WO2025106905A1 - Polythérapies comprenant un modulateur de kras et un inhibiteur d'immunomodulateur - Google Patents

Polythérapies comprenant un modulateur de kras et un inhibiteur d'immunomodulateur Download PDF

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WO2025106905A1
WO2025106905A1 PCT/US2024/056253 US2024056253W WO2025106905A1 WO 2025106905 A1 WO2025106905 A1 WO 2025106905A1 US 2024056253 W US2024056253 W US 2024056253W WO 2025106905 A1 WO2025106905 A1 WO 2025106905A1
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alkyl
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heterocycle
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Hong Lin
Cameron PITT
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Quanta Therapeutics Inc
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

  • KRAS The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • MAPK mitogen-activated protein kinase
  • Ras has been recognized as a target in cancer for about 40 years, Ras- driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies.
  • Ras encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP -bound state.
  • the most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4).
  • Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.
  • KRAS The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • MAPK mitogen-activated protein kinase
  • Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies.
  • Ras encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP -bound state.
  • the most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4).
  • Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.
  • GAP GTPase activating protein
  • GEF guanine nucleotide exchange factor
  • SOS guanine nucleotide exchange factor
  • KRAS G12C mutations most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP -bound state.
  • KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation.
  • oncogenic KRas mutations create an immunosuppressive microenvironment which can result in resistance to immune checkpoint blockade (ICB) therapy, including anti-PD-1 and anti-PD-Ll inhibitors.
  • Activated KRas has been demonstrated to repress the expression of interferon regulatory factor 2 (IRF2), which directly represses CXCL3 expression.
  • IRF2 interferon regulatory factor 2
  • This KRas-mediated repression of IRF2 leads to increased expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells (MDSC) promoting migration of these cells to the tumor microenvironment.
  • MDSC myeloid-derived suppressor cells
  • oncogenic KRas signaling has been shown to promote tumor immunoresistance to ICB therapy by stabilizing PD-L1 mRNA via repression of the AU- rich element-binding protein tristetraprolin (TTP), which negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA (e.g., see Coelho et al., (2017) Immunity 47(6): 1083-1099).
  • TTP AU- rich element-binding protein tristetraprolin
  • KRas activating mutations upregulate IL-8 expression in NSCLC
  • IL-8 plays a role in cell growth and migration in KRas-associated NSCLC (e.g., see Sunaga et al., (2012) Int. J. Cancer 130(8): 1733-1744).
  • activated KRas mutations or other KRas-activating generic alterations expression may modulate many aspects of the immune system and can be responsible for the immunosuppressive tumor microenvironment in KRas mutant or hyperactivated Kras wildtype- associated tumors.
  • the direct inhibition of KRas mutant or hyperactivated Kras wildtype-associated-mediated cell activity may reverse this reported immunosuppressive tumor microenvironment thereby improving the clinical activity of immune checkpoint blockade therapy, including the PD-1/PD-L1 pathway.
  • the compounds described herein direct potency against tumor cells, compounds described herein may modulate the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release.
  • TAE tumor microenvironment
  • the compounds described herein direct potency against tumor cells, compounds described herein may reprogram the tumor microenvironment (TME) in favor of antitumor immunity, by modulating tumor cell cytokine/chemokine release. Specifically, treatment with compounds described herein reduces immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS mutant cells. Results of our study herein (e.g., example 14) reveal a direct mechanism by which compounds described herein can modify tumor-cell-intrinsic immune signals to enhance antitumor immunity in a synergistic manner with the use of common immune checkpoint inhibitors.
  • TEE tumor microenvironment
  • the present disclosure provides combination therapies useful for treating a disease or disorder (e.g., cancer).
  • a disease or disorder e.g., cancer
  • an agent that disrupts Programmed cell death protein 1 (PD-1) and Programmed death-ligand 1 (PD-L1) axis signaling e.g., a PD-1 inhibitor, a PD-Ll inhibitor
  • kits comprising the compositions and methods of use thereof.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof wherein:
  • Y is selected from a bond, -0-, -S-, and -N(R 5 )-;
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of
  • Y is selected from a bond, and -O-;
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor and a compound represented by the structure of
  • Y is -0-
  • R 2 is selected from -L-heterocycle, and -L-N(R 23 ) 2 , wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R 6 .
  • R 3 is selected from hydrogen, halogen, -CN, -N(R 20 ) 2 , -OR 20 , -C(O)R 20 , Ci-6 alkyl-N(R 20 ) 2 , Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl; and each R 20 is independently selected from hydrogen; and Ci-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH 2 , -N(CI-6 alkyl) 2 , Cnio alkyl, -Ci-io haloalkyl, -O-Ci-io alkyl, and oxo.
  • a method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof; and a compound selected pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof.
  • a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutical composition thereof.
  • FIG. 1 illustrates that compounds herein reduce immunosuppressive cytokine release while increasing immunostimulatory chemokine release in KRAS-mutant HP AC cells.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (z.e., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (z.e., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (z.e., Ci-Cs alkyl).
  • an alkyl comprises one to five carbon atoms (z.e., C1-C5 alkyl).
  • an alkyl comprises one to four carbon atoms (z.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (z.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (z.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (z.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl).
  • an alkyl comprises two to five carbon atoms (z.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (z.e., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (z.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • C x -y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • Ci-ealkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • -C x.y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O- alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl).
  • an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl).
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (z.e., C2-C12 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (z.e., C2-C8 alkynyl).
  • an alkynyl comprises two to six carbon atoms (z.e., C2-C6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (z.e., C2-C4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C x -yalkenyl and “C x -yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term -C x.y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • -C2-ealkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term -C x.y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • -C2-ealkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkylene comprises one to ten carbon atoms (i.e., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene).
  • an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene).
  • an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene).
  • an alkenylene comprises five to eight carbon atoms (i.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).
  • Alkynylene or "alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain.
  • an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene).
  • an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene).
  • an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • “Aralkyl” refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • Carbocycle refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • An aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • unsaturated carbocycle refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles.
  • unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.
  • Cycloalkyl refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkylalkyl refers to a radical of the formula -R c -cycloalkyl where R c is an alkylene chain as described above.
  • Cycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -cycloalkyl where R c is an alkylene chain as described above.
  • Halo or "halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., tri chloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.).
  • each halogen may be independently selected
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane- 1,2-di amine, pentane- 1,2,4- triamine and the like.
  • Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1,4-diol, pentane- 1, 2, 4-triol, and the like.
  • Alkoxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3 -dimethoxybutane, 1- methoxypropane, 2-ethoxypentane, and the like.
  • Cyanoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
  • an aromatic ring e.g., pyridyl
  • a bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • Bicyclic heterocycles may be fused, bridged, or spiro-ring systems.
  • a spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”.
  • spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom.
  • the spiroheterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.
  • Heterocyclene refers to a divalent heterocycle linking the rest of the molecule to a radical group.
  • Heteroaryl or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.
  • An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • the term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles.
  • unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine.
  • Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, z.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.
  • electrophile or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and/or an excess of electrons, for example an — SH group).
  • Electrophiles typically are electron poor or comprise atoms which are electron poor.
  • an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge or partial positive charge.
  • an electrophile comprises a conjugated double bond, for example an a,P-unsaturated carbonyl or a,P-unsaturated thiocarbonyl compound.
  • the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /?-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treat may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of 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 either prophylactically and/or therapeutically.
  • G12 mutants refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X).
  • KRas G12D-associated cancer refers to cancers associated with or mediated by or having a KRas G12D mutation.
  • KRas G12V-associated cancer refers to cancers associated with or mediated by or having a KRas G12V mutation.
  • KRas wildtype-associated cancer refers to cancers associated with or mediated by or having a KRas wildtype.
  • immunomodulator inhibitor refers to an agent that modifies, or modulates, the immune system to help a subject respond to a disease or disorder.
  • PD-1 inhibitor refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-1 axis signaling activity and include agents that block PD- 1.
  • PD-L1 inhibitor refers to an agent that is capable of negatively modulating or inhibiting all or a portion of the PD-L1 axis signaling activity and include agents that block PD-L1.
  • PD-1 binding antagonist is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2.
  • PD-L1 binding antagonist is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1.
  • biosimilar means an antibody or antigen-binding fragment that has the same primary amino acid sequence as compared to a reference antibody (e.g., nivolumab or pembrolizumab) and optionally, may have detectable differences in post-translation modifications (e.g., glycosylation and/or phosphorylation) as compared to the reference antibody (e.g., a different glycoform).
  • a reference antibody e.g., nivolumab or pembrolizumab
  • post-translation modifications e.g., glycosylation and/or phosphorylation
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof' refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • administer are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • administer should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein.
  • the specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.
  • “synergy,” “synergetic,” “synergism,” or “synergistic effect” refer to two or more compounds or compositions, that individually produce an effect, however, together produce a combined effect that is greater than their individual effects.
  • the term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I- A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: i) an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the immunomodulator inhibitor is selected from a PD-1 inhibitor, a PD-Ll inhibitor, and a CTLA-4 inhibitor. In some cases, the immunomodulator inhibitor is a PD-1 inhibitor. In some cases, the immunomodulator inhibitor is a PD-L1 inhibitor. In some cases, the immunomodulator inhibitor is a CTLA-4 inhibitor. In some embodiments, the immunomodulator inhibitor is selected from a PD-1/PD-L1 checkpoint inhibitor.
  • the immunomodulator inhibitor is immune checkpoint inhibitor.
  • the immunomodulator inhibitor is pembrolizumab.
  • the immunomodulator inhibitor is relatlimab.
  • programmed death protein 1 is an immunoinhibitory receptor that is primarily expressed on activated T and B cells.
  • PD-1 is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72).
  • PD-1 contains a membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal tyrosine-based switch motif (ITSM).
  • ITIM immunoreceptor tyrosine inhibitory motif
  • ITSM membrane distal tyrosine-based switch motif
  • Two ligands that bind to PD-1 have been identified, PD-L1 and PD-L2, that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al.
  • PD-L1 is a ligand for PD-1 and is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9). In some cases, the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al. (2003) J. Mol. Med. 81 :281-7).
  • immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD- L2 is blocked as well.
  • disruption of the PD-1/PD-L1 interaction has been shown to increase T cell proliferation and cytokine production and block progression of the cell cycle.
  • PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system, blocking the interaction between PD-1 and PD-L1 has garnered the attention of the pharmaceutical industry leading to a new break-through class of immune checkpoint therapies for a wide range of cancers.
  • the PD-1/PD-L1 pathway is a well-validated target for the development of antibody therapeutics for cancer treatment and several anti -PD-1 and anti-PD-Ll antibodies have undergone human clinical trials for a wide- variety of cancers including NSCLC, renal cell carcinoma, melanoma, head and neck squamous cancer, ureothelial cancer, hepatocellular carcinoma, and other cancers.
  • anti-PD-1 antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®) and tislelizumab, and biosimilars thereof.
  • anti-PD-Ll antibodies include atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®), and biosimilars thereof.
  • agents that disrupt PD-1/PD-L1 signaling axis are well known to those skilled in the art and agents that disrupt PD-1/PD-L1 signaling axis may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or approved human clinical use.
  • suitable agents that disrupt PD-1/PD-L1 signaling for use in the compositions and methods disclosed herein and methods for preparing such agents, and diagnostic and efficacy markers useful for monitoring treatment are disclosed in US Patent Application Publication Nos: 20180327848; 20180237524; 20180148790; 20180111996; 20160305947; 20160304969;
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I-A), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: i) an PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a PD-1 inhibitor is selected from a PD-1 binding antagonist.
  • the PD-1 binding antagonist is selected from anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides.
  • the PD-1 binding antagonist is an anti-PD-1 antibody.
  • the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its binding partners. In some cases, the PD-1 inhibitor inhibits the binding of PD-1 to PD-L1 and/or PD-L2. In some cases, PD-1 inhibitors include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less non- dysfunctional.
  • the PD-1 inhibitor is an anti-PD-1 antibody.
  • the PD- 1 antibody is pembrolizumab, or a biosimilar thereof.
  • the PD-1 antibody is cemiplimab, or a biosimilar thereof.
  • the PD-1 antibody is tislelizumab, or a biosimilar thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I- A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I-B), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: i) an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a PD-L1 inhibitor is selected from a PD-L1 binding antagonist.
  • the PD-L1 binding antagonist is selected from an anti-PD-Ll antibody, antigen binding fragments thereof, immunoadhesins, aptamers, fusion proteins, and oligopeptides.
  • the PD-L1 binding antagonist is an anti-PD-Ll antibody.
  • a PD-L1 inhibitor is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • the PD-L1 inhibitor inhibits binding of PD-L1 to PD-1 and/or B7-1.
  • the PD-L1 inhibitors include anti-PD-Ll antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1.
  • a PD-L1 inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as render a dysfunctional T-cell less non-dysfunctional.
  • a PD-L1 inhibitor is an anti-PD-Ll antibody.
  • an anti- PD-L1 antibody is avelumab or a biosimilar thereof.
  • an anti-PD-Ll antibody is atezolizumab or a biosimilar thereof.
  • an anti-PD- Ll antibody is durvalumab or a biosimilar thereof.
