WO2025106901A1 - Polythérapies anticancéreuses avec un modulateur de kras et un inhibiteur de la voie rtk-mapk - Google Patents

Polythérapies anticancéreuses avec un modulateur de kras et un inhibiteur de la voie rtk-mapk Download PDF

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WO2025106901A1
WO2025106901A1 PCT/US2024/056246 US2024056246W WO2025106901A1 WO 2025106901 A1 WO2025106901 A1 WO 2025106901A1 US 2024056246 W US2024056246 W US 2024056246W WO 2025106901 A1 WO2025106901 A1 WO 2025106901A1
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compound
alkyl
salt
heterocycle
optionally substituted
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Hong Lin
Cameron PITT
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Quanta Therapeutics Inc
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • 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), norbornenyl, 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 –Rc-cycloalkyl where Rc 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, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, 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.).
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.
  • 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, 1-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-diamine, 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-1-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 saturated or unsaturated ring e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene.
  • 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 spiro- heterocycle, 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 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. Examples of 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. It will be understood that “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, i.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.
  • 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 ⁇ , ⁇ -unsaturated carbonyl or ⁇ , ⁇ -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.
  • the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.
  • 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, p-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.
  • 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 corn 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, corn 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 hydroxide;
  • the terms “treat,” “treating” or “treatment,” as used herein, 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).
  • RTK-MAPK pathway refers to the signaling cascade between Receptor Tyrosine Kinases (RTKs), including positive regulators of RTK activity, e.g., SHP2 or SOS1, and the RAF-MEK-ERK (i.e. MAPK) pathway.
  • RTK-MAPK pathway inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one protein within the RTK-MAPK pathway.
  • RAF-MEK-ERK pathway refers to the series of kinases activated sequentially downstream of activation of the RAS family of small GTPases.
  • RAF-MEK-ERK pathway inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one protein within the RAF-MEK-ERK pathway.
  • 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.
  • ERBB family or “ERBB family member” refers to a member of a mammalian transmembrane protein tyrosine kinase family including: EGFR, ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
  • ERBB family inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ERBB family.
  • EGFR inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of Epidermal Growth Factor Receptor (EGRF).
  • SHP-2 or “SHP2” refers to the mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signaling through the Ras- mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
  • SHP-2 inhibitor or a “SHP2 inhibitor” refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of SHP-2 phosphatase.
  • SOS1 refers to a mammalian Son of sevenless homolog 1 (SOS1) enzyme.
  • SOS1 inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the interaction of SOS1 with Ras family mutant or SOS1 activating mutation thereby reducing and/or modulating the nucleotide exchange activity of Ras family member - SOS1 complex.
  • 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.
  • the terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include 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.
  • 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.
  • 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.
  • any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.
  • COMPOSITIONS AND INHIBITORS RTK-MAPK Pathway Inhibitors [0083]
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) a RTK-MAPK pathway 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.
  • a RTK-MAPK pathway inhibitor a pharmaceutically acceptable salt or a pharmaceutical composition thereof
  • a compound of Formula (I-A) a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a RTK-MAPK pathway inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,
  • a RTK-MAPK pathway inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
  • the compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • the RTK-MAPK pathway inhibitor is selected from afatinib, dacomitinib, poziotinib, erlotinib, gefitinib, sapitinib, tarloxotinib, cetuximab, RMC-4550, SHP- 099 (6-(4-Amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)- 6-(2,3-dichlorophenyl)-5-
  • RAF-MEK-ERK pathway inhibitor a RAF-MEK-ERK pathway 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.
  • RAF-MEK-ERK pathway inhibitor a pharmaceutically acceptable salt or a pharmaceutical composition thereof
  • a compound of Formula (II) a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • RAF-MEK-ERK pathway inhibitor a RAF-MEK-ERK pathway 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.
  • RAF-MEK-ERK pathway inhibitor a RAF-MEK-ERK pathway 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.
  • RAF-MEK-ERK pathway inhibitor a pharmaceutically acceptable salt or a pharmaceutical composition thereof
  • a compound of Formula (I-B) a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • a RAF-MEK-ERK pathway inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,
  • the compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • ERBB family Inhibitors [0099] In an aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a combination of: i) a ERBB family 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.
  • provided herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of: i) a ERBB family 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) a ERBB family 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) a ERBB family 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) a ERBB family 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 compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • the ERBB family inhibitors used in the methods herein may be reversible or irreversible ERBB family inhibitors. In one embodiment, the ERBB family inhibitor inhibits the activity of more than one ERBB family member.
  • the modulation or inhibition of one or more ERBB family members may occur through modulating or inhibiting kinase enzymatic activity of one or more ERBB family member or by blocking homodimerization or heterodimerization of ERBB family members.
  • the ERBB inhibitor refers to the use of a single ERBB inhibitor. In some embodiments of the methods herein, the term ERBB inhibitor refers to the use of two ERBB inhibitors.
  • the ERBB family inhibitor is an irreversible inhibitor. In some cases, irreversible ERBB family inhibitors inhibit the activity of EGFR and HER2 by forming a covalent bond with the sulfhydryl group of cysteine 797 and cysteine 773, respectively, that blocks the binding of ATP to the intracellular catalytic domain.
  • exemplary irreversible ERBB family inhibitors for use in the methods include afatinib ((E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3- yl)oxy)quinazolin- 6-yl)-4-(dimethylamino)but-2-enamide); dacomitinib ((2E)-N- ⁇ 4-[(3-Chloro- 4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl ⁇ -4-(l-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3
  • the irreversible ERBB family inhibitor is afatinib. In one embodiment, the irreversible ERBB family inhibitor is dacomitinib. In some cases, the irreversible ERBB family inhibitors suitable for the provided compositions and methods include, but are not limited to, Afatinib; Dacomitinib; Canertinib; Poziotinib, AV 412; PF 6274484 and HKI 357. [00111] In some embodiments, the ERBB family inhibitor is a reversible inhibitor.
  • reversible inhibitors include erlotinib ([6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3- ethynyl-phenyl)-amine)), gefitinib (4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, sapitinib (2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidin-l-yl)-N-methylacetamide); varlitinib ((R)-N4-(3-chloro-4- (thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine);
  • the reversible ERBB family inhibitor is sapitinib. In some cases, the reversible ERBB family inhibitor is tarloxotinib. [00113] In some embodiments, the ERBB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of two of: AG 1478 HC1 (7V-(3-Chlorophenyl)-6,7-dimethoxy-4-quinazolinanine hydrochloride); AG 494 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-2-propenamide; AG 555 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-propenamide; AG 556 (E)-2- Cyano-3-(3,4-dihydroxyphenyl)-N-(4-
  • the ERBB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or a combination of an anti-EGFR antibody and anti-HER2 antibody, or pharmaceutical compositions thereof.
  • antibodies including monoclonal antibodies, antibody drug conjugates and bispecific antibodies, targeting EGFR and/or HER-2 are used.
  • exemplary anti-EGFR monoclonal antibodies approved for human clinical use include, but are not limited to, necitumumab (Eli Lilly), panitumumab (Amgen) and cetuximab (ImClone).
  • anti-EGFR antibodies suitable for use in the methods include EP384, Hl l, 11.6, 225 and 199.12 (Thermo Fisher), or GT133 (GeneTex).
  • the anti-EGFR monoclonal antibody is cetuximab.
  • exemplary anti-HER-2 monoclonal antibodies include but are not limited to, pertuzumab (Roche), trastuzumab (Roche) and trastuzumab emtansine (Roche).
  • the ERBB family inhibitor is an anti-EGFR antibody, an anti- HER2 antibody or a combination of an anti-EGFR antibody and anti-HER2 antibody, or pharmaceutical compositions thereof.
  • the anti-EGFR antibody is necitumumab, panitumumab or cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In some cases, the anti-HER2 antibodies suitable for use in the methods herein is pertuzumab, trastuzumab, or trastuzumab emtansine.
  • the ERBB family inhibitor is a an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are independently selected from two agents selected from the group consisting of: AG 1478 HC1 (N-(3-Chlorophenyl)-6,7- dimethoxy-4-quinazolinanine hydrochloride); AG 494 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N- phenyl-2-propenamide; AG 555 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)- 2- propenamide; AG 556 (E)-2-Cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2- propenamide; AG 825 (E)-3-[3-[2-Benzothiazolythio)methyl]-4-hydroxy-5-methoxy
  • EGFR Inhibitors [00120] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) an EGFR 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. [00121] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of: i) an EGFR 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 EGFR 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) an EGFR 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a combination of: i) a EGFR 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) a EGFR 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.
  • the compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • EGFR Epidermal Growth Factor Receptor
  • the EGFR receptor Upon binding epidermal growth factor (EGF), the EGFR receptor can homo-dimerize with another EGFR molecule or hetero-dimerize with another family member such as ErbB2 (HER2), ErbB3 (HER3), or ErbB4 (HER4).
