 1a’ is -O-C 1 -C 6 hydroxylalkyl and R 1b’ is halogen.
  • R 1a’ is -O-C 1 -C 3 hydroxylalkyl and R 1b’ is halogen.
  • R 1a’ is -O-CH 2 CH 2 OH and R 1b’ is halogen.
  • R 1a’ is -O-C 1 -C 6 hydroxylalkyl and R 1b’ is chloro. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -O-C 1 -C 3 hydroxylalkyl and R 1b’ is chloro. In some embodiments of a compound of Formula (IIa) , (IIb) , or (IIc) , R 1a’ is -O-CH 2 CH 2 OH and R 1b’ is chloro.
  • R 5’ is hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R’.
  • R 5’ is hydrogen, halogen, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R’.
  • R 5’ is hydrogen, -OR a’ , C 1 -C 6 alkyl, 3-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R’.
  • R 5’ is hydrogen
  • R 5’ is -OR a’ .
  • R 5’ is -O-C 1 -C 6 alkyl, wherein the alkyl is optionally substituted.
  • R 5’ is -O-C 1 -C 6 halolkyl.
  • R 5’ is -O-cycloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 5’ is -O-cycloalkyl, wherein the cycloalkyl is 3-6 membered ring and is optionally substituted with one or more R’.
  • R 5’ is -O-heterocycloalkyl, wherein the heterocycloalkyl is 5-6 membered ring and is optionally substituted with one or more R’.
  • R 5’ is C 1 -C 6 alkyl.
  • R 5 is
  • R 5’ is 3-6 membered cycloalkyl or 5-6 membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more R’.
  • R 2’ is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 2’ is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 2’ is C 1 -C 3 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 2’ is methyl.
  • U’ is N. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , U’ is CR U’ .
  • R U’ is hydrogen or -CN. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R U’ is -CN. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R U’ is hydrogen.
  • a compound of Formula (II) , (IIa) or (IIb) In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is In some embodiments of a compound of Formula (II) , (IIa) or (IIb) , is
  • Ring B’ is a 6-to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-to 8-membered heterocycloalkyl; comprising 1 to 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-to 8-membered heterocycloalkyl; comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring B’ is a 6-to 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring B’ is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • Ring B’ is a 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments of a compound of Formula (II) or (IIa) , Ring B’ is a 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N.
  • each R 3’ is independently halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa) , each R 3’ is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • m’ is 0-6. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0-5. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0-4. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0-3. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0-2. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0 or 1.
  • m’ is 1-6. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 1-5. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 1-4. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 1-3. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 0.
  • m’ is 1. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 2. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 3. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 4. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 5. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 6. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 7. In some embodiments of a compound of Formula (II) or (IIa) , m’ is 5-8.
  • X’ is N. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , X’ is CR X’ .
  • R X’ is hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R X’ is hydrogen, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R X’ is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R X’ is hydrogen.
  • Y’ is N. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , Y’ is CR Y’ .
  • R Y’ is hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R Y’ is hydrogen, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R Y’ is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R Y’ is hydrogen.
  • Z’ is N. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , Z’ is CR Z’ .
  • R Z’ is hydrogen, halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R Z’ is hydrogen, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R Z’ is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , or (IIb) , R Z’ is hydrogen.
  • a compound of Formula (II) or (IIa) is In some embodiments of a compound of Formula (II) or (IIa) , is In some embodiments of a compound of Formula (II) or (IIa) , is In some embodiments of a compound of Formula (II) or (IIa) , is In some embodiments of a compound of Formula (II) or (IIa) , is
  • R 4’ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a’ .
  • R 4’ is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally substituted with one or more R 4a’ .
  • R 4’ is 3-6 membered cycloalkyl optionally substituted with one or more R 4a’ .
  • R 4’ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each optionally substituted with one or more R 4a’ .
  • R 4’ is cyclopropyl optionally substituted with one or more R 4a’ .
  • R 4’ is In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 4’ is In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 4’ is In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 4’ is hydrogen. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , R 4’ is hydrogen, or C 1 -C 6 alkyl.
  • R 4’ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, 3-6 membered 3-to 6-membered cycloalkyl, 5-to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a’ .
  • each R 4a’ is independently halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is optionally and independently substituted with one or more R’.
  • each R 4a’ is independently halogen, -CN, -OH, -OR a’ , -NR c’ R d’ , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 4a’ is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R 4a’ is independently C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R 4a’ is independently C 1 -C 3 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R 4a’ is independently CF 3 .
  • each R a’ is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R’.
  • each R a’ is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R’.
  • each R a’ is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R a’ is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R a’ is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R a’ is independently C 1 -C 6 alkyl.
  • each R b’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R’.
  • each R b’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R’.