  • an anti-PD-Ll antibody is BMS-936559 (MDX-1105) or a biosimilar thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I- A), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an CTLA-4 inhibitor, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof, and ii) a compound of Formula (I-B), or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the CTLA-4 inhibitor is selected from Ipilimumab. KRAS Inhibitors
  • the compounds and salts may be used in combination with at least one other inhibitor (e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor).
  • the compounds and salts e.g., a compound of Formula (I), (I- A), or (I-B)
  • may be used in combination with one other inhibitor e.g., immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor.
  • a compound of Formula (I), (LA), or (LB) may be used in the methods of the disclosure.
  • a compound of Formula (I), (LA), or (LB) may be referred to as a KRAS inhibitor.
  • a compound of Formula (I), (LA), or (LB) may be referred to as a KRAS inhibitor.
  • Y is selected from a bond, -0-, -S-, and -N(R 5 )-;
  • B is selected from an optionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7-C15 fused carbocycle. In some cases, and optionally substituted C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl.
  • B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle. In some cases, and optionally substituted Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl.
  • B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted Cs-Cis fused aryl. In some cases, B is an optionally substituted unsaturated Cs-Cis fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 8- to 15- membered fused heterocycle, wherein the fused heterocycle is partially saturated.
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic).
  • B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic).
  • the optionally substituted 8- to 15- membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are each independently bicyclic or tricyclic.
  • the optionally substituted 8- to 15- membered fused heterocycle is bicyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is tricyclic. [00124] In some embodiments, for a compound or salt for Formula (I), the heterocycle or carbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.
  • the heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted Cs-Cis fused carbocycle are selected from , each of which is optionally substituted with one or more substituents.
  • B each of which is optionally substituted with one or more substituents.
  • B is selected from each of which is optionally substituted with one or more substituents.
  • B is selected from substituents.
  • the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH 2 , halogen, C1-C3 alkyl.
  • B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle.
  • the heterocycle of B has at least one sulfur atom.
  • the heterocycle of B has one or sulfur atoms.
  • the heterocycle of B has at least one substituted.
  • B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. In is optionally substituted.
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted. In some cases, B is substituted with at least one -NH2. In some cases, B is selected from some cases, B is substituted with at least one -NH2 at least one -CN. In some cases, B is selected
  • B is an optionally substituted 7- to 11 -membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, B is an optionally substituted 7-membered fused heterocycle. In some cases, B is an optionally substituted 8-membered fused heterocycle. In some cases, B is an optionally substituted 9-membered fused heterocycle. In some cases, B is an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non-aromatic heterocycle.
  • B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases,
  • B has at least 2 heteroatoms. In some cases, B is selected from each of which is optionally substituted. In some cases, B is selected from each of which is optionally substituted. In some cases, B is selected from
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN.
  • B is substituted with at least three substituents.
  • B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is selected from ,
  • R 3 is selected from hydrogen, halogen, -CN, -NO 2 , -N(R 20 ) 2 , -OR 20 , -SR 20 , -S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , - NR 20 S(O) 2 R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , - C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , Ci- 6 aminoalkyl, Ci- 6 alkoxy, Ci- 6 alkoxyalkyl, C1-6 hydroxyalkyl, C 1-6
  • R 3 is selected from hydrogen, halogen, -CN, -NO 2 , -N(R 20 ) 2 , -OR 20 , -SR 20 , -C(O)N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , Ci- 6 aminoalkyl, Ci- 6 alkoxy, Ci- 6 alkoxyalkyl, Ci- 6 hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, Ci-6 alkyl, C 2 -6 alkenyl, C 2 -e alkynyl.
  • R 3 is selected from hydrogen, halogen, -CN, -NO 2 , -NH 2 , -N(CI-6 alkyl)H -N(CI-6 alkyl) 2 ,-OH, - C(O)N(R 20 ) 2 , -C(O) R 20 , -C(O)OR 20 , -OC(O) R 20 , CI-6 aminoalkyl, Ci- 6 alkoxy, Ci- 6 alkoxyalkyl,
  • R 3 is selected from hydrogen, -CN, -C(O)R 20 , C 1-6 aminoalkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-e haloalkyl, and Ci-6 alkyl. In some cases, R 3 is selected from hydrogen, -CN, -C(O)R 20 , Ci-6 hydroxyalkyl, and Ci-6 alkyl.
  • R 3 is selected from hydrogen, -CN, -C(O)H, Ci hydroxyalkyl, and Ci-6 alkyl. In some cases, R 3 is selected from hydrogen, fluorine, and -CN. In some cases, R 3 is selected from fluorine. In some cases, R 3 is selected from hydrogen. In some cases, R 3 is selected from -CN.
  • Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R 5 )-.
  • L is selected from Ci- C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted Ci alkylene.
  • two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle.
  • L is selected from Ci- C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene.
  • the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from cases, each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 3- to 5- membered heterocycle.
  • each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • each L is independently selected cases, each L is independently selected from -k .
  • each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen and C1-C4 alkyl. In some cases, L is selected from
  • each L is independently selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from ⁇ and .
  • R 2 is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R 23 )2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R 6 , and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R 7 .
  • R 2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle.
  • R 2 is selected from a - L-5- to 10-membered heterocycle.
  • R 2 is selected from a -(C1-C2 alkylene)-5- to 10-membered heterocycle.
  • R 2 is selected from a -L-5- to 8-membered heterocycle. In some cases, R 2 is selected from a -L-5- to 8-membered saturated heterocycle. In some cases, R 2 is a -L-5-membered heterocycle. In some cases, R 2 is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. In some cases, the bicyclic heterocycle contains 1 nitrogen atom.
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted. In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl.
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 aminoalkyl.
  • the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen.
  • Y-R 2 is selected from In some cases, Y-R 2 is
  • R 2 is selected from optionally substituted -L-heterocycle.
  • the heterocycle is a bicyclic heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle has only 1 nitrogen atom.
  • the heterocycle has only 1 nitrogen atom and no other heteroatoms.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • the heterocycle is substituted with at least one halogen.
  • R 2 is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • the heteroaryl is selected from a 5- to 6-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • the heteroaryl is selected from a 5- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R 7 .
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has two nitrogen atoms.
  • the heteroaryl has three nitrogen atoms.
  • the heteroaryl is selected from which is optionally substituted. In some cases, the heteroaryl is which is optionally substituted. In some cases, Y-R 2 is selected from , wherein the heteroaryl portion is optionally substituted with one or more R 7 . In some cases, each R 7 is independently selected from C1-C4 alkyl, halogen,
  • R 2 is -L-aryl, optionally substituted with one or more R 7 .
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 7 .
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 7 .
  • R 2 is selected from [00142] In some embodiments, for a compound or salt of Formula (I), R 2 is -L-N(R 23 )2. In some cases, selected from
  • R 2 is heterocycle, optionally substituted with one or more R 6 .
  • the heterocycle which is optionally substituted.
  • the heterocycle some cases, Y-R 2 is
  • R 2 is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L- heterocycle, are each optionally substituted with one or more R 6 ; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R 7 ; and -L-N(R 23 )2.
  • the heterocycle of R 2 is selected from wherein the heterocycle of R 2 is optionally substituted with one or more R 6 ; wherein the aryl and heteroaryl of R 2 is selected from from from
  • -L-heterocycle are each optionally substituted with one or more R 6 ; the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with
  • L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, C1-C4 hydroxy alkyl and C1-C4 alkyl. In some cases, L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from C1-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene. In some cases, L is In some
  • the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and Ci-6 haloalkyl.
  • each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • each L is independently selected from a substituted C1-C4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
  • each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle.
  • each L is independently selected from
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle.
  • the heterocycle has at least one nitrogen atom and at least one sulfur atom.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more
  • R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 . In some cases, Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R 2 is selected from cases, Y-R 2 is selected from
  • Y is a bond.
  • R 2 is selected from an optionally substituted heteroaryl and optionally substituted aryl.
  • R 2 is selected from an optionally substituted heteroaryl.
  • the heteroaryl has at least one nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms.
  • the heteroaryl only contain nitrogen atom(s).
  • the heteroaryl is a 6- membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • the heteroaryl is selected from each of which is optionally substituted.
  • the heteroaryl is selected from each of which is optionally substituted.
  • R 2 is selected from an optionally substituted aryl.
  • the aryl is a phenyl.
  • the heteroaryl is optionally substituted with one or more R 6 , wherein each R 6 is selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -CHJieterocycle, -C1-C3 alkyl-N(R 5 )2, and -C(O)N(R 5 )2.
  • R 6 is selected from C1-C3 alkyl, -CH2heterocycle, and -C(O)N(R 5 )2.
  • the aryl is optionally substituted with one or more R 7 .
  • Y-R 2 is selected from
  • Y is -O- and R 2 is selected from L-5-membered heteroaryl.
  • the heteroaryl has at least 1 nitrogen atom.
  • the heteroaryl has at least two nitrogen atoms.
  • the heteroaryl has 3 nitrogen atoms.
  • L is selected from an optionally substituted C1-C4 alkylene.
  • L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen,
  • L is selected from In some cases, L is selected from . In some cases, the heteroaryl is optionally substituted with one or more R 7 . In some cases, each R 7 is selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In some cases, Y-R 2 is selected from
  • each R 6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, each R 6 is independently selected from halogen, C1-C3 alkyl, and C1-C3 haloalkyl.
  • each R 6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo. In some cases, each R 6 is independently selected from -OH, Ci- C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R 5 )2.
  • R 6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is halogen. In some cases, R 6 is C1-C3 alkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 2 is selected from
  • Y-R 2 is selected from
  • Y-R 2 is selected from
  • Y-R 2 is
  • L is selected from unsubstituted C1-C4 alkylene.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 of R 2 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.
  • R 6 of R 2 is independently selected at each occurrence from C1-C3 alkyl and halogen.
  • Y-R 2 is selected from
  • R 1 is selected from an optionally sub stituted 5- to 12-membered heterocycle.
  • the heterocycle of R 1 is selected from a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12- membered heterocycle, and 8- to 12-membered heterocycle.
  • the heterocycle of R 1 is selected from a 5- to 11 -membered heterocycle, 5- to 10-membered heterocycle, 5- to 9- membered heterocycle, and 5- to 8-membered heterocycle.
  • the heterocycle of R 1 is selected from a 6- to 11 -membered heterocycle, 6- to 10-membered heterocycle, 6- to 9- membered heterocycle, and 6- to 8-membered heterocycle. In some cases, the heterocycle of R 1 is selected from a 7- to 11 -membered heterocycle, 7- to 10-membered heterocycle, 7- to 9- membered heterocycle, and 7- to 8-membered heterocycle. In some cases, the heterocycle of R 1 is selected from a 5- to 6-membered heterocycle and 5- to 9-membered heterocycle. In some cases, the heterocycle of R 1 is selected from an 8- to 9-membered heterocycle.
  • R 1 is selected from an optionally substituted 5- to 7-membered heterocycle. In some cases, R 1 is selected from an optionally substituted 6- to 7-membered heterocycle. In some cases, R 1 is selected from an optionally substituted 7-membered heterocycle. In cases, the 5- to 12- membered heterocycle of R 1 is a bridged heterocycle. In cases, the 5- to 12-membered heterocycle of R 1 is not a bridged heterocycle. In some cases, the heterocycle of R 1 is saturated. In some cases, the heterocycle of R 1 is unsaturated. In some cases, the heterocycle of R 1 is an unbridged heterocycle. The heterocycle of R 1 is optionally substituted as described elsewhere herein.
  • the heterocycle of R 1 contains at most 1 nitrogen atom. In some embodiments, the heterocycle of R 1 contains at most 1 heteroatom atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle of R 1 contains at most 2 heteroatom atoms. In some cases, the heterocycle of R 1 contains 1 nitrogen atom. In some cases, the heterocycle of R 1 contains only 1 nitrogen atom. In some cases, the heterocycle of R 1 contains only 1 nitrogen atom and no other heteroatoms.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is selected from a saturated heterocycle and unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • R 1 is selected from 5- to 15-membered heterocycle, wherein the 5- to 15-membered heterocycle is optionally substituted. In some cases, R 1 is selected from an optionally substituted 6- to 15-membered heterocycle. In some cases, the heterocycle is a spiro heterocycle. In some cases, the heterocycle is a fused heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is an unsaturated heterocycle.
  • R 1 is a 6- to 12- membered fused heterocycle, which is optionally substituted.
  • R 1 is a 6- to 12- membered spiroheterocycle, which is optionally substituted. In some cases, R 1 is selected from optionally substituted 7- to 8-membered spiroheterocycle.
  • the heterocycle of R 1 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle.
  • the heterocycle of R 1 is a 5- to 11 -membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 6- to 11 -membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 7- to 11-membered heterocycle, 7- to 10- membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle.
  • the heterocycle of R 1 is an 8- to 9-membered heterocycle.
  • the heterocycle of R 1 is saturated. The heterocycle is optionally substituted as described elsewhere herein.
  • R 1 is a 5- to 12- membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 5- to 11 -membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 6- to 11 -membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a monocyclic 7- to 11 -membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 1 is an 8- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 1 is saturated.
  • the monocyclic heterocycle is optionally substituted as described elsewhere herein.
  • R 1 is a bridged heterocycle.
  • the heterocycle of R 1 is a 5- to 12-membered bridged heterocycle, 6- to 12-membered bridged heterocycle, 7- to 12-membered bridged heterocycle, or 8- to 12- membered bridged heterocycle.