  • the EGFR inhibitor is selected from cetuximab, afatinib and erlotinib.
  • SHP-2 Inhibitors [00130] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SHP-2 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. [00131] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of: i) a SHP-2 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) a SHP-2 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) a SHP-2 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 cancer in a subject in need thereof comprising administering to the subject a combination of i) a SHP-2 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 SHP-2 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
  • a SHP-2 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90
  • the compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • Src homology 2 (SH2) domain-containing phosphatase 2 (“SHP-2”) is a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT or the phosphoinositol 3-kinase (P13K)-AKT-mTOR pathways, SHP-2 polypeptide is comprised of two Src homology 2 (SH2) domains (N-SH2 and C-SH2) located in the N-terminal region and two potential Grb2 SH2 domain binding sites located in the C-terminal region.
  • SHP-2 has been shown to exhibit non-mutational drug resistance mechanism in response to anti-tyrosine kinase inhibitors (TKIs).
  • TKIs anti-tyrosine kinase inhibitors
  • an increase in SHP-2 phosphatase activity has been shown to confer resistance to the TKI inhibitor imatinib (e.g., see Li et. ah, (2016) Toxicol. Appl. Pharmacol.360-249-256).
  • the addition of a SHP-2 inhibitor was shown to overcome resistance by blocking both the RAF/MEK/ERK pathway as well as the PI3K/AKT/mTOR pathways.
  • Several inhibitors exhibiting activity against SHP-2 have been developed.
  • Exemplary SHP-2 inhibitors include, but are not limited to, SHP-099 (6-(4-Amino-4-methylpiperidin-1-yl)- 3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazin-2- yl)methanol), RMC-4630 (Revolution Medicine) and TNO155 (Novartis). RMC-4630 and TNO155 are in Phase 1 human clinical trials for adult patients having particular advanced solid tumors.
  • SOS1 Inhibitors [00142] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SOS1 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. [00143] In an aspect, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of: i) a SOS1 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.
  • provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: i) a SOS1 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of: i) a SOS1 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 a combination of: i) a SOS1 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.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a combination of: i) a SOS1 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 SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, ii) and a compound selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
  • the compound is compound 2. In some cases, the compound is compound 3. In some cases, the compound is compound 4. In some cases, the compound is compound 14. In some cases, the compound is compound 25. In some cases, the compound is compound 74.
  • SOS1 inhibitors block the interaction between SOS1 and Ras- family members and prevent the recycling of KRas in to the active GTP-bound form and, therefore, may provide therapeutic benefit for a wide range of cancers, particularly Ras family member-associated cancers. These compounds negatively modulate the activity of KRas through blocking SOS1- KRas interaction in a cell for treating various forms of cancer, including Ras- associated cancer, SOS1-associated cancer and NFl/NF2-associated cancer.
  • one SOS1 inhibitor that can be used for the methods described herein is BI-I-13 (aka BI-3406). It has the following structu re: KRAS Modulators [00152] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts may be used in combination with at least one other inhibitor (e.g., RTK-MAPK pathway inhibitor, RAF-MEK-ERK pathway inhibitor, ERBB family inhibitor, EGFR inhibitor, SHP-2 inhibitor, or SOS1 inhibitor).
  • at least one other inhibitor e.g., RTK-MAPK pathway inhibitor, RAF-MEK-ERK pathway inhibitor, ERBB family inhibitor, EGFR inhibitor, SHP-2 inhibitor, or SOS1 inhibitor.
  • the compounds and salts may be used in combination with one other inhibitor (e.g., RTK-MAPK pathway inhibitor, RAF-MEK-ERK pathway inhibitor, ERBB family inhibitor, EGFR inhibitor, SHP-2 inhibitor, or SOS1 inhibitor).
  • a compound of Formulas (I), (I-A), or (I-B) may be used in the methods of the disclosure.
  • a compound of Formulas (I), (I-A), or (I-B) may be referred to as a KRAS inhibitor.
  • a compound of Formulas (I), (I-A), or (I- B) may be referred to as a KRAS inhibitor.
  • a compound of Formulas (I), (I-A), or (I-B) may be referred to as a KRAS modulator.
  • 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 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle. In some cases, and optionally substituted C8-C15 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 C8-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C 8 -C 15 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 C8-C15 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.
  • 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.
  • the heterocycle and carbocycle are each independently bicyclic.
  • the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused c a rbocycle are selected from , , , , and , each of which is optionally substituted with one or more substituents.
  • the optionally substituted 8- to 15-me b d f d h l d i ll b i d C C 15 fused carbocycle are selected from , , , , and , each of which is optionally substituted with one or more substituents.
  • a nd each of which is optionally substituted with one or more substituents.
  • B i and 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 , e 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, -NH2, halogen, C1-C3 alkyl.
  • B the optionally substituted 8- to 15-membered fused heterocycle and optionally s , , , and .
  • B is selected f , , , , , , , , , , , , , , ,
  • 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 n , , , , , , and , each of which is optionally substituted.
  • B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur atom. In s ome cases, s se ec e rom , , , , , eac o which is optionally substituted.
  • the one or more optional substituents of B are independently selected at each occurrence from halogen, C 1 -C 3 alkyl, -NH 2 , and -CN.
  • B is substituted In some cases B is substituted In some cases B is substituted with at least one -NH 2 In some cases B is selected from , , , , and NH2 . In some cases, B is substituted with at least one -NH2 at least one -CN. In some cases, B is selected f .
  • 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.
  • 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. In some cases, 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.
  • , h is o , , , , , and each of which is o i ll bstituted.
  • B is selected from , , , and , each of which 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.
  • B is substituted with at least three substituents.
  • B is substituted with at least two substituents.
  • B is substituted with at least one substituent.
  • B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN.
  • B is substituted with at least one substituent selected from halogen.
  • B is substituted with at least one substituent selected from -NH 2 .
  • R3 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, C1-6 aminoalkyl, C1-6 alkoxy
  • 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 , C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl.
  • R 3 is selected from hydrogen, halogen, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl)H -N(C 1-6 alkyl) 2 ,-OH, - C(O)N(R 20 )2, -C(O) R 20 , -C(O)OR 20 , -OC(O) R 20 , C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • R 3 is selected from hydrogen, -CN, -C(O)R 20 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R 3 is selected from hydrogen, -CN, -C(O)R 20 , C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, R 3 is selected from hydrogen, -CN, -C(O)H, C 1 hydroxyalkyl, and C 1-6 alkyl. In some cases, R 3 is selected from hydrogen, fluorine, and -CN.
  • 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 C1- C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted C 1 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 C 1 - C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene.
  • the optional substituents of L are selected from Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or b i l d from h , , , , , , and .
  • L is selected from .
  • each L is independently selected from a substituted C 2-3 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 C 3 carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each L is independently selected from .
  • each L is independently selected from . In some cases, each L is independently selected fro . In some cases, each L is independently selected from a C l -C 4 alkylene optionally substituted with one or more substituents independently selected from halogen and Cl-C4 alkyl. In some cases, L is selected fro , , , . [00168] In some embodiments, for a compound or salt for Formula (I), each L is independently selected from an unsubstituted Cl-C4 alkylene. In some cases, L is selected fro m and . In some cases, L is selected from .
  • R2 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 .
  • R2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted.
  • R 2 is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, R 2 is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle. In some cases, R 2 is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle. In some cases, R 2 is selected from a - L-5- to 10-membered heterocycle. In some cases, R 2 is selected from a -(C 1 -C 2 alkylene)-5- to 10-membered heterocycle. In some cases, R 2 is selected from a -L-5- to 8-membered heterocycle.
  • 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. In some cases, Y-R2 is selected fro , wherein the heterocycle portion is optionally substituted.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl.
  • the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, C l -C 3 hydroxyalkyl, C l -C 3 alkyl, C l -C 3 haloalkyl, C1-C3 alkoxy, and Cl-C3 aminoalkyl.
  • the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alk l and halogen.
  • Y-R 2 is selected from , , , and some cases, Y-R 2 is selected fro . In some cases, Y-R 2 is selected from .
  • R 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-R2 is selected fro , 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.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted.
  • the heterocycle is substituted with at least one halogen.
  • R2 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. In some cases, the heteroaryl has two nitrogen atoms.
  • the heteroaryl has three nitrogen atoms. In some cases, the heteroaryl is selected from , , , which is optionally substituted. In some cases, the heteroaryl is , , , an , which is optionally substituted. In some cases, Y-R2 is selected from , , , and , wherein the heteroaryl portion is optionally substituted with one or more R 7 . In some cases, each R 7 is independentl selected from Cl-C4 alkyl, halogen, a d C C h l lkyl. In some cases, Y-R 2 is selected fr d . In some cases, Y-R2 is selected from and .
  • Y-R 2 is selected from , , .