  • each R b’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R b’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b’ is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R b’ is independently hydrogen or C 1 -C 6 alkyl.
  • each R b’ is hydrogen. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R b’ is independently C 1 -C 6 alkyl.
  • each R c’ and R d’ are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 - C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) ; wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R c’ and R d’ are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R’.
  • each R c’ and R d’ are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) .
  • each R c’ and R d’ are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl.
  • each R c’ and R d’ are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R c’ and R d’ are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R c’ and R d’ are hydrogen. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R c’ and R d’ are independently C 1 -C 6 alkyl.
  • R c’ and R d’ are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R’ is independently halogen, -CN, -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R’ on the same atom form an oxo.
  • each R’ is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; or two R’ on the same atom form an oxo.
  • each R’ is independently halogen, -CN, -OH, or C 1 -C 6 alkyl; or two R’ on the same atom form an oxo.
  • each R’ is independently halogen, -OH, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R’ is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) , (IIa) , (IIb) , or (IIc) , each R’ is independently halogen.
  • one or more of R’, R 1’ , R 2’ , R 3’ , R 4’ , R 4a’ , R 5’ , R X’ , R Y’ , R Z’ , R a’ , R b’ , R c’ , and R d’ groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R’, R 1’ , R 2’ , R 3’ , R 4’ , R 4a’ , R 5’ , R X’ , R Y’ , R Z’ , R a’ , R b’ , R c’ , and R d’ .
  • the abundance of deuterium in each of R’, R 1’ , R 2’ , R 3’ , R 4’ , R 4a’ , R 5’ , R X’ , R Y’ , R Z’ , R a’ , R b’ , R c’ , and R d’ is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more 1 H of Ring A’ or Ring B’ are replaced with one or more deuteriums.
  • the compound of Formula (I) disclosed herein is one of the compounds in Table 2.
  • the compound of Formula (II) disclosed herein is one of the compounds in Table 3.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium) , 2 H (deuterium) , and 3 H (tritium) .
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Compound 23 is 3- (2-hydroxyethoxy) -5-methyl-8- (4- (5-methylbenzo [d] oxazol-2-yl) piperidin-1-yl) -6-oxo-5, 6-dihydro-1, 5-naphthyridine-2-carbonitrile:
  • Compound 23 is a diacylglycerol kinase alpha (DGKalpha) inhibitor. In some embodiments, Compound 23 is in the form of a freebase. In some embodiments, Compound 23 is in the form of a pharmaceutically acceptable salt thereof.
  • DGKalpha diacylglycerol kinase alpha
  • Compound 13A is 6-chloro-7- (2-hydroxyethoxy) -1-methyl-4- (6- ( (1- (trifluoromethyl) cyclopropyl) ethynyl) -2, 3-dihydrobenzo [e] [1, 4] oxazepin-1 (5H) -yl) quinazolin-2 (1H) -one:
  • Compound 13A is a diacylglycerol kinase alpha (DGK ⁇ ) inhibitor. In some embodiments, Compound 13A is in the form of a freebase. In some embodiments, Compound 13A is in the form of a pharmaceutically acceptable salt thereof.
  • DGK ⁇ diacylglycerol kinase alpha
  • Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • the combined amount of the DGK ⁇ inhibitor, or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.
  • Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • the compound of Formula (I) or Formula (II) is selected from Table 1, Table 2 or Table 3.
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • the combined amount of the Compound 23 or Compound 13A, or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor is therapeutically effective for treating the cancer.
  • the cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML) , glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC) , bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.
  • AML acute myeloid leukemia
  • NSCLC non-small cell lung cancer
  • bladder cancer kidney cancer
  • colorectal cancer esophageal cancer
  • astrocytoma astrocytoma
  • osteosarcoma head and neck cancer
  • myxoid chondrosarcoma ovarian cancer
  • endometrial cancer breast cancer
  • the cancer is liver cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, gastrointestinal stromal tumor, biliary tract cancer, acute lymphoblastic leukemia (ALL) B-lineage, lymphoma, or T cell leukemia.