  • the heterocycle of R 1 is a 5- to 11 -membered bridged heterocycle, 5- to 10-membered bridged heterocycle, 5- to 9-membered bridged heterocycle, or 5- to 8-membered bridged heterocycle.
  • the heterocycle of R 1 is a 6- to 11 -membered bridged heterocycle, 6- to 10-membered bridged heterocycle, 6- to 9- membered bridged heterocycle, or 6- to 8-membered bridged heterocycle.
  • the heterocycle of R 1 is a bridged 7- to 11 -membered heterocycle, 7- to 10-membered bridged heterocycle, 7- to 9-membered bridged heterocycle, or 7- to 8-membered bridged heterocycle.
  • the heterocycle of R 1 is a 5- to 6-membered bridged heterocycle or 5- to 9- membered bridged heterocycle.
  • the heterocycle of R 1 is an 8- to 9-membered bridged heterocycle.
  • the heterocycle of R 1 is saturated.
  • the bridged heterocycle is selected from In some cases, the bridged heterocycle is selected from . Each bridged heterocycle is optionally substituted as described elsewhere herein.
  • R 1 is a spiro heterocycle.
  • the spiro heterocycle of R 1 is a 7- to 12-membered spiro heterocycle, 7- to 12- membered spiro heterocycle, or 8- to 12-membered spiro heterocycle.
  • the spiro heterocycle of R 1 is a 7- to 11 -membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle.
  • the spiro heterocycle of R 1 is a 7- to 11 -membered spiro heterocycle, 7- to 10-membered spiro heterocycle, 7- to 9-membered spiro heterocycle, or 7- to 8-membered spiro heterocycle.
  • the spiro heterocycle of R 1 is a 7- to 11 -membered spiro heterocycle.
  • the spiro heterocycle of R 1 is a 7-membered spiro heterocycle.
  • the spiro heterocycle of R 1 is an 8-membered spiro heterocycle.
  • the spiro heterocycle of R 1 is a 9-membered spiro heterocycle. In some cases, the spiro heterocycle of R 1 is a 10-membered spiro heterocycle. In some cases, the spiro heterocycle of R 1 contains at most 1 nitrogen atom. In some cases, the spiro heterocycle of R 1 contains only 1 nitrogen atom. In some cases, the spiroheterocycle of R 1 contains at most 2 heteroatom atoms. In some cases, the spiro heterocycle of R 1 contains at least 2 heteroatom atoms. In some cases, the spiro heterocycle of R 1 contains at least 3 heteroatom atoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the spiroheterocycle of R 1 is bound to the Formula via the nitrogen atom. heterocycle of R 1 is selected from . Each spiro heterocycle is optionally substituted as described elsewhere herein.
  • R 1 is a fused heterocycle.
  • the fused heterocycle of R 1 is a 6- to 12-membered fused heterocycle, 6- to 12-membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 6- to 11- membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 7- to 11 -membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle.
  • the fused heterocycle of R 1 is an 8- to 11-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 9-membered fused heterocycle.
  • the fused heterocycle of R 1 is a 10-membered fused heterocycle.
  • the fused heterocycle of R 1 is an 11 -membered fused heterocycle.
  • the fused heterocycle of R 1 is a 6-membered fused heterocycle. In some cases, the fused heterocycle of R 1 is a 7-membered fused heterocycle. In some cases, the fused heterocycle of R 1 is a 10-membered fused heterocycle. In some cases, the fused heterocycle is selected from Each fused heterocycle is optionally substituted as described elsewhere herein.
  • R 1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10- membered fused heterocycle is a bicyclic heterocycle.
  • the 8- to 10-membered fused heterocycle is a saturated heterocycle.
  • the 8- to 10-membered fused heterocycle is an unsaturated heterocycle.
  • the 8- to 10-membered heterocycle is a non-aromatic heterocycle.
  • R 1 is selected from an optionally substituted 9- membered fused heterocycle.
  • R 1 is selected from an optionally substituted 10- membered fused heterocycle.
  • the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10- membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms.
  • the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 9-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R 1 is selected from , each of which is optionally substituted with one or more substituents. In some cases, which is optionally substituted with one or more substituents. In some cases, , which is optionally substituted with one or more substituents.
  • Ci-6 alkyl-N(R 20 )2 Ci-6 aminoalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, C 1-6 cyanoalkyl, Ci-
  • R 1 6 haloalkyl, C1-6 alkyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the 5- to 12- membered heterocycle are each optionally substituted independently with one or more R 1 *.
  • R 1 is selected from
  • the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6 alkyl.
  • the further one or more optional substituents are selected from halogen, and C1-6 alkyl.
  • the further one or more optional substituents are selected from halogen.
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, each R 20 is independently selected from 5- to 6-membered saturated heterocycle. In some cases, the heterocycle of R 20 has at least one nitrogen atom. In some cases, the heterocycle of R 20 has at least one sulfur atom. In some cases, the heterocycle of R 20 has at least one oxygen atom. In some cases, the heterocycle of R 20 contains only 1 heteroatom.
  • the heterocycle of R 20 has at least two heteroatoms. In some cases, the heterocycle of R 20 contains only 2 heteroatoms. In some cases, the optional one or more substituents of R 1 are independently selected from halogen, -CN, C2 alkenyl, some cases, the optional one or more substituents of R 1 are independently selected from halogen, more substituents of R 1 are independently selected from halogen, and Ci-6 alkyl-N(R 20 )2. In some cases, the optional one or more substituents of R 1 are independently selected from halogen, , hydrogen, Ci-6 alkyl, and C3-6 carbocycle.
  • R 1 is selected from a
  • R B is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted independently with one or more R 1 * ; and R B is selected from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkynyl, and -CN.
  • R B is selected from hydrogen, and halogen.
  • R B is chloride.
  • R B is hydrogen.
  • has at least 1 oxygen atom. is a monocyclic heterocycle.
  • each R 1 * is independently selected from halogen, -OR 20 , -S(O) 2 (R 20 ), -
  • each R 1 * is independently selected from halogen, Ci-6 alkyl-N(R 20 ) 2 , Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl.
  • each R 1 * is independently selected from halogen, and Ci-6 alkyl. In some cases, is selected from
  • R 1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents.
  • R 1 is selected from a saturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents. In some cases, the 5- to 12-membered heterocycle of R 1 is bridged. In some cases, the 5- to 12-membered heterocycle of R 1 is not bridged. In some cases, the 5- to 12-membered substituents. [00189] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from , each of which is optionally substituted with one or more substituents.
  • R 1 is
  • R 1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.
  • the heterocycle of R 1 contains only 1 nitrogen atom and optionally one or more heteroatoms selected from oxygen, and sulfur.
  • the heterocycle is a fused heterocycle or a bridged heterocycle.
  • the heterocycle is a monocyclic heterocycle or a bridged heterocycle.
  • the heterocycle is a monocyclic heterocycle.
  • the heterocycle is a bridged heterocycle.
  • the heterocycle is selected from h e t er0C y Cie j s optionally substituted as described elsewhere herein.
  • the heterocycle of R 1 has at most 1 nitrogen atom. In some cases, the heterocycle of R 1 has only 1 nitrogen atom and optionally one or more other heteroatoms selected from oxygen and sulfur. In some cases, the heterocycle of R 1 has only 1 nitrogen atom and no other heteroatoms.
  • R 1 is selected from an optionally substituted 5- to 12-membered saturated heterocycle, wherein the heterocycle has as most one nitrogen atom.
  • the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom.
  • the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and 0-2 other heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and no further heteroatoms.
  • the 5- to 12-membered unsaturated heterocycle has three nitrogen atoms and no further heteroatoms.
  • R 1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has only one nitrogen atom and no further heteroatoms.
  • R 1 is selected from 6- to 7-membered heterocycle. In some cases, R 1 is selected from 7-membered heterocycle. In some cases, R 1 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of
  • R 1 is bound to Formula (I) via the only 1 nitrogen atom.
  • R 1 is selected which is substituted.
  • R 1 is selected from selected from each of which is optionally substituted.
  • the one or more optional substituents of R 1 are each independently selected from halogen, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R 1 are each independently selected from halogen, -OH, and -CN. In some cases, the one or more optional substituents of R 1 are each independently selected from fluorine, -
  • R 1 is selected from
  • R 1 is selected
  • R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds.
  • R 1 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R 1 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
  • R 1 is selected from more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R 1 is selected from , wherein each is substituted with one or more substituents independently selected from halogen.
  • R 1 is selected from an unsaturated 6- to 7-membered heterocycle, wherein the unsaturated 6- to 7-membered heterocycle is substituted with one or more substituents selected from halogen. In some cases, the unsaturated
  • 6- to 7-membered heterocycle is substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen. In some cases, the unsaturated 7-membered heterocycle is substituted with one fluorine. In some cases, R 1 is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen. In some cases, R 1 is selected from an unsaturated 7-membered heterocycle, substituted with at least one halogen. In some cases, R 1 is selected from
  • R 1 is selected from some cases, R 1 is
  • R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C1-6 alkoxy, Ci-e hydroxyalkyl, Ci-e haloalkyl, and C1-6 alkyl. In some cases, R4S selected from
  • R 1 is selected from an optionally substituted 6-membered heterocycle.
  • the 6-membered heterocycle contains only 1 nitrogen atom.
  • the 6-membered heterocycle of R 1 is bound to
  • R 1 is selected from of which is optionally substituted.
  • the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is a monocyclic 6- membered heterocycle. In some cases, the 6-membered heterocycle is not a bridged heterocycle.
  • R 1 is selected from
  • R 1 is selected from an optionally substituted 6-membered unsaturated heterocycle and 6-membered saturated heterocycle.
  • R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
  • R 1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, and Ci-e haloalkyl.
  • R 1 is selected from [00204] in some embodiments, for a compound or salt of Formula (I), R 1 is selected from [00205] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
  • R 1 is selected from , wherein each is optionally substituted with two substituents independently selected from halogen, and Ci-6 haloalkyl. In some cases,
  • R 1 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • the 6- to 10-membered heterocycle contains at least 1 nitrogen atom.
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, Ci-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 1 is selected from
  • R 1 is selected from 6- to 7-membered heterocycle. In some cases, R 1 is selected from 7-membered heterocycle. In some cases, R 1 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of
  • R 1 is bound to Formula (I) via the only 1 nitrogen atom.
  • R 1 is selected from -TML ⁇ - cases, R 1 is selected from each of which is substituted.
  • R 1 is selected from selected from each of which is optionally substituted.
  • the one or more optional substituents of R 1 are each independently selected from fluorine, -OH, -C(0)NH2, -NH-C(0)-(CI-6 alkoxy), -NH-C(0)-(CI-6 hydroxyalkyl), -NH2, -
  • NH(CN), 0, -CN, Ci-e hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl.
  • the one or more optional substituents of R 1 are each independently selected from halogen, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl.
  • the one or more optional substituents of R 1 are each independently selected from halogen, -OH, and -CN.
  • the one or more optional substituents of R 1 are each independently selected from fluorine, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl. In some cases, the one or more optional substituents of R 1 are each independently selected from fluorine, -OH, -CN, C 1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, R 1 is selected from
  • the 5- to 12-membered heterocycle of R 1 is unsaturated and a bridged heterocycle.
  • R 1 is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. In some cases, R 1
  • R 1 is selected from an optionally substituted 10-membered heterocycle.
  • the 10-membered heterocycle is a bicyclic heterocycle.
  • the 10-membered heterocycle is a spiro heterocycle.
  • the 10-membered heterocycle is a fused heterocycle.
  • the 10- membered heterocycle is a saturated heterocycle.
  • the 10-membered heterocycle is a non-aromatic heterocycle.
  • the 10-membered heterocycle contains at least 1 nitrogen atom.
  • the 10-membered heterocycle contains at least 2 nitrogen atoms.
  • R 1 is selected from some cases, R 1 is selected from
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -Ci-io haloalkyl, -O-Ci-10 alkyl, C2- 10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 1 is selected from some cases,
  • R 1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10- membered fused heterocycle is a bicyclic heterocycle.
  • the 8- to 10-membered fused heterocycle is a saturated heterocycle.
  • the 8- to 10-membered fused heterocycle is an unsaturated heterocycle.
  • the 8- to 10-membered heterocycle is a non-aromatic heterocycle.
  • R 1 is selected from an optionally substituted 10- membered fused heterocycle.
  • the 10-membered fused heterocycle is a bicyclic heterocycle.
  • the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R 1 is selected from , each of which is optionally substituted with one or more substituents.
  • R 1 is selected from hich is optionally substituted with one or more substituents. In some , , which is optionally substituted with one or more substituents. In some cases, the one or more optional substituents of R 1 are independently selected from halogen, -OH,
  • R 1 is selected from , each of which is further optionally substituted.
  • the further one or more optional substituents are selected from halogen and C1-6 alkyl.
  • the further one or more optional substituents are selected from halogen.
  • each R 20 is independently selected from hydrogen; and Cn 6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12- membered saturated heterocycle. In some cases, each R 20 is independently selected from 5- to 6- membered saturated heterocycle. In some cases, the heterocycle of R 20 has at least one nitrogen atom. In some cases, the heterocycle of R 20 has at least one sulfur atom. In some cases, the heterocycle of R 20 has at least one oxygen atom. In some cases, the heterocycle of R 20 contains only 1 heteroatom.