  • R2 is -L-ar l o tionally s , wherein the heterocycle portion is optionally substituted with one or more R 7 .
  • R2 is -L-N(R23)2.
  • R 2 is heterocycle, optionally substituted with one or more R6.
  • t 2 is , which is u ted.
  • R2 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 , ith one or more R 6 ; wherein the aryl and heteroaryl of R 2 is selected fr , and ryl and the heteroaryl are each optionally substituted with one or more R 7 ; .
  • the heterocycle o 2 f R is selected fr , , , , , , , , , , wherein the heterocycle is optionally substituted with one or more R 6 ; wherein the aryl and heteroaryl of R 2 is selected from , , , , , and ore R 7; and , .
  • L is independently selected from a C l -C 4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4 hydroxyalkyl and Cl-C4 alkyl.
  • L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from Cl-C4 alkyl.
  • L is selected from C1-C4 alkylene.
  • L is selected from C 1 -C 2 alkylene.
  • L i In some cases, .
  • the optional substituents of L are selected from C l -C 4 hydroxyalkyl, C l -C 4 alkyl, C 3 -C 6 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 C 1-6 haloalkyl.
  • each L is independently selected from a substituted Cl-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C l -C 4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, 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. In some cases, each L is independently selected from . [00181] In some embodiments, for a compound or salt of Formula (I), R2 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. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [00182] In some embodiments, for a compound or salt of Formula (I), R2 is selected from , wherein the heterocycle portion is optionally s ubstituted with one or more R 6 . [00183] In some embodiments, for a compound or salt of Formula (I), Y-R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R2 is selected from n is optionally substituted with one or more R 6 .
  • Y-R2 is selected from and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R2 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-R2 is selected from , , and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , , and , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl and oxo.
  • Y-R2 is selected from ome cases, Y-R2 is selected from . [00187]
  • 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. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl only contain nitrogen atom(s).
  • the heteroaryl is a 6- membered heteroaryl. In some cases, the heteroaryl is a 5-membered heteroaryl. In some cases, the heteroaryl is selected from , each of which is optionally substituted. In some cases, the heteroaryl is selected fro , each of which is optionally substituted.
  • R 2 is selected from an optionally substituted aryl. In some cases, 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, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C 1 -C 3 alkoxy, cyano, -CH 2 heterocycle, -C 1 -C 3 alkyl-N(R 5 ) 2 , and -C(O)N(R 5 ) 2 .
  • R 6 is selected from C l -C 3 alkyl, -CH 2 heterocycle, and -C(O)N(R 5 ) 2 .
  • the aryl is optionally substituted with one or more R 7 .
  • Y-R 2 is selected from a nd and .
  • Y is -O- and R2 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 selected from , .
  • L is selected from .
  • the heteroaryl is optionally substituted with one or more R 7 .
  • each R 7 is selected from halogen, Cl-C4 alkyl, and Cl-C4 haloalkyl.
  • Y-R 2 is selected from , , , .
  • each R6 is independently selected from halogen, -OH, C l -C 3 hydroxyalkyl, C l -C 3 alkyl, C l -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, each R 6 is independently selected from halogen, Cl-C3 alkyl, and Cl-C3 haloalkyl.
  • each R6 is independently selected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 aminoalkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo.
  • each R 6 is independently selected from -OH, Cl- C 3 hydroxyalkyl, C l -C 3 alkyl, C l -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R6 is selected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, R 6 is selected from halogen and Cl-C3 alkyl. In some cases, R 6 is halogen. In some cases, R 6 is C l -C 3 alkyl. In some cases, R 6 is selected from halogen and C l -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R2 is selected from , , .
  • Y-R2 is selected from , , and .
  • Y-R2 is selected from , , and .
  • L is selected from unsubstituted C1-C4 alkylene.
  • Y-R2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R6 of R2 is independently selected at each occurrence from halogen, hydroxy, C l -C 3 hydroxyalkyl, C l -C 3 alkyl, C l -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, and C l -C 3 aminoalkyl.
  • R6 of R2 is independently selected at each occurrence from C1-C3 alkyl and halogen.
  • Y-R2 is selected from .
  • R1 is selected from an optionally substituted 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 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. In some cases, 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.
  • 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. [00203] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1 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.
  • 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. In some cases, the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle. In some cases, the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle. [00205] In some embodiments, for a compound or salt of Formula (I), R1 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.
  • the heterocycle is a bridged heterocycle. In some cases, the heterocycle is an unsaturated heterocycle.
  • R1 is a 6- to 12- membered fused heterocycle, which is optionally substituted.
  • R1 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 R1 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. [00209]
  • R1 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. In some cases, the heterocycle of R 1 is saturated. The monocyclic heterocycle is optionally substituted as described elsewhere herein. [00210] In some embodiments, for a compound or salt of Formula (I), R1 is a bridged heterocycle. In some cases, 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. In some cases, the heterocycle of R 1 is an 8- to 9-membered bridged heterocycle. In som h h l f R 1 is saturated. In some cases, the bridged heterocycle is selected from , , and . In some cases, the bridged heterocycle is selected from . Each bridged heterocycle is optionally sub stituted as described elsewhere herein. [00211] In some embodiments, for a compound or salt of Formula (I), R1 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.
  • the spiroheterocycle of R 1 is bound to the Formula via the nitrogen atom. , , , , , and . In some cases, the spiro heterocycle of R1 is selected from . Each spiro heterocycle is optionally substituted as described elsewhere herein. [00212] In some embodiments, for a compound or salt of Formula (I), R1 is a fused heterocycle. In some cases, 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. In some cases, the fused heterocycle of R 1 is an 11-membered fused heterocycle. In some cases, 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 , , an . Each fused heterocycle is optionally substituted as described elsewhere herein.
  • R1 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, R1 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.
  • 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 .
  • the further one or more optional substituents are selected from halogen, -CN, C2 alkenyl, and C1-6 alkyl. In some cases, the further one or more optional substituents are selected from halogen, and C 1-6 alkyl. In some cases, 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.
  • each R 20 is independently selected from 5- to 6-membered saturated heterocycle.
  • the heterocycle of R 20 has at least one nitrogen atom.
  • the heterocycle of R 20 has at least one sulfur atom.
  • the heterocycle of R 20 has at least one oxygen atom.
  • the heterocycle of R 20 contains only 1 heteroatom.
  • the heterocycle of R 20 has at least two heteroatoms.
  • the heterocycle of R 20 contains only 2 heteroatoms.
  • the optional one or more substituents of R 1 are independently selected from halogen, -CN, C2 alkenyl , the optional one or more substituents of R 1 are independently selected from halog , , 1 are i , , , , , , , , , and . In some cases the optional one or more substituents of R1 are independently selected from halogen, , , d , , , , , , , ,
  • the optional one or more substituents of R 1 are independently selected from halogen, and C1-6 alkyl-N(R 20 )2. In some cases, the optional one or more substituents of R 1 are independently selected from halogen, om m hydrogen, C1-6 alkyl, and C3-6 carbocycle. In some cases, R1 is selecte , , , , and .
  • R 1 is selected from , which is optionally substituted with one more substituents independently selected from halogen and C1-6 alkyl.
  • R 1 is selected fro and [ m a , wherein 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, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, and -CN.
  • R B is selected from hydr and halogen.
  • R B is chloride.
  • R B is hydrogen. In some cases, has at least 1, 2, 3, or 4 heteroatoms.
  • B in some cases, has at least 1, 2, 3, or 4 nitrogen atoms. In some cas has at least 1 oxygen atom.
  • B is a monocyclic heterocycle. In some case is a bicyclic heterocycle. In some cases, is selected from an optionally substituted 5-membered heterocycle. In some cases, is selected from an optionally substituted 9-membered heterocycle. In some cases, , R1*. I , each of which is optionally substituted with one or more R 1* .
  • each R 1* is independently selected from halogen, C1-6 alkyl-N(R 20 )2, C1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen and C1-6 alkyl. In some cases is selected from , , and . [00215] In some embodiments, for a compound or salt of Formula (I), when R1 is substituted with -C(O)R 20 , R 20 is selected from a 5- to 12-membered heterocycle, which is optionally substituted. In some cases, R 1 is substituted with -C(O)R 20 .
  • R1 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents.
  • R1 is selected from a saturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents.
  • the 5- to 12-membered heterocycle of R 1 is bridged.
  • the 5- to 12-membered heteroc cle of R 1 is not brid ed
  • the 5- to 12-membered heterocycle is selected from , , , , , ,
  • R1 is selected from , , , , , , , , and , p y .
  • R 1 is s , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R1 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 R1 contains only 1 nitrogen atom and optionally one or more heteroatoms selected from oxygen, and sulfur. In some cases, the heterocycle is a fused heterocycle or a bridged heterocycle.
  • the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected from and . The heterocycle is optionally substituted as described elsewhere herein. [00225] In some embodiments, for a compound or salt of Formula (I), the heterocycle of R1 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.