  • ALL acute lymphoblastic leukemia
  • the additional agent is a PARP inhibitor, a CHK1 inhibitor, a MDM2 inhibitor, a hypomethylating agent, an mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, a PRMT1 inhibitor, an ATR inhibitor, a WEE1 inhibitor, an APE1 inhibitor, a topoisomerase inhibitor, a taxane, an immune checkpoint inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, a DNA synthesis inhibitor, an antimetabolite, an AURORA inhibitor, a microtubule stabilizer, a DNA cross-linker, a vinca alkaloid, an alkylating agent, a PRMT6 inhibitor, a PRMT7 inhibitor, a PRMT9 inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, a MEK inhibitor, a SHP2 inhibitor, a PI3K inhibitor, an AKT inhibitor, a BRAF inhibitor, an aroma
  • the immune checkpoint inhibitor is an inhibitor or antagonist of PD-1, PD-L1, PD-2, PD-L2, IDO-1, IDO-2, CTNNB1 ( ⁇ -catenin) , SIRP ⁇ , VISTA, RNASE H2, DNase II, CLEVER-1/Stabilin-1, LIGHT, HVEM, CTLA-4, LAG-3, TIGIT, Galectin-9, KIR, GITR, TIM-1, TIM-3, TIM-4, CEACAM1, OX40, OX40L, CD27, CD40/CD40L, CD48, CD70, CD80, CD86, CD112, CD137 (4-1BB) , CD155, CD160, CD200, CD226, CD244 (2B4) , CD272 (BTLA) , B7-H2, B7-H3, B7-H4, B7-H6, A2aR, CD73, NKG2A, CCR2, ICOS, A2bR, HHLA2, ILT-2, ILT
  • the immune checkpoint inhibitor is an antagonist of IDO-1, IDO-2, A2aR, CD73, or CCR2, or a pharmaceutically acceptable salt thereof.
  • the IDO-1 antagonist is LY3381916, epacadostat, linrodostat, BMT-297376, palmatine, PF-06840003, or a pharmaceutically acceptable salt thereof.
  • the IDO-2 antagonist is IDO2-IN-1, GNF-PF-3777, or a pharmaceutically acceptable salt thereof.
  • the A2aR antagonist is ciforadenant, imaradenant, etrumadenant, NIR178, inupadenant, CS3005, PBF-999, or INCB106385, or a pharmaceutically acceptable salt thereof.
  • the CD73 antagonist is quemliclustat, AB680, methADP, OP-5244, MRS4620, PSB-12379, or BK50164, or a pharmaceutically acceptable salt thereof.
  • the CCR2 antagonist is JNJ-41443532, CCR2-RA- [R] , PF-4136309, BMS CCR2 22, RS 504393, MK-0812, AZD2423, PF-0463481, BMS-813160, BMS-753426, RS102895, JNJ-27141491, cenicriviroc, BX471, INCB 3284, or INCB3344, or a pharmaceutically acceptable salt thereof.
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-A2aR antibody, an anti-CD73 antibody, an anti-NKG2A antibody, an anti-CCR2 antibody, an anti-HVEM antibody, an anti-KIR antibody, an anti-OX40 antibody, an anti-IgG antibody, an anti-IDO-1 antibody, an anti-IDO-2 antibody, an anti-CEACAM1 antibody, an anti-BTLA antibody, an anti-OX40L antibody, an anti-TIM-3 antibody, an anti-GAL9 antibody, an anti-VISTA antibody, an anti-TIGIT antibody, or a variant thereof or biosimilar thereof.
  • the anti-PD-L1 antibody is AUNP12, JS003, CS-1001, BMS-936559, atezolizumab, avelumab, betifisolimab, durvalumab, garivulimab, opucolimab, sugemalimab, tagitanlimab, envafolimab, cosibelimab, adebrelimab, socazolimab, or a variant thereof or biosimilar thereof.
  • the anti-PD-1 antibody is AMP-224, AMP-514, 14C12H1L1, BAT-1306, AK103, AK104, AK105, SG001, nivolumab, nofazinlimab, pembrolizumab, finotonlimab, genolimzumab, spartalizumab, serplulimab, dostarlimab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, pimivalimab, retifanlimab, sintilimab, zimberelimab or a variant thereof or biosimilar thereof.
  • the anti-CTLA-4 antibody is botensilimab, ipilimumab, zalifrelimab, or tremelimumab, or a variant thereof or biosimilar thereof.
  • the anti-LAG-3 antibody is relatlimab, fianlimab, miptenalimab, bootszelimab, ieramilimab, Sym022, GSK2831781, INCAGN02385, TSR-033, or a variant thereof or biosimilar thereof.
  • the anti-TIGIT antibody is tiragolumab, domvanalimab, vibostolimab, etigilimab, tamgiblimab, M6223, ociperlimab, or EOS884448, or a variant thereof or biosimilar thereof.
  • the anti-TIM-3 antibody is sabatolimab, surzebiclimab, cobolimab, Sym023, R07121661, LY3321367, ICAGN02390, or BMS-986258, or a variant thereof or biosimilar thereof.
  • the anti-B7-H3 antibody is enoblituzumab, omburtamab, vobramitamab, mirzotamab, B7-H3 TriKE, 131 I-omburtamab, DS-7300a, or 177 Lu-DTPA-omburtamab, or a variant thereof or biosimilar thereof.
  • the anti-B7-H4 antibody is alsevalimab, FPA150, or a variant thereof or biosimilar thereof.