  • the heterocycle of R 20 has at least two heteroatoms. In some cases, the heterocycle of R 20 contains only 2 heteroatoms. In some cases, the optional one or more substituents of R 1 are independently selected from halogen, . In some cases, the optional one or more substituents of R 1 are independently
  • R 1 independently selected from halogen, and Ci-6 alkyl-N(R 20 )2.
  • the optional one or more substituents of R 1 are independently selected from halogen, , , and .
  • R 1 is selected from .
  • each R 20 is independently selected from hydrogen, Ci-6 alkyl, and C3-6 carbocycle. In some cases, R 1 is
  • R 20 is selected from a 5- to 12-membered heterocycle.
  • heterocycle has at least two heteroatoms. In some cases, the heterocycle has at least three heteroatoms. In some cases, the heterocycle has at least four heteroatoms. In some cases, the heterocycle of the one or more optional substituents of R 1 is selected from , each of which is optionally substituted with one or more R 1 *. In some cases, the heterocycle of the one or more optional substituents of R 1 is selected from which is optionally substituted with one or more R 1 *.
  • each R 1 * is independently selected from halogen, Ci-6 alkyl-N(R 20 ) 2 , Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, Ci-6 cyanoalkyl, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R 1 * is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl. In some cases, each R 1 * is independently selected from halogen, and Ci-6 alkyl. In some cases, each R 1 * is independently selected from halogen. In some cases, each R 1 * is independently selected from Ci-6 alkyl. In some cases, each R 1 * is independently selected from -OR 20 . In some cases, each R 1 * is independently selected from -OH. In some cases, each R 1 * is independently selected from -OMe. In some cases,
  • each R 1 * is independently selected from halogen, C1-6 alkyl-N(R 20 )2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R 1 * is independently selected from halogen, C1-6 haloalkyl, and C1-6 alkyl. In some cases, each R 1 * is independently selected from halogen, and C1-6 alkyl. In some cases, each R 1 * is independently selected from halogen. In some cases, each R 1 * is independently selected from C1-6 alkyl.
  • R 1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10- membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, oxo, -C(O)N(R 20 )2, -C(O)NR 20 OR 20 , -N(R 20 )2, -C(O)R 20 , - C(O)OR 20 , -SO2R 20 , -NHCN, C 1-6 cyanoalkyl, Ci- 6 alkyl, Ci- 6 alkyl-N(R 20 ) 2 , C 2 -6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 9-membered heterocycle), wherein the 5- to 12- membered heterocycle are each optionally substituted independently with one or more R 1 *; each R 1 * is independently selected from halogen, C1-6
  • the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 is selected , , , each of which is optionally substituted. In some cases, R 1 is selected -1- , which is optionally substituted. In
  • R 1 is selected .
  • R 1 is selected from 5- to 15-membered heterocycle (preferably 8- to 10-membered heterocycle or preferably 10- membered heterocycle or preferably 8-membered heterocycle), each of which are optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R 20 )2, - C(O)NR 20 OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -NHCN, C I-6 cyanoalkyl, Ci- 6 alkyl, C 2-6 alkynyl, and 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle), wherein the 5- to 12-membered heterocycle are each optionally substituted independently with one or more R 1 *; each R 1 * is independently selected from halogen, Ci-6 haloalkyl, and Ci-6 alkyl.
  • the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R is selected -1- , ⁇ L , and -1- , each of which is optionally substituted. In some cases, R is selected -1- , which is optionally substituted. In
  • R 1 is selected from
  • R 1 is selected from an optionally substituted 7- to 10-membered spiro heterocycle and optionally substituted 7- to 10- membered fused heterocycle.
  • the heterocycle of R 1 has at least one nitrogen atom
  • the at least one nitrogen at of the heterocycle of R 1 is bound to Formula (I).
  • R 1 is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle.
  • R 1 is selected from
  • R 1 is selected from hydrogen
  • R 1 is selected from an optionally substituted 8- to 10-membered heterocycle.
  • the heterocycle is bicyclic.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has which is optionally substituted.
  • the optional one or more substituents of R 1 are independently selected from halogen,
  • R 1 * is selected from halogen, and Ci-6 alkyl.
  • the optional one or more substituents of R 1 are independently selected from chlorine,
  • R 1 is selected from an optionally substituted bridged 8- to 9-membered heterocycle.
  • the heterocycle of R 1 is selected from more substituents of R 1 are selected from halogen, Ci-6 alkyl, -N(R 20 )2, and Ci-6 aminoalkyl.
  • R 1 is selected from an optionally substituted bridged 8-membered heterocycle, wherein the heterocycle contains heteroatoms selected from nitrogen.
  • the one or more substituents of R 1 are selected from C i-6 alkyl, -N(R 20 )2, and Ci-6 aminoalkyl.
  • the heterocycle of R 1 is selected from each of which is optionally substituted. In some cases, , ,
  • R 1 is hydrogen
  • R 1 is an optionally substituted 12- to 15-membered heterocycle.
  • R 1 is an optionally substituted 12- membered heterocycle.
  • R 1 is an optionally substituted 13-membered heterocycle.
  • R 1 is an optionally substituted 14-membered heterocycle.
  • R 1 is an optionally substituted 15-membered heterocycle.
  • the heterocycle of R 1 is tricyclic.
  • the heterocycle of R 1 contains a fused heterocycle.
  • the heterocycle of R 1 contains a spiro-heterocycle.
  • the heterocycle of R 1 contains a fused and spiro-heterocycle. In some cases, the heterocycle of R 1 is an unsaturated heterocycle. In some cases, the heterocycle of R 1 is a non-aromatic heterocycle. In some cases, the heterocycle of R 1 has at least one double bond. In some cases, the heterocycle of R 1 has at least two double bonds. In some cases, the heterocycle of R 1 has at least 2 heteroatoms. In some cases, the heterocycle of R 1 has at least 3 heteroatoms. In some cases, the heterocycle of R 1 has at least 4 heteroatoms. In some cases, the heterocycle of R 1 has at least 5 heteroatoms. In some cases, the heterocycle of R 1 has at least 6 heteroatoms.
  • the heterocycle of R 1 has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 sulfur atom. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms, and at least 1 oxygen atom. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms. In some cases, the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms and no other heteroatoms. In some cases, the heteroatoms are selected from nitrogen and sulfur. In some cases, the heteroatoms are selected from nitrogen and oxygen. In some cases, R 1 is selected from
  • R 1 is selected from substituted with one or more substituents.
  • R 1 is an optionally substituted 12- to 15-membered heterocycle.
  • Ring W is an optionally substituted heterocycle and Ring P is an optionally substituted carbocycle or optionally substituted heterocycle, wherein Ring P forms a spirocycle with Ring W.
  • Ring W is an optionally substituted fused heterocycle.
  • Ring P and Ring W combine to form a heterocycle having at least 12 atoms and most 15 atoms.
  • Ring P and Ring W have in total at least 12 atoms and most 15 atoms.
  • Ring W is an optionally substituted 10-membered fused heterocycle.
  • R 1 is , wherein Ring P is an optionally substituted carbocycle or optionally substituted heterocycle.
  • Ring P is an optionally substituted carbocycle.
  • Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6 carbocycle or optionally substituted 4-to 6- membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted C4 carbocycle. In some cases, Ring P forms an optionally substituted C5 carbocycle. In some cases, Ring P forms an optionally substituted 4- membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P forms an optionally substituted 5-membered heterocycle. In some cases, Ring P has at least 1, 2, or 3 heteroatoms.
  • the heteroatoms are selected from oxygen, nitrogen, and sulfur.
  • Ring P has 1 sulfur atom.
  • Ring P has 1 nitrogen atom.
  • Ring P has 1 oxygen atom.
  • the one or more optional substituents of Ring W are independently selected from -C(O)R 20 .
  • Ring P is substituted.
  • Ring W is substituted.
  • R 1 is selected from a 5- to 12-membered bridged heterocycle, which is optionally substituted with one or more substituents. In some cases, R 1 is selected from an 8-membered bridged heterocycle, which is optionally substituted with one or more substituents. In some cases, the bridged heterocycle has at least 1 heteroatom. In some cases, the bridged heterocycle has at least 2 heteroatoms. In some cases, the bridged heterocycle has at least 1 nitrogen atom. In some cases, the bridged heterocycle has at least 2 nitrogen atoms. In some cases, the bridged heterocycle has 2 nitrogen atoms. In some cases, R 1 is selected from
  • R 1 is selected from — I— , which is optionally substituted with one or more substituents.
  • R 1 is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents.
  • the unsaturated 5- to 12-membered heterocycle is selected from each of which is optionally substituted with one or more substituents.
  • R 1 for a compound or salt of Formula (I), wherein the 5- to 12- membered heterocycle of R 1 is unsaturated and a bridged heterocycle.
  • R 1 is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle.
  • R 1 is selected from -J— .
  • R 1 is selected from an optionally substituted 10-membered heterocycle.
  • the 10-membered heterocycle is a bicyclic heterocycle.
  • the 10-membered heterocycle is a spiro heterocycle.
  • the 10-membered heterocycle is a fused heterocycle.
  • the 10- membered heterocycle is a saturated heterocycle.
  • the 10-membered heterocycle is a non-aromatic heterocycle.
  • the 10-membered heterocycle contains at least 1 nitrogen atom.
  • the 10-membered heterocycle contains at least 2 nitrogen atoms.
  • the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom.
  • R 1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10- membered fused heterocycle is a bicyclic heterocycle.
  • the 8- to 10-membered fused heterocycle is a saturated heterocycle.
  • the 8- to 10-membered heterocycle is a non-aromatic heterocycle.
  • R 1 is selected from an optionally substituted 10- membered fused heterocycle.
  • the 10-membered fused heterocycle is a bicyclic heterocycle.
  • the 10-membered fused heterocycle is a saturated heterocycle.
  • the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, R 1 is , each of which is optionally substituted with one or more substituents. In some cases, , which is optionally substituted with one or more substituents.
  • the optional one or more substituents are independently selected from -C(O)R 20 , -C(O)N(R 20 )2, and -C(O)NR 20 OR 20 . In some cases, the optional one or more substituents are independently selected from -C(O)R 20 . In some cases, the optional one or more substituents are independently selected from -C(O)N(R 20 )2. In some cases, the optional one or more substituents are independently selected from -C(O)NR 20 OR 20 . In some cases, each R 20 is independently selected from hydrogen; and Ci-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered heterocycle. In some cases, each R 20 is independently selected from hydrogen; and C1-6 alkyl, and 3- to 12-membered saturated heterocycle. In some cases, the optional one or more substituents of R 1 are independently selected from
  • R 1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle. In some cases, R 1 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R 1 is selected from —I— , which is optionally substituted. In some cases, the optional one or more substituents are independently selected from halogen, -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, Ci-6 cyanoalkyl, and Ci-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and Ci-6 alkyl. In some cases, R 1 is selected from — i— , which is substituted with one or more substituents selected from -NHCN, and Ci-6 alkyl. In some cases, R 1 is selected from , and
  • R 3 is -CN, and R 1 is substituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom.
  • R 3 is -CN, and R 1 is selected from .
  • R 3 is -CN, and R 1 is selected from .
  • R 3 is -CN, O and R 1 is selected from .
  • R 3 is -CN
  • R 1 is selected from some cases, selected from optionally substituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom
  • Y-R 2 is selected from -O-L-heterocycle, wherein the heterocycle portion of -O-L-heterocycle is optionally substituted with one or more R 6 .
  • B is an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10- membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9-membered fused carbocycle. In some cases, B is , which is optionally substituted with one or more substituents. In some cases, B is , which is substituted with one or more substituents. In some cases, for B, the one or more substituents are independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -
  • B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selected selected from halogen and Ci-e haloalkyl. In some cases, which is substituted with one or more substituents selected from halogen. In some cases, B is selected from which is substituted with one or more substituents selected from fluorine. In some cases, B is substituted with one or more substituents selected from chlorine. In some cases, B is selected
  • R 1 is selected from an optionally substituted unsaturated 10-membered fused heterocycle.
  • R 1 is , which is optionally substituted.
  • B is an optionally substituted 8- to 10-membered fused heterocycle, wherein the heterocycle each of which is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • n is 0.
  • R 3 is selected from hydrogen, halogen, -CN, -N(R 20 ) 2 , -OH, -S(O) 2 (R 20 ), -C(O)R 20 , Ci- 6 alkyl-N(R 20 ) 2 , Ci- 6 aminoalkyl, Ci- 6 alkoxy, Ci-6 alkoxyalkyl, Ci-e hydroxyalkyl, Ci-6 cyanoalkyl, C 1-6 haloalkyl, and Ci-6 alkyl.
  • R 3 is selected from hydrogen, halogen, and -CN.
  • R 1 is selected from an optionally substituted 11 -membered fused heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 11 -membered fused heterocycle. In some cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains 3 heteroatoms. In some cases, the heterocycle is — L ⁇ , which is optionally substituted. In some cases, R 1 is — L ⁇
  • the optional substituents for R 1 are each independently selected from halogen, -OH, -N(R 20 ) 2 , -NO 2 , C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl.
  • the optional substituents for R 1 are each independently selected from halogen, -CN, -OH, -NH 2 , C 1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 haloalkyl. . In some cases, the optional substituents for R 1 are each independently selected from -OH, and -NH 2 . In some cases, R 20 is selected from hydrogen and C1-3 alkyl.
  • n is selected from 0 to 4. In some cases, n is selected from 0 to 3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen and C1-6 alkyl.