  • R1 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.
  • R1 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. [00228] In some embodiments, for a compound or salt of Formula (I), R1 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.
  • 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 , , , , , , an , eac o w c s su st tute .
  • R1 is selected from , , , , , , and , each of which is substituted.
  • R 1 is selected from and , rom 1 R is 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, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl.
  • the one or more optional substituents of R 1 are each independently selected from fluorine, -OH, -CN, C1-6 cyanoalkyl, C1-6 alk l and C 2 6 alk n l
  • R 1 is selected from , , , , , , , , , , , , , , , , , , , R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • s [ , , , , , , , , and , each of which is optionally substituted with one or more substituents.
  • R1 is selecte , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R1 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 fr om , , , , an wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 1 is selected from , , , and wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alk h lk l h l lk l and C 1-6 alkyl.
  • R 1 is selected from , , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
  • R 1 is selected from , R1 is s , . In and , wherein each is substituted with one or more substituents independently selected from halogen.
  • R1 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.
  • the unsaturated 6- to 7-membered heterocycle is substituted with at least one halogen.
  • the unsaturated 6- to 7-membered heterocycle is substituted with at only one halogen.
  • the unsaturated 7-membered heterocycle is substituted with one fluorine.
  • R 1 is selected from an unsaturated 6-membered heterocycle, substituted with at least one halogen.
  • R 1 is selected from an unsaturated 7-membered heterocycle, substituted with at least , , R1 i . In some cases, R1 is selected from R1 is s R1 is . In some cases, R 1 is . [00232] In some embodiments, for a compound or salt of Formula (I), R1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 1 is selected from a i ll b i ed unsaturated 7-membered heterocycle.
  • R 1 is selected from , and , 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 . [0 0233] In some embodiments, for a compound or salt of Formula (I), R1 is selected from an optionally substituted 6-membered heterocycle. In some cases, the 6-membered heterocycle contains only 1 nitrogen atom. In some cases, the 6-membered heterocycle of R 1 is bound to Formula (I) via the only 1 nitrogen atom.
  • R1 is selected fro m , and , any 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.
  • R1 is selected from an optionally substituted 6-membered unsaturated heterocycle and 6-membered saturated heterocycle.
  • R1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
  • R1 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
  • R1 is selected from .
  • R1 is selected from and , wherein each is optionally substituted two substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R1 is selected from and , wherein each is optionally substituted with two substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R 1 is .
  • R1 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • 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.
  • the 6- to 7-membered heterocycle of R 1 is bound to Formula (I) via the only 1 nitrogen atom.
  • R 1 is selected fr , , each of which is substituted.
  • R1 is selected from h of which is substituted.
  • R 1 is selected from a nd .
  • R1 is selected from , rom , , , and , each of which is optionally substituted.
  • R1 is 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, - OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, oxo, and C2-6 alkynyl.
  • R 1 is selected f r , cted f ,
  • R1 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. 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 10-membered heterocycle contains at least 1 sulfur atom.
  • R1 is selected from , , and .
  • R1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle.
  • R 1 is selected from an optionally substituted unsaturated 10-membered heterocycle. In some cases, R 1 is selected from an optionally substituted unsaturated 10-membered fused heterocycle. In some cases, R 1 is , which is optionally substituted.
  • 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, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R1 is selected from a 7- to 11-membered spiro heterocycle.
  • R 1 is selected from a 10-membered spiro heterocycle.
  • the spiro heterocycle has at least 3 nitrogen atoms.
  • the spiro heterocycle has at least 1 sulfur atom.
  • R1 is selected fr and , each of which is optionally substituted.
  • R1 is selected fro , .
  • R 1 is .
  • R 1 is .
  • R 1 is .
  • R 1 is .
  • R1 is .
  • R1 is a compound or salt of Formula (I)
  • R1 is selected from an optionally substituted 8- to 10-membered fused heterocycle.
  • the 8- to 10- membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R 1 is selected from an optionally substituted 10- membered fused heterocycle. In some cases, 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 10-membered heterocycle is a non-aromatic heterocycle.
  • 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. In some cases, R1 is selected fr and , each of which is optionally substituted with one or more substituents.
  • R s 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 .
  • each R 20 is independently selected from hydrogen; and C1- 6 alkyl, C 3-12 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.
  • 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. In some cases, the heterocycle of R 20 has at least two heteroatoms. In some cases, the heterocycle of R 20 contains only 2 heteroatoms.
  • the optional one or more substituents of R1 are independently selected from haloge , and . In som 1 e cases, the optional one or more substituents of R are independently s , , , , , 1 is s , , , , an i e or more substituents of R 1 are independently selected fr m h l n , , and .
  • R1 is selected from .
  • each R20 is independently selected from hydrogen, C 1-6 alkyl, and C 3-6 carbocycle.
  • R 1 is ome , , , , and .
  • R 20 is selected from a 5- to 12-membered heterocycle.
  • the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least oxygen atom. In some cases, the heterocycle has at least one nitrogen atom and at least one oxygen atom. In some cases, 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.
  • the heterocycle of the one or more optional substituents of R 1 is selected from , , , , , , , , and , each of which is optionally substituted with one or more R 1* In m th h t r l f th n 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, 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, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, each R 1* is independently selected from halogen, and C 1-6 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. In some cases, each R 1* is independently selected from -OR 20 .
  • the one or more optional substituents of R 1 are independently selected from optionally substituted 5- to 12-membered h t r l In m th h t r l i l t d fr m , , , , , , , and , each of which is optionally substituted with one or more R 1* .
  • each R 1* is independently selected from halogen, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 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 C 1-6 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.
  • R1 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 , -SO 2 R 20 , -NHCN, C 1-6 cyanoalkyl, C 1-6 alkyl, C 1-6 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. I h 1 heterocycle is substituted.
  • R1 is selected , , , , and , each of which is optionally substituted.
  • R 1 is selecte , which is optionally substituted.
  • R1 is selected .
  • R1 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, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 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, C1-6 haloalkyl, and C1-6 alkyl.
  • the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 is selecte , each of which is optionally substituted. In some cases, R 1 is selecte , which is optionally substituted. In s , , , , . , . [00254] In some embodiments, for a compound or salt of Formula (I), R1 is selected from , , and . [00255] In some embodiments, for a compound or salt of Formula (I), R1 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. In some cases, the at least one nitrogen at of the heterocycle of R 1 is bound to Formula (I). In some cases, R 1 is selected from an optionally substituted 10-membered spiro heterocycle and optionally substituted 10-membered fused heterocycle.
  • R 1 is selected from , , , , , , , , 1 is selected from hydrogen, , , , , , , , , . In some cases, R 1 is selected from hydrogen, , , , , , and . [00257] In some embodiments, for a compound or salt of Formula (I), R1 is selected from hydrogen and optionally substituted 5- to 15-membered heterocycle. In some cases R 1 is selected from , , , , , , , and , each of which is optionally substituted.
  • R 1 is selected from hydrogen, , , , , , , , , , , and .
  • R1 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 at least two nitrogen atoms.
  • , , , a each of which is optionally substituted.
  • the optional one or more substituents of R 1 are independently selected from halogen, , oxo, , , , and 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is substituted with at least one R 1* , wherein the R 1* is selected from halogen, and C1-6 alkyl.
  • R1 is selected from an optionally substituted bridged 8- to 9-membered heterocycle.
  • the heterocycle of R 1 is selected from , , and , each of which is optionally substituted.
  • the one or more substituents of R 1 are selected from halogen C1-6 alkyl, -N(R 20 )2, and C1-6 aminoalkyl.
  • R 1 is selected , , and .
  • R1 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 C1-6 alkyl, -N(R 20 )2, and C1-6 aminoalkyl.
  • the heterocycle of R 1 is selected from , each of which is optionally substituted. In some cases, R 1 is selec a .
  • R1 is hydrogen.
  • R1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R 1 is an optionally substituted 12- membered heterocycle. In some cases, R 1 is an optionally substituted 13-membered heterocycle. In some cases, R 1 is an optionally substituted 14-membered heterocycle. In some cases, R 1 is an optionally substituted 15-membered heterocycle.
  • the heterocycle of R 1 is tricyclic. In some cases, the heterocycle of R 1 contains a fused heterocycle. In some cases, the heterocycle of R 1 contains a spiro-heterocycle. In some cases, 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.
  • 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. In some cases, 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.
  • the heterocycle of R 1 has at least 3, 4, or 5 nitrogen atoms and no other heteroatoms.
  • the heteroatoms are selected from nitrogen and sulfur.
  • some th h t r t m r selected from nitrogen and oxygen.
  • R1 is selected from , , N N N N H H , , each of which is optionally substituted with one or more N s , , , , , and , each of which is optionally substituted with one or more substituents.