  • the anti-CD73 antibody is oleclumab, mupadolimab, uliledlimab, MEDI9447, AK119, HLX23, IPH5301, Sym042, IBI325, PT199, JAB-BX102, NZV930, INCA00186, or BMS-986179, or a variant thereof or biosimilar thereof.
  • the anti-NKG2A antibody is monalizumab, or a variant thereof or biosimilar thereof.
  • the anti-CCR2 antibody is plozalizumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP-224, PF-06801591, MEDI0680, PDR001, REGN2810, SHR-1210, TSR-042, CA-170, atezolizumab, durvalumab, KN035, BMS-936559, ipilimumab, tremelimumab, avelumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tremelimumab, avelumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is nivolumab or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is pembrolizumab or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is pidilizumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is atezolizumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is ipilimumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is tremelimumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is avelumab, or a variant thereof or biosimilar thereof.
  • the additional agent is a PRMT1 inhibitor.
  • the PRMT1 inhibitor is GSK3368715 (EPZ019997) , C7280948, EPZ020411 2HC1, MS023, furamidine, C 21, or TC-E 5003, or a pharmaceutically acceptable salt thereof.
  • the PRMT1 inhibitor is GSK3368715 (EPZ019997) or a pharmaceutically acceptable salt thereof.
  • the additional agent is a PRMT6 inhibitor.
  • the PRMT6 inhibitor is SGC 6870 or a pharmaceutically acceptable salt thereof.
  • the additional agent is a protein arginine methyltransferase 5 (PRMT5) inhibitor, a protein arginine methyltransferase 7 (PRMT7) inhibitor, or a protein arginine methyltransferase 9 (PRMT9) inhibitor.
  • PRMT5 protein arginine methyltransferase 5
  • PRMT7 protein arginine methyltransferase 7
  • PRMT9 protein arginine methyltransferase 9
  • the additional agent is a PRMT5 inhibitor.
  • the PRMT5 inhibitor is JNJ-64619178 (AGI-931) , HLCL-61, GSK591, EPZ015666 (GSK3235025) , GSK3326595 (EPZ015938; AGI-219) , TNG908, TNG462, AMG193, AMG9747, MRTX1719, P305-05313, CTS3157, PH-020-803, or AZ-PRMT5i-1, or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is TNG908, TNG462, AMG193, AMG9747, MRTX1719, or P305-05313, or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931) , or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is GSK3326595 or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is JNJ-64619178 (AGI-931) or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is or a pharmaceutically acceptable salt thereof.
  • the PRMT5 inhibitor is selected from a compound disclosed in WO2021050915, WO2021086879, WO2021/163344, WO2022/026892, WO 2022/256806, WO2023036974, WO2021050915, WO2022192745, WO2023278564, WO2022132914, WO2022169948, WO2022115377, WO2021163344, WO2021086879, WO2022026892, US11077101, Malik, R., et al. AACR Annual Meeting, 2021, Abstract Number 1140, or Bonday, Z. Q., et al., ACS Med. Chem. Lett. 2018, 9, 612-617, the entire contents of which are hereby incorporated by reference in their entirety.
  • the additional agent is a PRMT7 inhibitor.
  • the PRMT7 inhibitor is SGC 3027 or a pharmaceutically acceptable salt thereof.
  • the additional agent is a PRMT9 inhibitor.
  • the additional agent is an ATR inhibitor.
  • the ATR inhibitor is RP-3500, M-6620, berzosertib (M-6620, VX-970; VE-822) , AZD-6738, AZ-20, M-4344 (VX-803) , BAY-1895344, M-1774, IMP-9064, nLs-BG-129, SC-0245, BKT-300, ART-0380, ATRN-119, ATRN-212, or NU-6027, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a WEE1 inhibitor.
  • the WEE1 inhibitor is AZD1775 (MK1775) , ZN-c3, debio 0123, IMP7068, SDR-7995, SDR-7778, NUV-569, PD0166285, PD0407824, SC-0191, DC-859/A, bosutinib, or Bos-I, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a topoisomerase inhibitor.
  • the topoisomerase inhibitor is epipodopyyllotoxin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, exatecan, lurtotecan, lamellarin D9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-8951f, MAG-CPT, thiotepa, cyclosphosphamide, amsacrine, etoposide, etoposide phosphate, teniposide, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, doxorubicin, or HU-331, or a pharmaceutically acceptable salt thereof.
  • the topoisomerase inhibitor is topotecan, daunorubicin, mitoxantrone, or, doxorubicin, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a cytotoxic agent.
  • the cytotoxic agent is an alkylating agent, a cytotoxic antibiotic agent, an antimetabolite, a vinca alkaloid, a platinum drug, a taxane, or a topoisomerase inhibitor.