  • each R 20 is independently selected from C1-6 alkyl.
  • each R 21 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen and C1-6 alkyl.
  • each R 21 is independently selected from C1-6 alkyl.
  • each R 20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen and C1-6 alkyl.
  • each R 20 is independently selected from C1-6 alkyl.
  • each R 23 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O- C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 23 is independently selected from hydrogen and C1-6 alkyl.
  • each R 23 is independently selected from C1-6 alkyl.
  • the present disclosure provides a compound of Formula (I- A) Formula (LA), or a pharmaceutically acceptable salt thereof wherein:
  • Y is selected from a bond, -0-, -S-, and -N(R 5 )-;
  • Y is -O-
  • R 2 is selected from -L-heterocycle, -L-N(R 23 )2, wherein the heterocycle portion of -L- heterocycle is optionally substituted with one or more R 6 .
  • R 3 is selected from hydrogen, halogen, -CN, -N(R 20 )2, -OR 20 , -C(O)R 20 , C1-6 alkyl-N(R 20 )2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; and each R 20 is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(Ci-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, and oxo.
  • a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), Y is -O-.
  • a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), R 2 is selected from optionally substituted -L-heterocycle, and -L-N(R 23 )2.
  • R 2 is selected from optionally substituted -L- 5-to 8-membered heterocycle, and -L-N(R 23 )2.
  • R 2 is selected from optionally substituted -L-heterocycle.
  • R 2 is selected from -L-N(R 23 )2.
  • the heterocycle contains at least one nitrogen atom.
  • the heterocycle contains at least one sulfur atom.
  • the heterocycle contains at least one oxygen atom.
  • R 6 when R 2 is a heteroaryl, R 6 is selected from halogen and C1-C3 haloalkyl, C1-C3 alkyl.
  • R 2 when R 2 is a heteroaryl, R 6 is selected from a halogen.
  • R 23 is selected from hydrogen and C1-C3 alkyl.
  • each R 23 is selected from C1-C3 alkyl.
  • each R 23 is selected from methyl.
  • each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and
  • each L is selected from ' » [00256]
  • a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl.
  • the heterocycle of B is selected from substituted with one or more substituents independently selected from halogen, -CN, -NH2, and
  • a compound or salt of Formula (I), Formula (I-A), or Formula (I-B), R 3 is -CN.
  • R 3 is hydrogen.
  • R 3 is halogen.
  • R 3 is fluorine.
  • a compound or salt of Formula (I), Formula (I-A), or Formula which is optionally substituted with one or more substituents.
  • the one or more optional substituents of R 1 are not electrophiles.
  • R 1 is selected from a compound in the Examples.
  • B is selected from a compound in the Examples.
  • Y is selected from a compound in the Examples.
  • R 2 is selected from a compound in the Examples.
  • R 3 is selected from a compound in the Examples.
  • each R 20 is selected from hydrogen and C1-3 alkyl. In some cases, each R 20 is selected from hydrogen and Ci alkyl.
  • the compounds of Formula (I), (I-A), or (I-B) used in the methods include trifluoroacetic acid salts of the above compounds.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 500 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 100 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) of is administered to a subject at about 5 mg to about 75 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg.
  • the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • a compound or salt of Formula (I), (I- A), or (I-B) is administered once daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I- B) is administered twice daily. In some embodiments, the compound or salt of Formula (I), (I- A), or (I-B) is administered 3 times daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered once weekly. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered every other day. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered every 3 days.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg to 150 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) or a salt thereof is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 25 mg to 100 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 50 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 5 mg to 75 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg.
  • the compound or salt of Formula (I) is administered to a subject at 15 mg.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 45 mg. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg, daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 75 mg, daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg, daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered once daily. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 150 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 125 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 25 mg to about 100 mg, twice daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 50 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 5 mg to about 75 mg, twice daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg, twice daily.
  • the compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • the compound or salt of Formula (I), (I- A), or (I-B) is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I- A), or (I-B) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 45 mg, twice daily.
  • the compound or salt of Formula (I), (I-A), or (I-B) is administered to a subject at about 60 mg, twice daily.
  • the subject is between 12 years old to 18 years old.
  • the subject is between greater than or equal 12 years old to less than or equal to 18 years.
  • the subject is an adult.
  • the subject is greater than or equal to 18 years old.
  • a compound of Formula (I), (I-A), or (I-B) is administered as a capsule during the period of time.
  • a tablet or capsule formulation of a compound of Formula (I), (I-A), or (I-B) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15
  • a compound of Formula (I), (I- A), or (I-B) is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment, a compound of Formula (I), (I- A), or (I-B) is orally administered twice a day (BID) on a daily basis during a period of time.
  • a compound of Formula (I), (I- A), or (I-B) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg
  • the combination therapy comprises oral administration of a compound of Formula (I), (I- A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg,
  • CTLA-4 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the inhibitor is an immunomodulator inhibitor.
  • the inhibitor is an PD-1 inhibitor.
  • the inhibitor is an PD-L1 inhibitor.
  • the inhibitor is an CTLA-4 inhibitor.
  • the compound of Formula (I), (I-A), or (I-B) is selected from compounds 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is selected compound2, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 14.
  • the compound of Formula (I), (I-A), or (I-B) is compound 25, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 74 or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is orally administered once daily. In one embodiment, the compound of Formula (I), (I-A), or (I-B) is orally administered twice daily.
  • a compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as a tablet or capsule.
  • a tablet or capsule formulation of a compound of Formula (I), (I- A), or (I-B) comprises about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15
  • a compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • a compound of Formula (I), (I-A), or (I-B) is orally administered once a day (QD) on a daily basis during a period of time.
  • a compound of Formula (I), (I-A), or (I-B) is orally administered twice a day (BID) on a daily basis during a period of time.
  • a compound of Formula (I), (I-A), or (I-B) is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg
  • an inhibitor selected from:
  • CTLA-4 inhibitor wherein the inhibitor is administered, for example, once a week, once every two weeks, once every three weeks, or once every four weeks, depending on the dosage.
  • the compound of Formula (I), (I- A), or (I-B) is selected compound 2, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 3, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 25, or a pharmaceutically acceptable salt of any one thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 74 or a pharmaceutically acceptable salt of any one thereof. Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein.
  • the compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged, such as those with a quaternary nitrogen can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the compounds disclosed herein have some or all of the J H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are 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.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • compositions comprising a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).
  • compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions is 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. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
  • compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the pharmaceutical agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop.
  • routes of administration including, for example, orally, for example, drenches as in aque
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • the dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre- clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • compositions are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvent
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • At least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringelike applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously.
  • the active compositions can also be delivered via iontophoresis.
  • Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • an aerosol forming device such as a jet, vibrating porous plate or ultrasonic nebulizer
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • suitable devices including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffetechnik (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
  • AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc.
  • the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • lanolin lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a crosslinked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release.
  • Bioadhesive polymers described in the art may be used.
  • a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • the polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses are provided.
  • kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • kits and products that include the compound or salt of Formula (I), (I-A), or (I-B) and/or an immunomodulator inhibitor.
  • the kit or product can include a package or container with a compound of Formula (I), (I-A), or (I-B) or pharmaceutically acceptable salt.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I-A), or (I-B) in combination with an immunomodulator inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound or salt of Formula (I), (I-A), or (I-B) and an immunomodulator inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I-A), or (I-B) in combination with an immunomodulator inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • the compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • kits and products that include the compound or salt of Formula (I), (I-A), or (I-B) and/or at least one PD-1 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formula (I), (I-A), or (I-B).
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I-A), or (I-B) in combination with an PD-1 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound of Formula (I), (I-A), or (I-B) and at least one PD-1 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I-A), or (I-B) in combination with an PD-1 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound of Formula (I), (I-A), or (I-B) and/or at least one PD-L1 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formula (I), (I-A), or (I-B) .
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I- A), or (I-B) in combination with an PD-L1 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound of Formula (I), (I- A), or (I-B) and at least one PD-L1 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound or salt of Formula (I), (I- A), or (I-B) in combination with an PD-L1 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein. In some cases, the compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • kits and products that include the compound of Formula (I), (I-A), or (I-B) and/or at least one CTLA-4 inhibitor.
  • the kit or product can include a package or container with a compound of Formula (I), (I-A), or (I-B).
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (I), (I-A), or (I-B) in combination with an CTLA-4 inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits or products can include both a compound or salt of Formula (I), (LA), or (I-B) and at least one CTLA-4 inhibitor.
  • kits can include one or more containers or packages, which include one or both combination drugs together in a single container and/or package, or in separate packages/containers. In some instances, the two drugs are separately wrapped, but included in a single package, container or box.
  • kits and products can further include a product insert or label with approved drug administration and indication information, including how to use the compound of Formula (I), (I-A), or (LB) in combination with an CTLA-4 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein. In some cases, the compound is selected from compounds 2, 3, 4, 14, 25, and 74. DOSINGS
  • the dosage regimen for the compounds herein (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutical composition of any one thereof) will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • an immunomodulator inhibitor e.g., PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor
  • a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutical composition of any one thereof will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health
  • the dosing frequency for the therapeutic agent may vary, for example, from once per day to six times per day. That is, the dosing frequency may be QD, i.e., once per day, BID, i.e., twice per day; TID, i.e., three times per day; QID, i.e., four times per day; five times per day, or six times per day.
  • dosing frequency may be BIW, i.e., twice weekly, TIW, i.e., three times a week, or QIW, i.e. four times a week.
  • the treatment cycle may have a period of time where no therapeutic agent is administered.
  • val administration refers to administration of the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (LA), or (I-B)) followed by void days or void weeks.
  • the treatment cycle may be 3 weeks long which includes 2 weeks of dosing of the therapeutic agent(s) followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 4 weeks long which includes 3 weeks of dosing followed by 1 week where no therapeutic agent is administered.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • active ingredient e.g, immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (I- A), or (LB)
  • an active ingredient e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (LA), or (LB)
  • an active ingredient may be administered at a dose of between about 10 mg/day and about 200 mg/day.
  • an active ingredient e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (LA), or (LB)
  • an active ingredient may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the dose may be any value or subrange within the recited ranges.
  • treatment cycle means a pre-determined period of time for administering the therapeutic agent (e.g, an immunomodulator inhibitor, PD-1 inhibitor, PD- L1 inhibitor, CTLA-4 inhibitor; or a compound or salt of Formula (I), (I-A), or (I-B)).
  • the patient is examined at the end of each treatment cycle to evaluate the effect of the therapy.
  • each of the treatment cycle has about 3 or more days.
  • each of the treatment cycle has from about 3 days to about 60 days.
  • each of the treatment cycle has from about 5 days to about 50 days.
  • each of the treatment cycle has from about 7 days to about 28 days.
  • each of the treatment cycle has 28 days.
  • the treatment cycle has about 29 days. In some cases, the treatment cycle has about 30 days. In some cases, the treatment cycle has about 31 days. In some cases, the treatment cycle has about a month-long treatment cycle. In some cases, the treatment cycle is any length of time from 3 weeks to 8 weeks. In some cases, the treatment cycle is any length of time from 3 weeks to 6 weeks. In some cases, the treatment cycle is 3 weeks. In some cases, the treatment cycle is one month. In some cases, the treatment cycle is 4 weeks. In some cases, the treatment cycle is 5 weeks. In some cases, the treatment cycle is 6 weeks. In some cases, the treatment cycle is 7 weeks. In some cases, the treatment cycle is 8 weeks. In some cases, the duration of the treatment cycle may include any value or subrange within the recited ranges, including endpoints.
  • drugs are administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects.
  • MTD maximum tolerated dose
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered prior to administration of the compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered after administration of the compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof.
  • separate administration of each inhibitor/compound, at different times and by different routes may be advantageous.
  • the components in the combination i.e.
  • a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • a pharmaceutical composition comprises an immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, for use in the methods for simultaneous, separate or sequential use.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (I), (I- A), or (I- B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments the therapeutically effective amount of the immunomodulator inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the immunomodulator inhibitor of the combination may be any value or subrange within the recited ranges.
  • the immunomodulator inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other.
  • the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for coadministration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor is administered to a subject at about 25 mg to about 100 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg,
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg.
  • the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered twice daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once weekly. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every other day. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 3 days. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered once a week. In some embodiments, the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every two weeks.
  • the immunomodulator inhibitor, or pharmaceutically salt thereof is administered every 4 weeks. [00344] In some embodiments, the immunomodulator inhibitor is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes.
  • the immunomodulator inhibitor is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, the immunomodulator inhibitor, is administered intravenously over 60 minutes.
  • the immunomodulator inhibitor is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, the immunomodulator inhibitor, is administered intravenously over 60 minutes.
  • a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • a pharmaceutical composition comprises a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (I), (I-A), or (I- B), or a pharmaceutically acceptable salt thereof, for use in the methods which may be for simultaneous, separate or sequential use.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • separate administration of each inhibitor, at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may need not to be administered at essentially the same time or in any order.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (I), (I-A), or (I- B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • a PD-1 inhibitor the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the combination (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the combination (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 480 mg/time, 600 mg/time 1000 mg/time.
  • the therapeutically effective amount of the PD-1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the time is 1 day. In some cases, the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days.
  • the PD-1 inhibitor e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof
  • the compound of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other.