  • R1 is independently selected from halogen, -OH, C 1-6 alkyl, and -C(O)N(R 20 ) 2 . In some cases, R 1 is selected from , , , and . [00264] In some embodiments, for a compound or salt of Formula (I) R1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R 1 is , wherein 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. In some cases, Ring W is an optionally substituted fused heterocycle.
  • Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted C 4 carbocycle. In some cases, Ring P forms an optionally substituted C 5 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. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, Ring P has 1 sulfur atom. In some cases, Ring P has 1 nitrogen atom. In some cases, 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.
  • R1 is selected from a 5- to 12-membered bridged heterocycle, which is optionally substituted with one or more substituents.
  • R 1 is selected from an 8-membered bridged heterocycle, which is optionally substituted with one or more substituents.
  • the bridged heterocycle has at least 1 heteroatom.
  • the bridged heterocycle has at least 2 heteroatoms.
  • the bridged heterocycle has at least 1 nitrogen atom.
  • the bridged heterocycle has at least 2 nitrogen atoms.
  • the bridged heterocycle has 2 nitrogen atoms.
  • R1 is selected fro , ses, R 1 is selected from , which is optionally substituted with one or more substituents.
  • R1 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.
  • R167 In some embodiments, 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. In some cases, R 1 is selected from . [00268] In some embodiments, for a compound or salt of Formula (I), R1 is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro heterocycle. In some cases, the 10-membered heterocycle is a fused heterocycle. In some cases, the 10- membered heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle.
  • 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, the 10-membered heterocycle contains at least 1 sulfur atom.
  • R1 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 s ore 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 C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen; and C 1-6 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 heterocycl es, the optional one or more substituents of R 1 are independently selected from ,
  • R1 is selected from an optionally substituted saturated 6- to 7-membered heterocycle.
  • R 1 is selected from an optionally substituted saturated 6-membered heterocycle.
  • R 1 is selected from , which is optionally substituted.
  • the optional one or more substituents are independently selected from halogen, -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C 1-6 alkyl.
  • the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -NHCN, and C1-6 alkyl. In some cases, R1 is selected from , which is substituted with one or more substituents selected from -NHCN, and C 1-6 alkyl. In some cases, R 1 is selected fro , and .
  • R3 is -CN, and R1 is s e ecte rom , , an ; an s an opt onally 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 , , and ; and B is selected from , and .
  • R3 is -CN, and R1 is selected from .
  • R3 is -CN, a In some cases, R3 is -CN, and R1 is selected from .
  • R is -CN, and R is selected from , , and ; B is an optionally substituted 8- to 9-membered fused heterocycle, wherein the 8- to 9-membered fused heterocycle has at least one sulfur atom; and 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.
  • 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 f . , , ents selected from halogen and C1-6 haloalkyl. In some cases , B is , which is substituted with one or more substituents selected from halogen. In some cases B is selected from , , , , , and . In some cases, B is , w B is selected from , and In some cases, B is , which is substituted with one or more substituents selected from chlorine. In some cases, B is selected from .
  • R1 is selected from an optionally substituted unsaturated 10-membered fused heterocycle.
  • R 1 is N , 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 , C1-6 alkyl-N(R 20 )2, C1-6 aminoalkyl, C1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 3 is selected from hydrogen, halogen, and -CN.
  • R1 is selected from an optionally substituted 11-membered fused heterocycle.
  • R 1 is selected from an optionally substituted unsaturated 11-membered fused heterocycle.
  • the heterocycle contains at least one sulfur atom.
  • the heterocycle contains at least one nitrogen atom.
  • the heterocycle contains 3 heteroatoms.
  • the heterocycle i which is optionally substituted. In some cas .
  • the optional substituents for R 1 are each independently selected from halogen, -OH, -N(R 20 )2, -NO2, 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, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 1-6 haloalkyl.. In some cases, the optional substituents for R 1 are each independently selected from -OH, and -NH2. In some cases, R 20 is selected from hydrogen and C 1-3 alkyl. [00276] In some embodiments, for a compound or salt for Formula (I), 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.
  • Q is a bond.
  • Q is a S.
  • Q is a O.
  • each R20 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, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1- 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 C 1-6 alkyl.
  • each R21 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, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 21 is independently selected from hydrogen and C1-6 alkyl. In some cases, each R 21 is independently selected from C 1-6 alkyl.
  • each R20 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, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1- 10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • each R 20 is independently selected from hydrogen and C1-6 alkyl. In some cases, each R 20 is independently selected from C 1-6 alkyl. [00283] In some embodiments, for a compound or salt for Formula (I), each R23 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(C1-6 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 C 1-6 alkyl. In some cases, each R 23 is independently selected from C 1-6 alkyl. [00284]
  • R 3 is selected from hydrogen, halogen, -CN, -N(R 20 ) 2 , -OR 20 , -C(O)R 20 , C 1-6 alkyl-N(R 20 ) 2 , C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalky
  • 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 .
  • R 6 when R 2 is a heteroaryl, R 6 is selected from halogen and C l -C 3 haloalkyl, C l -C 3 alkyl.
  • R 23 is selected from hydrogen and Cl-C3 alkyl.
  • each R 23 is selected from Cl-C3 alkyl.
  • each R 23 is selected from methyl.
  • each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from halogen, and Cl-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen.
  • each L is selected fro , . In s , a , , , , , , , and .
  • Y-R is selected , , and .
  • Y-R 2 is selected .
  • Y-R 2 i .
  • Y-R2 is , , and .
  • 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, -NH 2 , and C 1-6 alkyl.
  • the heterocycle of B is selected fr , r om ally substituted with one or more substituents independently selected from halogen, -CN, -NH2, and , 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 (I B R1 i In some cases, R1 is . In some cases, R1 is .
  • R 1 is , which is optionally substituted with one or more substituents.
  • R 1 is .
  • each R 1* is independently selected from halogen, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R1 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 R20 is selected from hydrogen and C 1-3 alkyl. In some cases, each R 20 is selected from hydrogen and C 1 alkyl.
  • the compounds of Formula (I), Formula (I-A), or Formula (I- B), used in the methods include trifluoroacetic acid salts of the above compounds.
  • the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74.
  • the compound or salt of Formula (I) is compound 2.
  • the compound or salt of Formula (I) is compound 3.
  • the compound or salt of Formula (I) is compound 4.
  • the compound or salt of Formula (I) is compound 14.
  • the compound or salt of Formula (I) is compound 25.
  • the compound or salt of Formula (I) is compound 74. [00299]
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 5 mg to about 500 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B), is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 25 mg to about 100 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B), is administered to a subject at about 5 mg to about 75 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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 2, 3, 4, 14, 25, or 74 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), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B), is administered to a subject at about 15 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 30 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 45 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 60 mg.
  • 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 or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered once daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered 3 times daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered once weekly. In some embodiments the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered every other day. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered every 3 days. [00302] In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at 10 mg to 150 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 10 mg to 125 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 10 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 25 mg to 100 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 50 mg to 100 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 5 mg to 75 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 15 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 30 mg. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 45 mg.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at 60 mg.
  • 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.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 10 mg to about 150 mg, daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered to a subject at about 25 mg to about 100 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I- B) is administered to a subject at about 50 mg to about 100 mg, daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 5 mg to about 75 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered to a subject at about 15 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 30 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 45 mg, daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 60 mg, daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (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. [00304] In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B), is administered to a subject at about 10 mg to about 150 mg, twice daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered to a subject at about 25 mg to about 100 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 50 mg to about 100 mg, twice daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 5 mg to about 75 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (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 or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered to a subject at about 15 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 30 mg, twice daily. In some embodiments, the compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is administered to a subject at about 45 mg, twice daily.
  • the compound or salt of Formula (I), Formula (I-A), or Formula (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), Formula (I-A), or Formula (I-B) is administered as a capsule during the period of time.
  • a tablet or capsule formulation of a compound of Formula (I), Formula (I-A), or Formula (I-B), or a pharmaceutically acceptable salt of any one thereof 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 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65
  • the compound or salt of Formula (I) is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, and
  • a compound or salt of Formula (I), Formula (I-A), or Formula (I-B) is orally administered twice a day (BID) on a daily basis during a period of time.
  • a compound of Formula (I), Formula (I-A), or Formula (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
  • the compound or salt of Formula (I) is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, and
  • the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74.
  • the compound or salt of Formula (I) is compound 2.
  • the compound or salt of Formula (I) is compound 3.
  • the compound or salt of Formula (I) is compound 4.
  • the compound or salt of Formula (I) is compound 14.
  • the compound or salt of Formula (I) is compound 25.
  • the compound or salt of Formula (I) is compound 74.
  • the combination therapy comprises oral administration of a compound of Formula (I), Formula (I-A), or Formula (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
  • the inhibitor is an RTK-MAPK pathway inhibitor. In some cases, the inhibitor is an ERBB family inhibitor. In some cases, the inhibitor is an RAF-MEK-ERK pathway inhibitor. In some cases, the inhibitor is an EGFR inhibitor. In some cases, the inhibitor is an SHP-2 inhibitor.