  • the additional agent is a cytotoxic antibiotic agent.
  • the cytotoxic antibiotic agent is an anthracycline (e.g., doxorubicin and valrubicin) .
  • the cytotoxic antibiotic agent is a non-anthracycline (e.g., bleomycin and dactinomycin) .
  • the additional agent is an agent that is detrimental to the viability of cells.
  • the additional agent is platinum drug.
  • the platinum drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.
  • the additional agent is a taxane.
  • the taxane is docetaxel, paclitaxel, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, chalcomenite, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, or 10-deacetyl chalcomenite, or a pharmaceutically acceptable salt thereof.
  • the taxane is docetaxel, or paclitaxel, or or a pharmaceutically acceptable salt thereof.
  • the taxane is docetaxel or a pharmaceutically acceptable salt thereof.
  • the taxane is paclitaxel or a pharmaceutically acceptable salt thereof.
  • the additional agent is a CDK7 inhibitor.
  • the CDK7 inhibitor is LDC4297, THZ1, THZ2, YKL-5-124, BS-181, samuraciclib, LY3405105, PHA-793887, SNS-032 (BMS-387032) , PF-562271, or milciclib (PHA-848125) , or a pharmaceutically acceptable salt thereof.
  • the additional agent is a CDK9 inhibitor.
  • the CDK9 inhibitor is SNS-032 (BMS-387032) , LY2857785, alvocidib, or riviciclib hydrochloride (P276-00) , or a pharmaceutically acceptable salt thereof.
  • the additional agent is a DNA synthesis inhibitor.
  • the DNA synthesis inhibitor is 5-fluorouracil (5-FE1) , 6-mercaptopurine (6-MP) , capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, or pemetrexed, or a pharmaceutically acceptable salt thereof.
  • the DNA synthesis inhibitor is 5-fluorouracil (5-FE1) , fludarabine, gemcitabine, or pemetrexed, or a pharmaceutically acceptable salt thereof.
  • the DNA synthesis inhibitor is 5-fluorouracil (5-FE1) or a pharmaceutically acceptable salt thereof.
  • the DNA synthesis inhibitor is fludarabine or a pharmaceutically acceptable salt thereof.
  • the DNA synthesis inhibitor is gemcitabine or a pharmaceutically acceptable salt thereof. In some embodiments, the DNA synthesis inhibitor is pemetrexed or a pharmaceutically acceptable salt thereof.
  • the additional agent is an antimetabolite.
  • the antimetabolite is 5-fluorouracil (5-FU) , 6-mercaptopurine (6-MP) , capecitabine, cytarabine, Floxuridine, fludarabine, gemcitabine, hydroxy carbamide, methotrexate, pemetrexed, or phototrexate, or a pharmaceutically acceptable salt thereof.
  • the antimetabolite is pemetrexed or a pharmaceutically acceptable salt thereof.
  • the additional agent is an AURORA inhibitor.
  • the AURORA inhibitor is alisertib (MLN8237) , tozasertib (VX-680, MK-0457) , barasertib (AZDI 152-HQPA) , ZM 447439, MLN8054, danusertib (PHA-739358) , AT9283, JNJ-7706621, hesperadin, aurora A inhibitor I (TC-S7010) , KW-2449, SNS-314, ENMD-2076, PHA-680632, MK-5108 (VX-689) , CYC116, AMG-900, PF-03814735, CCT 129202, GSK1070916, TAK-901, CCT137690, MK-8745, ENMD-2076, aurora kinase inhibitor III, SNS-314 mesylate, BI-847325, reversine, or ABT-348, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a KRAS inhibitor.
  • the KRAS inhibitor is a KRAS G12C inhibitor.
  • the KRAS inhibitor is a KRAS G12D inhibitor.
  • the KRAS inhibitor is a KRAS G12S inhibitor.
  • the KRAS inhibitor is 6H05, adagrasib, ARS-1323, ARS-1323-alkyne, ARS-1620, ARS-1630, ARS-853, ASP2453 , AZD4625, BAY-293, BI-0474, BI-2852, BI-3406, divarasib, G12Si-1, G12Si-5 formic, G12Si-5, garsorasib, K20, KRAS G12C inhibitor 1, KRAS G12C inhibitor 2, KRAS G12C inhibitor 3, KRAS G12C inhibitor 4, KRAS G12C inhibitor 5, KRAS G12C inhibitor 13, KRAS G12C inhibitor 14, KRAS G12C inhibitor 15, KRAS G12C inhibitor 16, KRAS G12C inhibitor 17, KRAS G12C inhibitor 18, KRAS G12C inhibitor 23, KRAS G12C inhibitor 24, KRAS G12C inhibitor 25, KRAS G12C inhibitor 26, KRAS G12C inhibitor 27, KRAS G12C
  • the KRAS inhibitor is ARS-3248 (JNJ-74699157) , AMG510, MRTX849, MRTX1133, ASP245, 3GDC6036, BI-2852, BI 1701963, mRNA-5671, JDQ443, RAS (ON) inhibitors, BBP-454, RM-018, RMC-6291, or RMC-6236, or a pharmaceutically acceptable salt thereof.