  • the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of coadministration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 5 mg to about 600 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg to about 150 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 10 mg to about 125 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the PD-1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the PD-1 inhibitor is administered to a subject at about 25 mg to about 100 mg.
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg,
  • the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 45 mg. In some embodiments, the PD-1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 60 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered once daily.
  • the PD-1 inhibitor ⁇ . g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof is administered twice daily.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily.
  • the PD-1 inhibitor e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof
  • the PD-1 inhibitor(e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof) is administered every other day.
  • the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 3 days. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered once a week. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every two weeks. In some embodiments, the PD-1 inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, tislelizumab, or a biosimilar thereof), is administered every 4 weeks.
  • the PD-1 inhibitor e.g.,
  • the PD-1 inhibitor is nivolumab or a biosimilar thereof.
  • nivolumab or a biosimilar thereof is administered at a dose of 240 mg intravenously once every 2 weeks (Q2W).
  • nivolumab or a biosimilar thereof is administered at a dose of 480 mg intravenously once every 4 weeks (Q4W).
  • nivolumab or a biosimilar thereof is administered intravenously over 30 minutes.
  • the PD-1 inhibitor is pembrolizumab or a biosimilar thereof.
  • pembrolizumab is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W). In one embodiment, pembrolizumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-1 inhibitor is cemiplimab or a biosimilar thereof. In one embodiment, cemiplimab or a biosimilar thereof is administered at a dose of 350 mg intravenously once every 3 weeks (Q3W). In one embodiment, cemiplimab or a biosimilar thereof is administered intravenously over 30 minutes.
  • the PD-1 inhibitor is tislelizumab or a biosimilar thereof.
  • tislelizumab or a biosimilar thereof is administered at a dose of 200 mg intravenously once every 3 weeks (Q3W).
  • the therapeutically effective amount of pembrolizumab or biosimilar thereof in the combination is about 350 mg administered every three weeks.
  • the PD-1 inhibitor is tislelizumab or a biosimilar thereof.
  • the therapeutically effective amount of tislelizumab, or biosimilar thereof, in the combination is about 200 mg administered every three weeks.
  • the PD-1 inhibitor is atezolizumab or a biosimilar thereof.
  • the therapeutically effective amount of atezolizumab or biosimilar thereof in the combination is about 1200 mg administered every three weeks.
  • the PD-1 inhibitor is the PD-L1 inhibitor is avelumab or a biosimilar thereof.
  • the therapeutically effective amount of avelumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks or 800 mg every two weeks.
  • the PD-L1 inhibitor is durvalumab or a biosimilar thereof.
  • the therapeutically effective amount of durvalumab or biosimilar thereof in the combination is about 10 mg/kg administered every two weeks.
  • a pharmaceutical compositions comprise a PD-Ll inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • the pharmaceutical compositions comprise a PD-Ll inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • separate administration of each inhibitor, at different times and by different routes, may be advantageous.
  • the components in the combination i.e.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the PD- L1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may need not be necessarily administered at essentially the same time or in any order.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In some cases, the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • a PD-L1 inhibitor the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof) of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per time, and most preferably between about 0.1 to about 20 mg/kg/time. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the PD-L1 inhibitor of the combination will range between about 10 mg/time and about 200 mg/time.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be administered at a dose of about 10 mg/time, 20 mg/time, 30 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 70 mg/time, 80 mg/time, 90 mg/time, 100 mg/time, 110 mg/time, 120 mg/time, 130 mg/time, 140 mg/time, 150 mg/time, 160 mg/time, 170 mg/time, 180 mg/time, 190 mg/time, 200 mg/time, 240 mg/time, 300 mg/time, 480 mg/time.
  • the therapeutically effective amount of the PD-L1 inhibitor of the combination may be any value or subrange within the recited ranges. In some cases, the time is 1 day.
  • the time is 7 days. In some cases, the time is 14 days. In some cases, the time is 21 days. In some cases, the time is 28 days.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the compound of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g.
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the PD-L1 inhibitor is administered to a subject at about 200 mg to about 500 mg. In some embodiments, PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments PD-L1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, PD-L1 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg.
  • the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg , about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the PD-L1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered once daily. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered twice daily. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the PD-L1 inhibitor ⁇ .
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the PD-L1 inhibitor is administered once weekly.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the PD-L1 inhibitor is administered every other day.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the PD-L1 inhibitor is administered every 3 days.
  • the PD-L1 inhibitor e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof
  • the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every two weeks. In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, or a biosimilar thereof), is administered every 4 weeks.
  • the PD-L1 inhibitor is avelumab or a biosimilar thereof. In one embodiment, avelumab or a biosimilar thereof is administered intravenously in the amount of about 800 mg every 2 weeks (Q2W) or about 10 mg/kg every 2 weeks (Q2W). In one embodiment, avelumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-L1 inhibitor is atezolizumab or a biosimilar thereof. In some cases, atezolizumab or a biosimilar thereof is administered at a dose of 1200 mg intravenously once every 3 weeks (Q3W) or at a dose of 840 mg intravenously two weeks apart. In some cases, atezolizumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • the PD-L1 inhibitor is durvalumab or a biosimilar thereof.
  • durvalumab or a biosimilar thereof is administered at a dose of 10 mg/kg intravenously once every 2 weeks (Q2W). In one embodiment, durvalumab or a biosimilar thereof is administered intravenously over 60 minutes.
  • a pharmaceutical composition comprises a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be used in the methods simultaneously, separately, or sequentially.
  • the pharmaceutical compositions comprising a CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formula (I), (LA), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at about the same time as administration of the compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • separate administration of each inhibitor, at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof need not be necessarily administered at essentially the same time or in any order.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formula (I), (I- A), or (I- B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD.
  • the compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
  • the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In some cases, the CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • a single dose of compound or salt of Formula (I), (I- A), or (I- B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.001 to about 1000 mg/kg of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 0.1 to about 50 mg/kg of body weight. In some embodiments, the therapeutically effective amount of the CTLA-4 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be administered at a dose of about 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day.
  • the therapeutically effective amount of the CTLA-4 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the CTLA-4 inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other.
  • the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of coadministration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formula (I), (I-A), or (I-B) once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg and oral administration of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time).
  • the CTLA-4 inhibitor is administered to a subject at about 200 mg to about 500 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 170 mg, about 190 mg, about 210 mg, about 240 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 540 mg, about 580 mg, or about 650 mg.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 480 mg. In some embodiments, the subject is between 12 years old to 18 years old. In some embodiments, the subject is between greater than or equal 12 years old to less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered once daily. In some embodiments, the CTLA-4 inhibitor, is administered twice daily. In some embodiments, the CTLA-4 inhibitor, or pharmaceutically salt thereof is administered 3 times daily. In some embodiments, the CTLA-4 inhibitor, is administered once weekly. In some embodiments, the CTLA-4 inhibitor, is administered every other day. In some embodiments, the CTLA-4 inhibitor, is administered every 3 days. In some embodiments, the CTLA-4 inhibitor, is administered once a week. In some embodiments, the CTLA-4 inhibitor, is administered every two weeks. In some embodiments, the CTLA-4 inhibitor, is administered every 4 weeks.
  • a single dose of compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered per day (i.e., in about 24 hour intervals) (i.e., QD).
  • two doses of the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered per day (i.e., BID).
  • three doses of the compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered per day (i.e., TID).
  • the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (LA), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (LA), or (LB), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V- associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation.
  • the cancer is a KRAS wildtype- associated cancer.
  • the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the compound of Formula (I), (I- A), or (I-B) is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (I), (I- A), or (I-B) is compound 2.
  • the compound of Formula (I), (I- A), or (I-B) is compound 3.
  • the compound of Formula (I), (I- A), or (I-B) is compound 4.
  • the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (II) selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (II) is compound 2.
  • the compound of Formula (II) is compound 3.
  • the compound of Formula (II) is compound 63.
  • the compound of Formula (II) is compound 4.
  • the compound of Formula (II) is compound 14.
  • the compound of Formula (II) is compound 25.
  • the compound of Formula (II) is compound 74.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (I-A), or (I-B) selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2.
  • the compound of Formula (I), (I-A), or (I-B) is compound 3.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4.
  • the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound of Formula (I), (I-A), or (I- B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the immunomodulator inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (I), (I-A), or (I-B).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of an immunomodulator inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof and an immunomodulator inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (I), (I-A), or (I-B) or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • an immunomodulator inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of compounds of Formula (I), (I- A), or (I-B) and an immunomodulator inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an immunomodulator inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and an immunomodulator inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • the KRas G12 mutants or wildtype associated cancer is solid tumor cancer.
  • the KRAS G12 mutants are selected from G12D and G12V.
  • the KRAS G12 mutants is G12D.
  • the KRAS G12 mutants is G12V.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a immunomodulator inhibitor and a compound or salt of Formula (I), (I- A), or (I-B), synergistically increases the potency of the compound or salt of Formula (I), (I- A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formula (I), (I- A), or (I-B) results in an improved efficacy of the compound or salt of Formula (I), (I-A), or (I-B).
  • the therapeutically effective amount of a combination of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12D inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in a complete durable response in subjects relative to treatment with only the KRas G12D inhibitor.
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12D inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12D inhibitor.
  • OS overall survival
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12D inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12D inhibitor.
  • PFS progression-free survival
  • the therapeutically effective amount of a combination of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12V inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in a complete durable response in subjects relative to treatment with only the KRas G12V inhibitor.
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12V inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12V inhibitor.
  • OS overall survival
  • the therapeutically effective amount of the combination of a PD-1/PD-L1 inhibitor or a pharmaceutical composition thereof and a KRas G12V inhibitor compound of Formula (I), Formula I-A, or Formula I-B or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12V inhibitor.
  • PFS progression-free survival
  • the compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PD- 1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation.
  • the cancer is a KRAS wildtype-associated cancer.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • the cancer is a KRas wildtype-associated cancer.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (I), (I-A), or (I-B) is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 3. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 4. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (I-A), or (I-B) selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2.
  • the compound of Formula (I), (I-A), or (I-B) is compound 3.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4.
  • the compound of Formula (I), (I- A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (I), (I-A), or (I-B).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor.
  • the contacting is in vitro. In some cases, the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and a PD-1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • the present disclosure provides methods of reprogramming a tumor microenvironment (TME) of a subject in favor of antitumor immunity, wherein reprogramming includes modulating tumor cell cytokine/chemokine release in the tumor microenvironment of the subject.
  • the method includes providing a compound described herein (a compound of Formula (I, e.g., a compound selected from compounds 2, 3, 4, 14, 25, and 74).
  • the method also includes providing an immunomodulator (e.g., checkpoint inhibitors (inhibitors targeting: cytotoxic T lymphocyte associated antigen 4 (CTLA-4), e.g.
  • CTLA-4 cytotoxic T lymphocyte associated antigen 4
  • the method can also include providing a compound of Formula (I) and an immunomodulator in combination (sequentially or simultaneously).
  • the subject has a KRas-associated cancer.
  • the present disclosure provides methods of treating a KRas G12D- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • the present disclosure provides methods of treating a KRas G12V- associated cancer in a subject in need thereof, comprising administering to the subject a combination of an immunomodulator, and a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • the compound is selected from compounds 2, 3, 4, 14, 25, and 74.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (I), (I-A), or (I-B) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a PD-1 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype -associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I-A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-1 inhibitor are provided.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a PD-1 inhibitor and a compound or salt of Formula (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formula (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formula (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formula (I), (I-A), or (I-B).
  • the compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation.
  • the cancer is a KRAS wildtype-associated cancer.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • the cancer is a KRas wildtype-associated cancer.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation. In some cases, the cancer is a KRAS wildtype-associated cancer. In some cases, the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the compound of Formula (I), (I-A), or (I-B) is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 3. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 4. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (I-A), or (I-B) selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2.
  • the compound of Formula (I), (I-A), or (I-B) is compound 3.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4.
  • the compound of Formula (I), (I- A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the PD-L1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (I), (I-A), or (I-B).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants or wildtype activity is desired with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor.
  • the contacting is in vitro. In some cases, the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (I), (I-A), or (I-B) or pharmaceutically acceptable salt of any one thereof and an PD-L1 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and an PD-L1 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRAS G12 mutants and wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (I), (I-A), or (I-B) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an PD- L1 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a PD-L1 inhibitor are provided.
  • the KRas G12 mutants or wildtype associated cancer is lung cancer.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a PD-L1 inhibitor and a compound or salt of Formula (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formula (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formula (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formula (I), (I-A), or (I-B).
  • the compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is a solid tumor cancer with a KRAS mutation.
  • the cancer is a KRAS wildtype-associated cancer.
  • the cancer is a KRas G12D-associated cancer. In one embodiment, the cancer is a KRas G12V- associated cancer. In one embodiment, the cancer is a KRas wildtype-associated cancer. In some cases, the cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the cancer is a solid tumor cancer with a KRAS mutation. In some cases, the cancer is a solid tumor cancer with KRAS wildtype. In some cases, the cancer is a solid tumor cancer with a G12D mutation. In some cases, the cancer is a solid tumor cancer with a G12V mutation.
  • the cancer is a KRAS wildtype- associated cancer.
  • the KRas G12D-associated cancer is pancreatic, colorectal, endometrial, and non-small cell lung cancer.
  • the compound of Formula (I), (I- A), or (I-B) is selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt of anyone thereof.