  • the compound or salt of Formula (I) is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, and
  • the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74.
  • the compound or salt of Formula (I) is compound 2.
  • the compound or salt of Formula (I) is compound 3.
  • the compound or salt of Formula (I) is compound 4.
  • the compound or salt of Formula (I) is compound 14.
  • the compound or salt of Formula (I) is compound 25.
  • the compound or salt of Formula (I) is compound 74.
  • the compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day. [00308] 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.
  • 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, 11 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.
  • 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).
  • 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 are preferred prodrugs of the present disclosure.
  • 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.
  • 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.
  • 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.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
  • compositions comprising a therapeutically effective amount of a compound of Formulas (I), (I-A), or (I-B); and a RTK- MAPK pathway inhibitor, an ERBB family inhibitor, a RAF-MEK-ERK pathway inhibitor, an EGFR inhibitor, a SHP-2 inhibitor, or a SOS1 inhibitor; or a pharmaceutically acceptable salt of any one thereof (also referred to herein as “a pharmaceutical agent”).
  • a pharmaceutical agent also referred to herein as “a pharmaceutical agent”.
  • Pharmaceutical 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.
  • 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 When administered to an animal, such as a human, 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.
  • 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.
  • 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 (preparation) 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
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • 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 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. [00335]
  • 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 parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition for treatment of an ophthalmological condition or disease, 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.
  • 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.
  • 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 syringe- like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • 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 ⁇ .
  • 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.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • 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 ⁇ . Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ 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, AeroNeb ⁇ and AeroDose ⁇ 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 Aerosonic ⁇ (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.
  • 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.
  • 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 cross-linked 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. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • Examples of 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. [00349] 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 RTK-MAPK combination Kit [00350] Some embodiments relate to kits and products that include the compound or salt of Formulas (I), (I-A), or (I-B); and at least one RTK-MAPK pathway inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), in combination with an RTK-MAPK pathway inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • the kits or products can include both a compound or salt of Formulas (I), (I-A), or (I-B), and at least one RTK-MAPK pathway 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.
  • 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 Formulas (I), (I-A), or (I-B), in combination with an RTK-MAPK pathway inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • RAF-MEK-ERK pathway inhibitor combination Kit [00353] Some embodiments relate to kits and products that include the compound or salt of Formulas (I), (I-A), or (I-B), and at least on RAF-MEK-ERK pathway inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), in combination with an RTK-MAPK pathway inhibitor that is separately provided.
  • the kits can be used in the methods of treating cancer as described herein.
  • the kits or products can include both a compound or salt of Formulas (I), (I-A), or (I-B), and at least one RTK-MAPK pathway 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 Formulas (I), (I-A), or (I-B), in combination with an RTK-MAPK pathway inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound of Formulas (I), (I-A), or (I-B), and/or at least one ERBB inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), in combination with an ERBB 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 Formulas (I), (I-A), or (I-B), and at least one ERBB 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 Formulas (I), (I-A), or (I-B), in combination with an ERBB inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound or salt of Formulas (I), (I-A), or (I-B), and/or at least one EGFR inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B) in combination with an EGFR 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 Formulas (I), (I-A), or (I-B), and at least one EGFR 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 Formulas (I), (I-A), or (I-B), in combination with an EGFR inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound of Formulas (I), (I-A), or (I-B), and/or at least one SHP-2 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), in combination with a SHP-2 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 Formulas (I), (I-A), or (I-B) and at least one SHP-2 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 Formulas (I), (I-A), or (I-B), in combination with a SHP-2 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • kits and products that include the compound or salt of Formulas (I), (I-A), or (I-B), and/or at least one SOS1 inhibitor.
  • the kit or product can include a package or container with a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), in combination with a SOS1 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 Formulas (I), (I-A), or (I-B) and at least one SOS1 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 Formulas (I), (I-A), or (I-B), in combination with a SOS1 inhibitor.
  • the kits can be used in the methods of treating cancer as described herein.
  • the dosage regimen for the compounds herein (e.g, an RTK- MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (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.
  • the compounds herein e.g, an RTK- MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (I), (I-
  • 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 RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (I), (I-A), 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 l00 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • an active ingredient e.g, an RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF- MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (I), (I-A), or (I-B)
  • 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 RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (I), (I-A), or (I-B)
  • 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 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 l00 mg/kg of body weight per day, and most preferably between about 0.1 to about 20 mg/kg/day.
  • an active ingredient e.g, an RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formula (I)
  • 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 RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formula (I)
  • 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.
  • treatment cycle means a pre-determined period of time for administering the therapeutic agent (e.g, an RTK-MAPK pathway inhibitor; an ERBB family inhibitor; an RAF-MEK-ERK pathway inhibitor; an EGFR inhibitor; a SHP-2 inhibitor; an SOS1 inhibitor; or a compound or salt of Formulas (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. In some cases, 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. In some cases, each of the treatment cycle has from about 7 days to about 28 days. In some cases, each of the treatment cycle has 28 days. In some cases, 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.
  • 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
  • RTK-MAPK pathway inhibitor Dosing [00373] In some embodiments, the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered prior to administration of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered after administration of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.
  • the RTK-MAPK pathway 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 Formulas (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 a RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (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 Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the RTK-MAPK pathway 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 Formulas (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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other. [00378] In some embodiments, the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In some cases, the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID.
  • the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. In some cases, the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered twice weekly. In some cases, the RTK-MAPK pathway inhibitor is administered intraperitoneally. [00379] In some embodiments, a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and RTK- MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the RTK-MAPK pathway 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 RTK-MAPK pathway inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the RTK-MAPK pathway 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 RTK-MAPK pathway inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the RTK-MAPK pathway 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 RTK-MAPK pathway 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 RTK-MAPK pathway inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the RTK-MAPK pathway inhibitor is administered to a subject at about 200 mg to about 500 mg. In some embodiments, the RTK-MAPK pathway inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the RTK-MAPK pathway inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the RTK-MAPK pathway inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the RTK- MAPK pathway inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg.
  • the RTK-MAPK pathway inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg. In some embodiments, the RTK-MAPK pathway 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 RTK-MAPK pathway 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 RTK-MAPK pathway inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the RTK-MAPK pathway inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the RTK-MAPK pathway inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the RTK-MAPK pathway 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.
  • 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. [00383]
  • the RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. In some embodiments, if 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 co-administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formulas (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 RTK-MAPK pathway 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).
  • RAF-MEK-ERK pathway inhibitor Dosing
  • a pharmaceutical composition comprises a RAF-MEK-ERK inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (I), (I-A), or (I-B), for use in the methods which may be for simultaneous, separate or sequential use.
  • the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the RAF-MEK-ERK pathway 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 Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof, and the RAF-MEK-ERK pathway 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at its MTD and the RAF-MEK-ERK pathway 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the RAF-MEK-ERK pathway 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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • the RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered twice weekly.
  • the RAF-MEK-ERK pathway inhibitor is administered intraperitoneally.
  • a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and RAF- MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the RAF-MEK-ERK pathway 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.
  • a RAF-MEK-ERK pathway inhibitor the therapeutically effective amount of the RAF-MEK-ERK pathway inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the RAF-MEK-ERK pathway 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 RAF-MEK-ERK pathway inhibitor of the combination may be any value or subrange within the recited ranges.
  • the RAF-MEK-ERK inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the RAF-MEK-ERK inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg.
  • the RAF-MEK-ERK inhibitor is administered to a subject at about 10 mg to about 100 mg.
  • the RAF-MEK-ERK inhibitor is administered to a subject at about 240 mg to about 480 mg.
  • the RAF-MEK-ERK inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the RAF-MEK-ERK inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the RAF-MEK- ERK 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 RAF-MEK-ERK 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 RAF-MEK-ERK inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the RAF-MEK- ERK inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the RAF-MEK-ERK inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the RAF-MEK-ERK 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. [00393] In some embodiments, the RAF-MEK-ERK inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. In some cases, if the route of administration is the same (e.g.
  • the combination therapy comprises oral administration of a compound of Formulas (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 RAF-MEK-ERK pathway 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).
  • a pharmaceutical composition comprises a ERBB family inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 comprises a ERBB family inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (I), (I-A), or (I-B), for use in the methods may be for simultaneous, separate or sequential use.
  • the ERBB family inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the ERBB family inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the ERBB family 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 Formulas (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 Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the ERBB family 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 Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the ERBB family 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 Formulas (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 ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the ERBB family 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 ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • the ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered twice weekly.
  • the ERBB family pathway inhibitor is administered intraperitoneally.
  • a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof, and ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the ERBB family 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.
  • an ERBB family inhibitor the therapeutically effective amount of the ERBB family inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the ERBB family 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 ERBB family inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the ERBB family 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 ERBB family 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 ERBB family inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the ERBB family 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 ERBB family inhibitor of the combination may be any value or subrange within the recited ranges.