  • the KRAS inhibitor is adagrasib, divarasib, garsorasib, opnurasib, or sotorasib, or a pharmaceutically acceptable salt thereof.
  • the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.
  • the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.
  • the KRAS inhibitor is selected from a compound disclosed in WO2018119183, WO2018217651, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019232419, WO2019241157, WO2020106640, WO2021081212, WO2022083569, WO2022093856, WO2022232332, WO2022232331, WO2020146613, WO2020097537, WO2015054572, WO2020177629, WO2019141250, WO2020081282, WO2020085493, WO2018143315, WO2018206539, WO2019110751, WO2019195609, WO2021207172, WO2021041671, WO2021150613, WO2021142252, WO2021152149, WO2021248090, WO2021216770, WO2022002102, WO2022031678, US10662204B2, US10
  • the additional agent is an EGFR inhibitor.
  • the EGFR inhibitor is Erlotinib (OSI-774) HCl, Gefitinib (ZD1839) , Lapatinib (GW-572016) Ditosylate, Afatinib (BIBW2992) , Saracatinib (AZD0530) , Vandetanib (ZD6474) , Neratinib (HKI-272) , Canertinib (CI-1033) , Lapatinib (GW-572016) , AG-490 (Tyrphostin B42) , CP-724714, Dacomitinib (PF-00299804) , WZ4002, Sapitinib (AZD8931) , CUDC-101, AG-1478 (Tyrphostin AG-1478) , PD153035 HCl, Pelitinib (EKB-569) , AEE788 (NVP-AEE788) , AC480 (BMS-5996
  • the additional agent is a VEGFR inhibitor.
  • the VEGFR inhibitor is Sorafenib (BAY 43-9006) tosylate, Sunitinib (SU11248) malate, Cabozantinib (BMS-907351) , Ponatinib (AP24534) , Axitinib (AG 013736) , Foretinib (GSK1363089) , Vandetanib (ZD6474) , Nintedanib (BIBF 1120) , Regorafenib (BAY 73-4506) , Pazopanib HCl (GW786034 HCl) , Cediranib (AZD2171) , PD173074, Dovitinib (TKI-258) , Linifanib (ABT-869) , Vatalanib (PTK787) 2HCl, RAF265 (CHIR-265) , Tivozanib (AV-951) , Motesanib Diphosphate (AMG-706) ,
  • the additional agent is an aromatase inhibitor.
  • the aromatase inhibitor is Letrozole (CGS 20267) , Anastrozole (ZD-1033) , Exemestane (FCE 24304) , Formestane, Fadrozole (CGS16949A) , alpha-Naphthoflavone, or Obacunone (AI3-37934) , or a pharmaceutically acceptable salt thereof.
  • the additional agent is a mitotic inhibitor.
  • the mitotic inhibitor is a taxane (e.g., Paclitaxel and Docetaxel) , a vinca alkaloid (e.g., Vinblastine, Vincristine, Vindesine, and Vinorelbine) , Colchicine, Podophyllotoxin, Griseofulvin, or Glaziovianin A, or a pharmaceutically acceptable salt thereof.
  • a taxane e.g., Paclitaxel and Docetaxel
  • a vinca alkaloid e.g., Vinblastine, Vincristine, Vindesine, and Vinorelbine
  • Colchicine e.g., Colchicine
  • Podophyllotoxin e.g., Podophyllotoxin
  • Griseofulvin e.g., Glaziovianin A
  • the additional agent is a microtubule stabilizer.
  • the microtubule stabilizer is paclitaxel, nab-paclitaxel, docetaxel, colchicine, podophyllin, epothilone A, or epothilone B, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a radiopharmaceutical agent.
  • the additional agent is a DNA cross-linker.
  • the DNA cross-linker is oxaliplatin, cisplatin, or a pharmaceutically acceptable salt thereof.
  • the additional agent is a vinca alkaloid.
  • the vinca alkaloid is vinorelbine, vincristine, vinblastine, vinblastine N-oxide, vindesine, vinflunine, vincamine, vintafolide, or deacetoxyvinzolidine, or a pharmaceutically acceptable salt thereof.
  • the additional agent is an alkylating agent.
  • the alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum coordination complexes, or a pharmaceutically acceptable salt thereof.