  • the compound of Formula (I), (I- A), or (I-B) is compound 2.
  • the compound of Formula (I), (I- A), or (I-B) is compound 3.
  • the compound of Formula (I), (I- A), or (I-B) is compound 4.
  • the compound of Formula (I), (I-A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), (I-A), or (I-B) selected from compound 2, 3, 4, 14, 25, and 74, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I), (I-A), or (I-B) is compound 2.
  • the compound of Formula (I), (I-A), or (I-B) is compound 3.
  • the compound of Formula (I), (I-A), or (I-B) is compound 4.
  • the compound of Formula (I), (I- A), or (I-B) is compound 14. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 25. In some cases, the compound of Formula (I), (I-A), or (I-B) is compound 74.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formula (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formula (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the CTLA-4 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formula (I), (I-A), or (I-B).
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • the present disclosure provides methods of inhibiting KRas G12 mutants or wildtype in a subject comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • inhibiting KRas G12 mutants or wildtype activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor.
  • the contacting is in vitro. In some cases, the contacting is in vivo.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formula (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12 mutants or wildtype activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12 mutants or wildtype.
  • the ability of compounds to bind KRas G12 mutants or wildtype may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds and a CTLA-4 inhibitor in cells may be monitored, for example, by measuring the inhibition of KRas G12 mutants or wildtype activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound or salt of Formula (I), (I-A), or (I-B) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a CTLA- 4 inhibitor.
  • compositions and methods provided herein may be used for the treatment of a KRas G12 mutants or wildtype-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided.
  • KRas G12 mutants or wildtype associated cancer is lung cancer.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (I- A), or (I-B), a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a CTLA-4 inhibitor are provided.
  • the method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a CTLA-4 inhibitor and a compound or salt of Formula (I), (LA), or (LB), synergistically increases the potency of the compound or salt of Formula (I), (LA), or (LB).
  • the synergistic increase in potency of the compound or salt of Formula (I), (LA), or (LB) results in an improved efficacy of the compound or salt of Formula (I), (LA), or (LB).
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRas G12 mutants or wildtype with a compound provided herein and an immunomodulator inhibitor includes the administration of the compound provided herein and an immunomodulator inhibitor to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein and an immunomodulator inhibitor into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants.
  • compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be coadministered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • a patient susceptible to or otherwise at risk of a particular disease, disorder or condition is defined to be a "prophylactically effective amount or dose.”
  • dose a pharmaceutically effective amount or dose.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub -doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Nonlimiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof.
  • the disease, state or condition may be selected from a group as described elsewhere herein.
  • compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein.
  • another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPS) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe- Paganon S, Bradner JE.
  • a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome- mediated degradation of selected proteins.
  • the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art.
  • disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein.
  • the target protein-binding moiety is derived from a compound of Formula (I), (I-A), or (I-B).
  • the compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.
  • the compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein.
  • Step 1 Synthesis of 2-nitro-prop-2-ynyl-benzenesulfonamide (Int-la).
  • a solution of prop-2-yl-l -amine (1.87 mL, 29.1 mmol) and 7V,7V-diisopropylethylamine (10.15 mL, 58.3 mmol) in DCM (100 mL) was cooled to 0 °C.
  • 2-nitrobenzenesulfonyl chloride (6.46 g, 29.15 mmol) was added portion wise.
  • the solution was then allowed to warm to rt and was further stirred for 1 hr.
  • the mixture was washed with water and brine, dried over ISfeSCh, concentrated.
  • Step 2 Synthesis of (3-chloropropyl)-2-nitro-prop-2-ynyl-benzenesulfonamide (Int- 1b).
  • a solution of 2-nitro-prop-2-ynyl-benzenesulfonamide (Int-la, 1.0 g, 4.16 mmol) and cesium carbonate (6.764 g, 20.81 mmol) in acetone (30 mL) was added neat l-bromo-3 -chloropropane (6.05 mL, 61.19 mmol) dropwise.
  • the reaction mixture was stirred at rt for 2 hrs. The mixture was concentrated, then washed with water and brine, dried over Na2SO4, concentrated.
  • Step 3 Synthesis of ethyl 5-(2-nitrophenyl)sulfonyl -4,6,7, 8-tetrahydropyrazolo[ 1,5- a][l,4]diazepine-2-carboxylate (Int-lc).
  • Step 4 Synthesis of ethyl 5-(2-nitrophenyl)sulfonyl -4,6,7, 8-tetrahydropyrazolo[ 1,5- a][l,4]diazepine-2-carboxylate (Int-ld).
  • Step 5 Synthesis of A,A-dimethyl-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxamide (Int-le).
  • Step 6 Synthesis of 3-chloro- N ,N -dimethyl-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxamide (Int-lf).
  • Step 7 Synthesis of 3-chloro-N ,N -dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxamide (Intermediate 1).
  • Step 1 Synthesis of diethyl 4-chloro-lH-pyrazole-3,5-dicarboxylate (Int-lg). To a solution of diethyl lH-pyrazole-3,5-dicarboxylate (20 g, 94.25 mmol) in Acetic acid (360mL) was added dropwise NaClO (264 mL, 1980 mmol). After stirring for 3 h at 25 °C, the remaining mixture was diluted with water, and the mixture was extracted with ethyl acetate.
  • Step 2 Synthesis of diethyl l-[3-(tert-butoxycarbonylamino)propyl]-4-chloro- pyrazole-3,5-dicarboxylate (Int-lh).
  • Diethyl l-[3-(tert- butoxycarbonylamino)propyl]-4-chloro-pyrazole-3,5-dicarboxylate Int-lg, 24.7 g,24.46 mmol, 39.70% yield
  • DMF 150mL
  • tert-butyl N-(3-bromopropyl)carbamate 16141.77 mg, 67.79 mmol
  • Potassium Iodide (204.6 mg, 1.2 3mmol
  • CS2CO3 40157.83 mg, 123.25 mmol
  • Step 3 Synthesis of diethyl l-(3-aminopropyl)-4-chloro-pyrazole-3,5- dicarboxylate;hydrochloride (Int-li). To a solution of diethyl l-(3-aminopropyl)-4-chloro- pyrazole-3,5-dicarboxylate;hydrochloride (Int-lh, 25.5 g, 23.99 mmol, 98.05% yield) in 1,4- Di oxane (50mL) was added HCl/Dioxane (150 mL, 600 mmol), then the mixture was stirred at 25 °C for Ih.
  • Step 4 Synthesis of ethyl 3-chloro-4-oxo-5,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2-carboxylate (Int-lj).
  • Diethyl l-(3-aminopropyl)-4-chloro- pyrazole-3,5-dicarboxylate;hydrochloride Int-li, 25.5 g, 23.99 mmol
  • EtsN (16.74 mL, 119.93 mmol
  • Step 5 Synthesis of ethyl 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxylate (Int-lk).
  • ethyl 3-chloro-4-oxo-5, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxylate Int-lj, 4.8 g, 18.63 mmol
  • THF 60mL
  • Borane-Methyl Sulfide Complex 27.94 mL, 55.89 mmol
  • Step 6 Synthesis of 05-tert-butyl 02-ethyl 3-chloro-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2,5-di carboxylate (Int-11).
  • Step 7 Synthesis of 5-tert-butoxycarbonyl-3-chloro-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2-carboxylic acid (Int-lm).
  • Step 8 Synthesis of tert-butyl 3-chloro-2-(dimethylcarbamoyl)-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate (Int-ln).
  • Step 9 Synthesis if 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine-2-carboxamide (Intermediate 1).
  • Step 1 Synthesis of tert-butyl 2-amino-3-cyano-spiro[5,6- dihy drocy cl openta[b]thiophene-4, 3 '-azetidine]- l'-carboxylate (Int-2a).
  • Step 2 Synthesis of 2-aminospiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]- 3 -carbonitrile (Intermediate 2).
  • Step 1 Preparation of tert-butyl 2-[methoxy(methyl)carbamoyl]-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate (Int-5b).
  • Step 2 Preparation of tert-butyl 3-chloro-2-[methoxy(methyl)carbamoyl]-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate (Int-5c).
  • Step 3 Preparation of tert-butyl 2-acetyl-3-chloro-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-5-carboxylate (Int-5d).
  • Step 4 Preparation of l-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepin-2-yl)ethenone (Intermediate 5).
  • tert-butyl 2-acetyl-3-chloro-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate Int-5d, 140 mg, 0.45 mmol
  • HC1 in Dioxane 56 mL, 224 mmol
  • Step 1 Preparation of tert-butyl 7-methyl-5-oxo-2-azaspiro[3.4]octane-2-carboxylate (Int-6b) To a solution of THF (4 mL) was added 1.6M butyllithium in hexane (4.12 mL, 6.59 mmol) at -68 °C. The mixture was stirred at -68 °C for 10 min.
  • Step 2 Preparation of tert-butyl 2-amino-3-cyano-6-methyl-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3 '-azetidine]- 1 '-carboxylate (Int-6c).
  • Step 3 Preparation of 2-amino-6-methyl-spiro[5,6-dihydrocyclopenta[b]thiophene- 4,3 '-azetidine]-3 -carbonitrile (Intermediate 6).
  • Step 1 Preparation of 3-[(E)-(3-methylsulfanyl-lH-pyrazol-5- yl)methyleneamino]propan-l-ol (Int-8a).
  • 3-methylsulfanyl-lH-pyrazole-5- carbaldehyde Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 3, p. 1319 1336, 1.1 g, 7.74 mmol
  • 3 -aminopropan- l-ol (639.21 mg, 8.51 mmol) in Ethanol (10 mL) was stirred at 80 °C for 16 h. The mixture was concentrated to afford a crude product which was used directly in the next step.
  • Step 2 Preparation of 3-[(3-methylsulfanyl-lH-pyrazol-5-yl)methylamino]propan-l- ol (Int-8b)
  • To a solution of 3-[(E)-(3-methylsulfanyl-lH-pyrazol-5-yl)methyleneamino]propan- l-ol (Int-8a crude, 1.7 g, 8.53 mmol) in Methanol (30mL) was added Sodium triacetoxyborohydride (3.62 g, 17.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 6 h. The mixture was concentrated directly to lOmL.
  • Step 3 Preparation of tert-butyl N-(3-hydroxypropyl)-N-[(3-methylsulfanyl-lH- pyrazol-5-yl)methyl]carbamate (Int-8c).
  • Step 4 Preparation of 3-[tert-butoxycarbonyl-[(3-methylsulfanyl-lH-pyrazol-5- yl)methyl]amino]propyl methanesulfonate (Int-8d).
  • tert-butyl N-(3- hydroxypropyl)-N-[(3-methylsulfanyl-lH-pyrazol-5-yl)methyl]carbamate (Int-8c, 50 mg, 0.17 mmol) and in DCM (2 mL) was added MsCl (28.5 mg, 0.25 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 5 Preparation of tert-butyl 2-methylsulfanyl-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-5-carboxylate (Int-8e).
  • Step 6 Preparation of 2-methylsulfanyl-5,6,7,8-tetrahydro-4H-pyrazolo[l,5- a][l,4]diazepine (Intermediate 8).
  • tert-butyl 2-methylsulfanyl-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate Int-8e, 120 mg, 0.42 mmol
  • DCM 4 mL
  • TFA 0.4 mL, 5.23 mmol
  • Step 1 Preparation of tert-butyl 6-bromo-5-oxo-2-azaspiro[3.4]octane-2-carboxylate (Int-9a). To the solution of tert-butyl 5-oxo-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.89 mmol) in Ether (5 mL) was added 5, 5-dibromohexahydropyrimidine-2, 4, 6-trione (507.6 mg, 1.78 mmol), and the mixture was stirred at 35 °C for 48h.
  • Step 2 Preparation of tert-butyl 2-aminospiro[5,6-dihydrocyclopenta[d]thiazole-4,3'- azetidine]-l'-carboxylate (Int-9b).
  • tert-butyl 6-bromo-5-oxo-2- azaspiro[3.4]octane-2-carboxylate Int-9a 140 mg, 0.46 mmol
  • Ethanol 2 mL
  • Thiourea 35.03 mg, 0.46 mmol
  • Step 3 Preparation of spiro[5,6-dihydrocyclopenta[d]thiazole-4,3'-azetidine]-2-amine (Intermediate 9).
  • the solution of tert-butyl 2-aminospiro[5,6-dihydrocyclopenta[d]thiazole-4,3'- azetidine]-l'-carboxylate (Int-9b, 15 mg, 0.05 mmol) and Trifluoroacetic acid (0.04 mL, 0.53 mmol) in DCM (2 mL) was stirred at 25 °C for Ih.
  • Step 2 Synthesis of tert-butyl 2-cyano-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-5-carboxylate (Intermediate 10).
  • tert-butyl 2-carbamoyl- 4,6,7,8-tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate Int-lOa, 300 mg, 1.07 mmol
  • Pyridine (0.26 mL, 3.21 mmol
  • TFAA 674.36 mg, 3.21 mmol
  • Step 1 Synthesis of [5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepin-2-yl]methanol (Int-l la).
  • Step 2 Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2-carbaldehyde (Int-llb).
  • Step 3 Synthesis of 2-(l-methylbenzimidazol-2-yl)-5-(2-nitrophenyl)sulfonyl- 4,6,7,8-tetrahydropyrazolo[l,5-a][l,4]diazepine (Int-llc) .