  • the ERBB family inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the ERBB family inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the ERBB family inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the ERBB family inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the ERBB family inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the ERBB family inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the ERBB family 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 ERBB family 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 ERBB family inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the ERBB family inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the ERBB family inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the ERBB family 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.
  • 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 ERBB family inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. oral) two active compounds can be formulated into a single form for co-administration, 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 Formulas (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 ERBB 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 compound and inhibitor are administered on separate days.
  • the compound and inhibitor are administered on the same day.
  • a pharmaceutical composition comprises a EGFR inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (I), (I-A), or (I-B), for use in the methods may be for simultaneous, separate or sequential use.
  • the EGFR inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the EGFR inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the EGFR 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 Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), and the EGFR 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at its MTD and the EGFR 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the EGFR 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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
  • the EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered twice weekly (BIW).
  • the EGFR inhibitor is administered intraperitoneally.
  • a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof, and EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the EGFR 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 EGFR inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the EGFR 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 EGFR inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the EGFR 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 EGFR 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 EGFR inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the EGFR 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 EGFR inhibitor of the combination may be any value or subrange within the recited ranges. [00409]
  • the EGFR inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the EGFR inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the EGFR inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the EGFR inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the EGFR inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the EGFR inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the EGFR 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 EGFR 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 EGFR inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the EGFR inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the EGFR inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the EGFR 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.
  • 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 EGFR inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. In some cases, if 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 co- administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formulas (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 EGFR 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 compound and inhibitor are administered on separate days. In some cases, the compound and inhibitor are administered on the same day.
  • a pharmaceutical composition comprises a SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 comprise a SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (I), (I-A), or (I-B), for use in the methods may be for simultaneous, separate or sequential use.
  • the SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered prior to administration of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the SHP-2 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • each inhibitor at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt thereof, and the SHP-2 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at its MTD and the SHP-2 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the SHP-2 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 SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
  • the SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
  • the SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. In some cases, the SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered twice weekly. In some cases, the SHP-2 is administered intraperitoneally. [00416] In some embodiments, a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof, and SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the SHP-2 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 SHP-2 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the SHP-2 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 SHP-2 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the SHP-2 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 SHP-2 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 SHP-2 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the SHP-2 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 SHP-2 inhibitor of the combination may be any value or subrange within the recited ranges. [00419] In some embodiments, the SHP-2 inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the SHP-2 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the SHP-2 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the SHP-2 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the SHP-2 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the SHP-2 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the SHP-2 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 SHP-2 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 SHP-2 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the SHP-2 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the SHP-2 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the SHP-2 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.
  • 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 SHP-2 inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. oral) two active compounds can be formulated into a single form for co-administration, both methods of co- administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound or salt of Formulas (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 SHP-2 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).
  • SOS1 inhibitor Dosing [00421]
  • a pharmaceutical composition comprises a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises a compound of Formulas (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 comprise a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a compound or salt of Formulas (I), (I-A), or (I-B), for use in the methods may be for simultaneous, separate or sequential use.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof is administered prior to administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered after administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof is administered at about the same time as administration of the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • each inhibitor at different times and by different routes, may be advantageous.
  • the components in the combination i.e. compound or salt of Formulas (I), (I-A), or (I-B), and the SOS1 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
  • the compound or salt of Formulas (I), (I-A), or (I-B), a pharmaceutical composition thereof is dosed at its MTD and the SOS1 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
  • the compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. In some cases, the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD. In some cases, the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID. In some cases, the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered twice weekly. In some cases, the SOS1 inhibitor is administered intraperitoneally. [00425] In some embodiments, a single dose of compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof, and SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
  • the therapeutically effective amount of the SOS1 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 SOS1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the SOS1 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 SOS1 inhibitor of the combination may be any value or subrange within the recited ranges.
  • the therapeutically effective amount of the SOS1 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 SOS1 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 SOS1 inhibitor of the combination will range between about 10 mg/day and about 200 mg/day.
  • the therapeutically effective amount of the SOS1 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 SOS1 inhibitor of the combination may be any value or subrange within the recited ranges. [00428]
  • the SOS1 inhibitor is administered to a subject at about 200 mg to about 500 mg.
  • the SOS1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 440 mg to about 520 mg. In some embodiments the SOS1 inhibitor is administered to a subject at about 10 mg to about 100 mg. In some embodiments, the SOS1 inhibitor is administered to a subject at about 240 mg to about 480 mg. In some embodiments, the SOS1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 50 mg to about 100 mg. In some embodiments, the SOS1 inhibitor, or pharmaceutically salt thereof of is administered to a subject at about 5 mg to about 75 mg.
  • the SOS1 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 SOS1 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 SOS1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 15 mg. In some embodiments, the SOS1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 30 mg. In some embodiments, the SOS1 inhibitor, or pharmaceutically salt thereof is administered to a subject at about 240 mg. In some embodiments, the SOS1 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.
  • the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years old.
  • the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and the compound of Formulas (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. In some cases, if 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 co-administration, however, being part of the same therapeutic treatment or regimen.
  • the combination therapy comprises oral administration of a compound of Formulas (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 SOS1 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).
  • a single dose of compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof are administered per day (i.e., BID).
  • three doses of the compound or salt of Formulas (I), (I-A), or (I-B), 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 combination of an RTK- MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), 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 an RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formula (I), 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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I-A), or (I-B), 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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • 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. 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. 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.
  • 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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B).
  • the compound of Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75
  • 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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B).
  • the compound of Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76,
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I-A), or (I-B),comprising contacting the cancer cell with an effective amount of a combination of a compound of Formulas (I), (I-A), or (I-B),or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a RTK- MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the RTK-MAPK pathway inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formulas (I), (I-A), or (I-B),In some cases, the contacting is in vitro.
  • 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 RTK-MAPK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the method may inhibit KRas G12 mutants or wildtype activity in a cell.
  • a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a RTK-MAPK pathway inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • a compound of Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a RTK-MAPK pathway 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 Formulas (I), (I-A), or (I-B), and a RTK-MAPK pathway 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a RTK-MAPK pathway 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 Formulas (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 RTK- MAPK pathway 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. In some cases, the KRAS G12 mutants is G12V. [00443] In some embodiments, 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 RTK-MAPK pathway inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (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 combination of a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), 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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (II), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formulas (I), (I- A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107
  • 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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,
  • 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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I- A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formulas (I), (I- A), or (I-B), or a pharmaceutical composition thereof, and a RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the RAF- MEK-ERK pathway inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formulas (I), (LA), 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 RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a RAF-MEK-ERK pathway 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 Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a RAF-MEK-ERK pathway inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • a compound of Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a RAF-MEK-ERK pathway 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 RAF- MEK-ERK pathway 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a RAF-MEK-ERK pathway 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 Formulas (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 RAF- MEK-ERK pathway 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 Formulas (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 RAF-MEK-ERK pathway 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 RAF-MEK-ERK pathway inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formulas (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formulas (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 combination of an ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), 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 an ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formulas (I) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 74A, 74B, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, and
  • 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 ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
  • 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 ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I- A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formulas (I), (I-
  • 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 ERBB family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 or salt of Formulas (I), (I-A), or (I-
  • the contacting is in vitro. In some cases, the contacting is in vivo. In some cases, a cell in which inhibition of KRas G12 mutants or wildtype activity is desired is contacted with an effective amount of a compound of Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and an ERBB family 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 ERBB family 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an ERBB family 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 Formulas (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 ERBB family 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 ERBB family inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formulas (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formulas (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.
  • EGFR Epidermal growth factor receptor
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of a EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), 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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
  • the EGFR inhibitor is selected from cetuximab, afatinib and erlotinib. In some cases, the EGFR inhibitor is cetuximab. In some cases, the compound or salt of Formula (I) is selected from compounds 2, 3, 4, 14, 25, and 74. In some cases, the compound or salt of Formula (I) is compound 2. In some cases, the compound or salt of Formula (I) is compound 3. In some cases, the compound or salt of Formula (I) is compound 4. In some cases, the compound or salt of Formula (I) is compound 14. In some cases, the compound or salt of Formula (I) is compound 25. In some cases, the compound or salt of Formula (I) 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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formulas (I) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
  • 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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and nonsmall 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. 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. 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.
  • 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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I- A), or (I-B).
  • the compound of Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the EGFR inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formulas (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 EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and an EGFR 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 Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and an EGFR 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 EGFR 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and an EGFR 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 Formulas (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 EGFR 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 Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and an EGFR 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 an EGFR inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formulas (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formulas (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 combination of a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), 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 SHP- 2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
  • 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 SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the cancer is a KRas G12D-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.
  • the cancer is a KRAS wildtype-associated cancer. In one embodiment, 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.
  • 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.