  • the additional agent is folic acid analogs, pyrimidine analogs, purine analogs, antibiotics, L-asparaginase, interferons, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestin, estrogen, antiestrogen receptor inhibitor, androgen, antiandrogen receptor inhibitor, endocrine/hormonal agents, or gonadotropin-releasing hormone analog, or a pharmaceutically acceptable salt thereof.
  • the antiestrogen receptor inhibitor is Fulvestrant (ICI-182780) , Raloxifene HCl, Bazedoxifene (WAY-140424) HCl, G-1, Amcenestrant (SAR439859) , Estrogen receptor modulator 1, Lasofoxifene Tartrate, H3B-5942, Raloxifene, Brilanestrant (GDC-0810) , Tamoxifen (ICI 46474) Citrate, Toremifene Citrate (NK 622) , Clomifene citrate, Estriol, Estrone, Bazedoxifene (TSE-424) acetate, SPP-86, Enclomiphene Citrate, Phenol Red sodium salt, Camizestrant (AZD9833) , G15 (GRB-G15) , Cyclofenil, PHTPP, AZD9496, Chlorotrianisene, Endoxifen HCl, Ospemifene, or Tamoxifen (ICI
  • the antiandrogen receptor inhibitor is Enzalutamide (MDV3100) , Bicalutamide (ICI-176334) , Ostarine, Apalutamide (ARN-509) , Galeterone, Flutamide, Cyproterone Acetate, AZD3514, Spironolactone, ORM-15341, CLP-3094, Proxalutamide (GT0918) , JNJ-63576253 (TRC-253) , Bavdegalutamide (ARV-110) , ACP-105, Ailanthone, UT-34, Triptophenolide, 4, 4'-DDE, EPI-001, Darolutamide (ODM-201) , Megestrol Acetate, Clascoterone, Inobrodib (CCS-1477) , GSK-2881078, (S, R, S) -AHPC (MDK7526) , Dimethylcurcumin (ASC-J9) , RU58841, Nilutamide, 3,
  • the additional agent is a chemotherapeutic agent.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:
  • the immune checkpoint inhibitor is an inhibitor or antagonist of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A or CCR2.
  • the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tremelimumab, avelumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is nivolumab or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is pembrolizumab or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is pidilizumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is atezolizumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is ipilimumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is tremelimumab, or a variant thereof or biosimilar thereof.
  • the immune checkpoint inhibitor is avelumab, or a variant thereof or biosimilar thereof.
  • the present disclosure provides use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.
  • the present disclosure provides use of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.
  • the present disclosure provides use of Compound 23 or Compound 13A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is formulated for being administered in combination with an additional agent.
  • the present disclosure provides use of Compound 23 or Compound 13A or a pharmaceutically acceptable salt thereof and an additional agent in the manufacture of a medicament for treating cancer.
  • the additional agent is an immune checkpoint inhibitor. In some embodiments, the additional agent is nivolumab, pembrolizumab, pidilizumab, atezolizumab, ipilimumab, tremelimumab, avelumab, or a variant thereof or biosimilar thereof.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • Example 13A Synthesis of 6-chloro-7- (2-hydroxyethoxy) -1-methyl-4- (6- ( (1- (trifluoromethyl) cyclopropyl) ethynyl) -2, 3-dihydrobenzo [e] [1, 4] oxazepin-1 (5H) -yl) quinazolin-2 (1H) -one (Compound 13A)
  • IC 50 (nM) 0 ⁇ A ⁇ 10; 10 ⁇ B ⁇ 100; 100 ⁇ C ⁇ 1000
  • Each mouse will be subcutaneously inoculated with MC38, CT26 or B16F10 tumor cells in 0.1 mL of DPBS at the right flank for tumor development.
  • the animals will be randomized and treatment will be started when the average tumor volume reaches approximately ⁇ 30-100 mm 3 for each in vivo efficacy study.
  • Anti-mPD-1 (BP0146) , Anti-mPD-L1 (BP0101) and Anti-mCTLA-4 (BP0164) were used in the single arms and combination arms treatment. The major endpoint is to see if the tumor growth can be delayed or mice can be cured.
  • CDI The coefficient of drug interaction

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement du cancer chez un sujet en ayant besoin, comprenant l'administration au sujet (a) d'un inhibiteur de DGKα ou d'un sel pharmaceutiquement acceptable de celui-ci ; et (b) d'un agent supplémentaire, en particulier d'un inhibiteur de point de contrôle immunitaire.