  • Step 4 Synthesis of 2-(l-methylbenzimidazol-2-yl)-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,4]diazepine (Intermediate 11) .
  • Step 1 Synthesis of l-(2',2'-difluorospiro[azetidine-3,l'-tetralin]-l-yl)-2,2,2-trifluoro- ethanone (Int-12b). l-(2,2,2-trifluoroacetyl)spiro[azetidine-3,l'-tetralin]-2'-one (Int-12a ref. Angew. Chem. Int. Ed. 2021, 60, 7360-7365, 120 mg, 0.42 mmol) was weighed in a vial and DCM (1.69 mL) was added.
  • Step 2 Synthesis of 2',2'-difluorospiro[azetidine-3,r-tetralin].
  • Intermediate 12 1- (2',2'-difluorospiro[azetidine-3,r-tetralin]-l-yl)-2,2,2-trifluoro-ethanone (Int-12b, 20 mg, 0.07 mmol) was weighed in a vial and Methanol (0.65 mL) was added. Potassium Carbonate (13.58 mg, 0.1 mmol) was added, and reaction was heated to reflux for 1 hour. Reaction was then evaporated and redissolved in 10% MeOH/DCM.
  • Step 1 Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2-carboxamide (Int-14a).
  • Step 2 Synthesis of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[l,5- a][l,4]diazepine-2-carbonitrile (Int-14b) .
  • Step 4 Synthesis of 3-chloro-N-hydroxy-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxamidine (Int-14d).
  • Step 5 Synthesis of 3-[3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepin-2-yl]-5-methyl-l,2,4-oxadiazole (Int-14e).
  • Step 6 Synthesis of 3-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin- 2-yl)-5-methyl-l,2,4-oxadiazole.
  • Step 1 Synthesis of ethyl 3-chloro-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxylate (Int-17a).
  • Step 2 Synthesis of 3-chloro-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-2-carboxamide (Int-17b).
  • Step 1 Synthesis of tert-butyl 3-chloro-2-[methoxy(methyl)carbamoyl]-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate.
  • Step 2 Synthesis of tert-butyl 3-chloro-2-(cyclopropanecarbonyl)-4, 6,7,8- tetrahydropyrazolo[l,5-a][l,4]diazepine-5-carboxylate.
  • Step 3 Synthesis of (3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a][l,4]diazepin-2- yl)-cyclopropyl-methanone.
  • Step 1 Synthesis of 3-(l-azabicyclo[1.1.0]butan-3-yl)thietan-3-ol (Int-17a). 2,3- dibromopropan-l-amine;hydrobromide (5000 mg, 16.79 mmol) in THF (lOOmL) at -78 °C, Phenyllithium (50.37 mL, 50.37 mmol) was added, The mixture was stirred at -78 °C for 2h, After this time, the reaction mixture was removed from the cooling bath and warmed to room temperature over 10 minutes with stirring.
  • Step 2 Synthesis of 2-(2,2,2-trifluoroacetyl)-6-thia-2-azaspiro[3.4]octan-8-one (Int- 17b). 3-(l-azabicyclo[1.1.0]butan-3-yl)thietan-3-ol (Int-17a, 3000 mg, 20.95 mmol) in DCM at -78 °C, TFAA (2.91 mL, 20.95 mmol) was added. The mixture was stirred at -78 °C for 2h. The mixture was quenched with NaEtCCL (100 mL), extracted with DCM (100 mLx2), dried over Na2SO4, concentrated.
  • Step 3 Synthesis of 5-amino-l'-(2,2,2-trifluoroacetyl)spiro[2H-thieno[2,3- b]thiophene-3,3'-azetidine]-4-carbonitrile (Int-17c).
  • 2-(2,2,2-trifluoroacetyl)-6- thia-2-azaspiro[3.4]octan-8-one Int-17b, 500 mg, 2.09 mmol
  • L-Proline 240.65 mg, 2.09 mmol
  • propanedinitrile 207.12 mg, 3.14 mmol
  • Sulfur 100.52 mg, 3.14 mmol
  • Step 4 Synthesis of tert-butyl N-tert-butoxy carbonyl-N-[4-cyano-l '-(2,2,2- trifluoroacetyl)spiro[2H-thieno[2,3-b]thiophene-3,3'-azetidine]-5-yl]carbamate (Int-17d).
  • Step 5 Synthesis of tert-butyl N-(4-cyanospiro[2H-thieno[2,3-b]thiophene-3,3'- azetidine]-5-yl)carbamate (Intermediate 17).
  • tert-butyl N-[4-cyano-l'-(2,2,2- trifluoroacetyl)spiro[2H-thieno[2,3-b]thiophene-3,3'-azetidine]-5-yl]carbamate Int-17d, 300 mg, 0.58 mmol) in Methanol (3mL) was added K2CO3 (239.41 mg, 1.73 mmol) at 25 °C.

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L'invention propose des méthodes de traitement du cancer chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'une combinaison d'un inhibiteur d'immunomodulateur et d'un composé de formule (I).
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Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
US20090217401A1 (en) 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US20110123550A1 (en) 2008-07-04 2011-05-26 Ono Pharmaceutical Co., Ltd. Use of an efficacy marker for optimizing therapeutic efficacy of an anti-human pd-1 antibody on cancers
US20140234296A1 (en) 2011-03-31 2014-08-21 Merck Sharp & Dohme Corp. Stable formulations of antibodies to human programmed death receptor pd-1 and related treatments
US20140271684A1 (en) 2007-07-23 2014-09-18 Medarex, Inc. Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof
US20150079109A1 (en) 2013-09-13 2015-03-19 Beigene, Ltd. Anti-PD1 Antibodies and their Use as Therapeutics and Diagnostics
US20150232555A1 (en) 2007-06-18 2015-08-20 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
US20160305947A1 (en) 2013-12-10 2016-10-20 Merck Sharp & Dohme Corp. Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue
US20160304969A1 (en) 2013-12-17 2016-10-20 Merck Sharp & Dohme Corp. Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists
US20180148790A1 (en) 2015-04-17 2018-05-31 Merck Sharp & Dohme Corp. Blood-based biomarkers of tumor sensitivity to pd-1 antagonists
WO2018098352A2 (fr) * 2016-11-22 2018-05-31 Jun Oishi Ciblage d'expression du point de contrôle immunitaire induit par kras
US20180237524A1 (en) 2015-02-27 2018-08-23 Merck Sharp & Dohme Corp. Crystals of anti-human pd-1 monoclonal antibodies
US20180327848A1 (en) 2014-12-09 2018-11-15 Merck Sharp & Dohme Corp. System and methods for deriving gene signature biomarkers of response to pd-1 antagonists
WO2022241265A1 (fr) * 2021-05-14 2022-11-17 Syndax Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2023230190A1 (fr) * 2022-05-25 2023-11-30 Quanta Therapeutics, Inc. Modulateurs à base de pyrimidine et leurs utilisations

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US20090217401A1 (en) 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US20130133091A1 (en) 2005-05-09 2013-05-23 Ono Pharmaceutical Co., Ltd. Human Monoclonal Antibodies To Programmed Death 1 (PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone Or In Combination With Other Immunotherapeutics
US20140294852A1 (en) 2005-05-09 2014-10-02 Ono Pharmaceutical Co., Ltd. Monoclonal antibodies to programmed death 1 (pd-1)
US20140348743A1 (en) 2005-05-09 2014-11-27 Ono Pharmaceutical Co., Ltd. Monoclonal antibodies to programmed death 1 (pd-1)
US20160304606A9 (en) 2007-06-18 2016-10-20 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
US20180111996A1 (en) 2007-06-18 2018-04-26 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
US20150232555A1 (en) 2007-06-18 2015-08-20 Merck Sharp & Dohme B.V. Antibodies to human programmed death receptor pd-1
US20140271684A1 (en) 2007-07-23 2014-09-18 Medarex, Inc. Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof
US20110123550A1 (en) 2008-07-04 2011-05-26 Ono Pharmaceutical Co., Ltd. Use of an efficacy marker for optimizing therapeutic efficacy of an anti-human pd-1 antibody on cancers
US20140234296A1 (en) 2011-03-31 2014-08-21 Merck Sharp & Dohme Corp. Stable formulations of antibodies to human programmed death receptor pd-1 and related treatments
US20150079109A1 (en) 2013-09-13 2015-03-19 Beigene, Ltd. Anti-PD1 Antibodies and their Use as Therapeutics and Diagnostics
US20160305947A1 (en) 2013-12-10 2016-10-20 Merck Sharp & Dohme Corp. Immunohistochemical proximity assay for pd-1 positive cells and pd-ligand positive cells in tumor tissue
US20160304969A1 (en) 2013-12-17 2016-10-20 Merck Sharp & Dohme Corp. Ifn-gamma gene signature biomarkers of tumor response to pd-1 antagonists
US20180327848A1 (en) 2014-12-09 2018-11-15 Merck Sharp & Dohme Corp. System and methods for deriving gene signature biomarkers of response to pd-1 antagonists
US20180237524A1 (en) 2015-02-27 2018-08-23 Merck Sharp & Dohme Corp. Crystals of anti-human pd-1 monoclonal antibodies
US20180148790A1 (en) 2015-04-17 2018-05-31 Merck Sharp & Dohme Corp. Blood-based biomarkers of tumor sensitivity to pd-1 antagonists
WO2018098352A2 (fr) * 2016-11-22 2018-05-31 Jun Oishi Ciblage d'expression du point de contrôle immunitaire induit par kras
WO2022241265A1 (fr) * 2021-05-14 2022-11-17 Syndax Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2023230190A1 (fr) * 2022-05-25 2023-11-30 Quanta Therapeutics, Inc. Modulateurs à base de pyrimidine et leurs utilisations

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Curr., Pharm. Des.", vol. 6, 2000, article "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development", pages: 110
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"The AACR Project GENIE Consortium", CANCER DISCOVERY, vol. 7, no. 8, 2017, pages 818 - 831
AGATA ET AL., INT IMMUNOL, vol. 8, 1996, pages 765 - 72
ANGEW. CHEM. INT. ED., vol. 60, 2021, pages 7360 - 7365
BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 20, no. 3, 2012, pages 1319 - 1336
COELHO ET AL., IMMUNITY, vol. 47, no. 6, 2017, pages 1083 - 1099
CULLY, M.J. DOWNWARD: "SnapShot: Ras Signaling", CELL, vol. 133, no. 7, 2008, pages 1292 - 1292
DONG ET AL., J. MOL. MED., vol. 81, 2003, pages 281 - 7
DONG ET AL., NAT. MED., vol. 8, 2002, pages 787 - 9
DROSTEN, M. ET AL.: "Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival", EMBO J, vol. 29, no. 6, 2010, pages 1091 - 104, XP093208809, DOI: 10.1038/emboj.2010.7
EDWARD B. ROCHE: "Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
EL-JAWHARI ET AL., MOLECULAR IMMUNOLOGY, vol. 58, no. 2, 2014, pages 160 - 168
EVANS, E. ANTHONY: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, no. 1-2, 1981, pages 9 - 32
FEDORAK ET AL., AM. J. PHYSIOL., vol. 269, 1995, pages 210 - 218
FREEMAN ET AL., J EXP MED, vol. 192, 2000, pages 1027 - 34
GEORGE W.VARMA, RAJENDER S: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
HOCHHAUS ET AL., BIOMED. CHROM., vol. 6, 1992, pages 283 - 286
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
J. LARSEN ET AL., INT. J. PHARMACEUTICS, vol. 47, 1988, pages 103
J. LARSENH. BUNDGAARD, INT. J. PHARMACEUTICS, vol. 37, 1987, pages 87
JEAN JACQUESANDRE COLLETSAMUEL H. WILEN: "Enantiomers, Racemates and Resolutions", 1981, JOHN WILEY AND SONS, INC.
L. FIESERM. FIESER, FIESER AND FIESER'S REAGENTS FOR ORGANIC SYNTHESIS, 1994
LIAO ET AL., CANCER CELL, vol. 35, 2019, pages 559 - 572
MCLOED ET AL., GASTROENTEROL, vol. 106, 1994, pages 405 - 413
R. LAROCK, COMPREHENSIVE ORGANIC TRANSFORMATIONS, 1989
REMINGTON: "Encyclopedia of Reagents for Organic Synthesis", 1995, MACK PUBLISHING COMPANY
REMINGTON: "The Science and Practice of Pharmacy", 2005, MACK PUB. CO.
ROWE ET AL.: "Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety", 2006
SINKULA ET AL., J. PHARM. SCI., vol. 64, 1975, pages 181 - 210
STEPHEN, A.G. ET AL.: "Dragging ras back in the ring", CANCER CELL, vol. 25, no. 3, 2014, pages 272 - 81, XP028633347, DOI: 10.1016/j.ccr.2014.02.017
SUNAGA ET AL., INT. J. CANCER, vol. 130, no. 8, 2012, pages 1733 - 1744
T. HIGUCHI, V. STELLA: "A.C.S. Symposium Series", PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, vol. 14
T. W. GREENE, P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991
WINTER GEBUCKLEY DLPAULK JROBERTS JMSOUZA ADHE-PAGANON SBRADNER JE: "Phthalimide conjugation as a strategy for in vivo target protein degradation. Science", DRUG DEVELOPMENT, vol. 348, no. 6241, 19 June 2015 (2015-06-19), pages 1376 - 81, XP055328122, DOI: 10.1126/science.aab1433

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