  • 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 SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formulas (I), (I- A), or (I-B), or a pharmaceutical composition thereof, and a SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SHP-2 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formulas (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 SHP-2 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a SHP-2 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 Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a SHP-2 inhibitor to negatively modulate the activity of KRas G12 mutants or wildtype.
  • a compound of Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a SHP-2 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 affect 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 SHP-2 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a SHP-2 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 Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a SHP-2 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 Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a SHP-2 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 SHP-2 inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formulas (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formulas (I), (I-A), or (I-B)
  • the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination of a S0S1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), 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 S0S1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formula (I), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the compound of Formula (I) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
  • 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 S0S1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), or a pharmaceutical composition thereof.
  • the cancer is pancreatic, colorectal, endometrial, and nonsmall 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 Formulas (I), (I-A), or (I-B) is selected from compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
  • 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 S0S1 family inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
  • the present disclosure provides methods for increasing the sensitivity of a cancer cell to a compound or salt of Formulas (I), (I-A), or (I-B), comprising contacting the cancer cell with an effective amount of a combination of a compound or salt of Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a S0S1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the S0S1 inhibitor synergistically increases the sensitivity of the cancer cell to the compound or salt of Formulas (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 S0S1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a compound or salt of Formulas (I), (I-A), or (I-B), 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 Formulas (I), (I-A), or (I-B), or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt of any one thereof and a S0S1 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 Formulas (I), (I-A), or (I-B), or pharmaceutically acceptable salt of any one thereof and a S0S1 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 affect 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 S0S1 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 Formulas (I), (I-A), or (I-B), or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided and a S0S1 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 Formulas (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 S0S1 inhibitor are provided.
  • the KRas G12D and/or other G12 mutants 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 Formulas (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 S0S1 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 S0S1 inhibitor and a compound or salt of Formulas (I), (I-A), or (I-B), synergistically increases the potency of the compound or salt of Formulas (I), (I-A), or (I-B).
  • the synergistic increase in potency of the compound or salt of Formulas (I), (I-A), or (I-B) results in an improved efficacy of the compound or salt of Formulas (I), (I-A), or (I-B).
  • 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 a RTK-MAPK pathway inhibitor includes the administration of the compound provided herein and a RTK-MAPK pathway 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 a RTK-MAPK pathway 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.
  • 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.
  • an RTK-MAPK pathway inhibitor synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • the addition of an RAF-MEK-ERK pathway inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • an ERBB family inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • the addition of an EGFR inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • the KRas mutation is KRas G12D.
  • the addition of cetuximab, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • the KRas mutation is KRas G12D.
  • an SHP-2 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, synergistically increases the activity of the compound of Formulas (I), (I-A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • an S0S1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, synergistically increases the activity of the compound of Formulas (I), (I- A), or (I-B), or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing a KRas mutation or KRas wildtype.
  • any method for determining whether two compounds exhibit synergy may be used for determining the synergistic effect of the combination (e.g., example 14).
  • the Zip synergy score is at least 8. In some cases, the Zip synergy score is at least 9. In some cases, the Zip synergy score is at least 10. In some cases, the Zip synergy score is at least 11. In some cases, the Zip synergy score is at least 12. In some cases, the Zip synergy score is at least 13. In some cases, the Zip synergy score is at least 14. In some cases, the Zip synergy score is at least 15. In some cases, the Zip synergy score is at least 16. In some cases, Zip the synergy score is at least 17.
  • the Zip synergy score is at least 18. In some cases, the Zip synergy score is at least 19. In some cases, the Zip synergy score is at least 20. In some cases, the Zip synergy score is at least 21. In some cases, the Zip synergy score is at least 22. In some cases, the Zip synergy score is from 8 to 10. In some cases, the Zip synergy score is from 8 to 24. In some cases, the Zip synergy score is from 10 to 24. In some cases, the Zip synergy score is from 10 to 20. In some cases, the ZIP synergy score is from 10 to 15. In some cases, the Zip synergy score is from 9 to 15.
  • the Zip synergy score is from 8 to 15. In some cases, the Zip synergy score is from 9 to 24. In some cases, the Zip synergy score is from 9 to 12. In some cases, the Zip synergy score is from 9 to 15. In some cases, the Zip synergy score is from 9 to 16. In some cases, the Zip synergy score is from 10 to 14. In some cases, the Zip synergy score is from 17 to 23. In some cases, the Zip synergy score is from 13 to 18. In some cases, the Zip synergy score is from 9 to 19. In some cases, the Zip synergy score is from 9 to 20. In some cases, the Zip synergy score is from 11 to 18. In some cases, the Zip synergy score is from 8 to 14. In some cases, the Zip synergy score is from 9 to 18.
  • 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. DRUG DEVELOPMENT.
  • Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation.
  • 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 Formulas (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 diethyl 4-chloro-1H-pyrazole-3,5-dicarboxylate (Int-1g). To a solution of diethyl 1H-pyrazole-3,5-dicarboxylate (20 g, 94.25 mmol) in Acetic acid (360mL) was added dropwise NaClO (264 mL, 1980 mmol).
  • Step 9 Synthesis if 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (Intermediate 1).
  • reaction mixture was purified by prep-HPLC (eluted with CH 3 CN in H 2 O from 5.0% to 95%) to afford tert-butyl 2-amino-3-cyano-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-2a, 380 mg, 1.244 mmol, 56.1% yield) as yellow solid.
  • LCMS calcld for C15H19N3O2S (M+H) + m/z 306.1, found: 306.1.
  • Step 4 Synthesis of 3-chloro-N-hydroxy-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamidine (Int-14d).
  • Step 4 Synthesis of 3-chloro-2-(4,5-dimethyl-1,2,4-triazol-3-yl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine (Intermediate 17).
  • Step 7 Preparation of tert-butyl 2-amino-3-cyano-5-fluoro-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-20g) [00611] To a solution of tert-butyl 5-fluoro-8-oxo-2-azaspiro[3.4]octane-2-carboxylate (Int- 20f, 600 mg, 2.47 mmol), sulfur (118.68 mg, 3.7 mmol), NH 4 OAc (287.83 mg, 3.7 mmol) in ethanol (12mL) was added propanedinitrile (244.4 mg, 3.7 mmol) at rt.
  • Step 1 Synthesis of 2-(2-aminoethylsulfanyl)pyridine-3-carboxamide (Int-22a)To the suspension of 2-aminoethanethiol;hydrochloride (4.25 g, 37.41 mmol) and 2-chloropyridine- 3-carboxamide (3.91 g, 24.97 mmol) in Ethanol (50mL) was added the solution of KOH (4.2 g, 70 mmol) in Ethanol (25mL) at reflux dropwise over 0.5 h. The mixture was stirred for 1 h and cooled to rt.
  • Example 1 Exemplary synthesis of 1-[6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4- yl]spiro[azetidine-3,9'-fluorene]-3'-ol (Compound 1).
  • Step 1 Synthesis of tert-butyl (1R,5S)-3-(2,6-dichloropyrimidin4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1a).
  • tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.157g , 5.45 mmol) in DCM (20 mL) at -60 °C were added 2,4,6-trichloropyrimidine (1 g, 5.45 mmol) and DIEA (2.7 mL, 16.36 mmol) under N2.
  • Step 2 Synthesis of tert-butyl (1R,5S)-3-(6-chloro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1b).
  • Step 3 Synthesis of 3-(methoxymethoxy)-9H-fluorene (1c). To a solution of 9H- fluoren-3-ol (1.70 g, 9.33 mmol) and bromo(methoxy)methane (1.17 mL, 14.0 mmol) in acetonitrile (30 mL) was added DIEA (4.87 mL, 28.0 mmol). The mixture was stirred at rt for 1 h.
  • Step 8 Synthesis of tert-butyl (1R,5S)-3-[6-(3'-hydroxyspiro[azetidine-3,9'-fluorene]- 1-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1h).
  • Step 9 Synthesis of 1-[6-[(1R,5S)-3,8-diazabicyclo[3.2.1]octa3-yl]-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]spiro[azetidine-3,9'- fluorene]-3'-ol (compound 1).
  • Step 3 Synthesis of 3-chloro-5-[6-chloro-5-cyano-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2c).
  • Step 5 Synthesis of tert-butyl N-[3-cyano-1'-[5-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-[(3R)-3-hydroxy-3-methyl-1- piperidyl]pyrimidin-4-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-2- yl]carbamate (6e).

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Abstract

L'invention concerne des méthodes de traitement du cancer chez un patient en ayant besoin, comprenant l'administration au patient d'une dose thérapeutiquement efficace d'une association d'un inhibiteur de la voie RTK-MAPK et d'un composé de formule (I).
PCT/US2024/056246 2023-11-17 2024-11-15 Polythérapies anticancéreuses avec un modulateur de kras et un inhibiteur de la voie rtk-mapk Pending WO2025106901A1 (fr)

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WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
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WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
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WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
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