PCT/CN2024/116517 2023-09-04 2024-09-03 Combinaisons de traitements par inhibiteurs de diacylglycérol kinase (dgk) alpha et d'autres thérapies Pending WO2025051110A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2023/116718 2023-09-04
CN2023116718 2023-09-04

Publications (1)

Publication Number Publication Date
WO2025051110A1 true WO2025051110A1 (fr) 2025-03-13

Family

ID=94922962

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/116517 Pending WO2025051110A1 (fr) 2023-09-04 2024-09-03 Combinaisons de traitements par inhibiteurs de diacylglycérol kinase (dgk) alpha et d'autres thérapies

Country Status (1)

Country Link
WO (1) WO2025051110A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021105117A1 (fr) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Aminoquinolones substituées en tant qu'inhibiteurs de dgkalpha pour activation immunitaire
WO2021133752A1 (fr) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Composés hétéroaryle substitués utiles en tant qu'activateurs de lymphocytes t
WO2022271677A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2023165504A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de diacylglycérol kinase (dgk) alpha et leurs utilisations
WO2023165509A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de diacylglycérol kinase (dgk) alpha et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021105117A1 (fr) * 2019-11-28 2021-06-03 Bayer Aktiengesellschaft Aminoquinolones substituées en tant qu'inhibiteurs de dgkalpha pour activation immunitaire
WO2021133752A1 (fr) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Composés hétéroaryle substitués utiles en tant qu'activateurs de lymphocytes t
WO2022271677A1 (fr) * 2021-06-23 2022-12-29 Gilead Sciences, Inc. Composés de modulation de la diacylglycérol kinase
WO2023165504A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de diacylglycérol kinase (dgk) alpha et leurs utilisations
WO2023165509A1 (fr) * 2022-03-01 2023-09-07 Insilico Medicine Ip Limited Inhibiteurs de diacylglycérol kinase (dgk) alpha et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FUSCO, C.D. ET AL.: "Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model", J. MED. CHEM., vol. 64, 26 April 2021 (2021-04-26), pages 6814 - 6826, XP055830958, DOI: 10.1021/acs.jmedchem.1c00067 *

Similar Documents

Publication Publication Date Title
CN113980032B (zh) 稠合四环类衍生物、其制备方法及其在医药上的应用
JP6563623B1 (ja) ピリドピリミジノンｃｄｋ２／４／６阻害剤
JP2025037892A (ja) ピロロピリミジンｉｔｋ阻害剤
EP3999507B1 (fr) Dérivés d'imidazo [4,5-c] pyridine en tant qu'agonistes du récepteur de type toll
WO2024217502A1 (fr) Combinaisons d'inhibiteurs de méthionine adénosyltransférase 2a (mat2a) et leurs utilisations
CA2778291C (fr) Inhibiteurs d'akt
CA2992688A1 (fr) Nouveaux analogues nucleosidiques substitues par un cycle aromatique bicyclique 6-6 utiles comme inhibiteurs de prmt5
UA119767C2 (uk) Лікування b-клітинних злоякісних новоутворень із застосуванням комбінації інгібіторів jak та pi3k
JP2013177421A (ja) Ｐｄｅ４の二環式ヘテロアリール阻害剤
CA2907751A1 (fr) Derives de 3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1h-pyrrolo[2,3-c]pyridine en tant qu'inhibiteurs de nik dans le traitement du cancer
TW201838981A (zh) 嘧啶基-吡啶氧基-萘基化合物以及治療ire1相關之疾病及病症的方法
CA3161339A1 (fr) Composes cycliques et leurs procedes d'utilisation
US12077538B2 (en) Diacylglycerol kinase (DGK) alpha inhibitors and uses thereof
AU2021265578A1 (en) Azalactam compounds as HPK1 inhibitors
US10501466B2 (en) WDR5 inhibitors and modulators
CN116888119A (zh) 腺苷A2a受体的拮抗剂
WO2023165528A1 (fr) Inhibiteurs de la diacylglycérol kinase (dgk) alpha et leurs utilisations
US20250214990A1 (en) Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof
WO2025067468A1 (fr) Inhibiteurs de cbl-b et leurs méthodes d'utilisation
WO2025007955A1 (fr) Combinaisons d'inhibiteurs d'ecto-nucléotide pyrophosphatase/phosphodiestérase 1 (enpp1) et leurs utilisations
WO2025167978A1 (fr) Combinaisons d'inhibiteurs de kinase dépendante des cyclines (cdk) 12 et/ou cdk13 et leurs utilisations
WO2024217563A1 (fr) Inhibiteur de lysine acétyltransférase 6a (kat6a), associations et utilisations associées
EA052540B1 (ru) Ингибиторы альфа-диацилглицеринкиназы (дгк) и способы их применения
JP2026514893A (ja) メチオニンアデノシルトランスフェラーゼ２ａ（ｍａｔ２ａ）阻害剤の組合せ及びその使用
WO2024243485A1 (fr) Inhibiteurs de cdk2 et leurs utilisations

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: 24861953

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE