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WO2024086809A1 - Méthodes de traitement du cancer - Google Patents

Méthodes de traitement du cancer Download PDF

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Publication number
WO2024086809A1
WO2024086809A1 PCT/US2023/077441 US2023077441W WO2024086809A1 WO 2024086809 A1 WO2024086809 A1 WO 2024086809A1 US 2023077441 W US2023077441 W US 2023077441W WO 2024086809 A1 WO2024086809 A1 WO 2024086809A1
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WIPO (PCT)
Prior art keywords
optionally substituted
compound
amino
prop
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2023/077441
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English (en)
Inventor
Benjamin C. MILGRAM
Jack Anthony HENDERSON
Angel Guzman-Perez
JR. David St. Jean
Robert Hicklin
Heidi KOLDSOE
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Scorpion Therapeutics Inc
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Scorpion Therapeutics Inc
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Priority to CN202380088588.8A priority Critical patent/CN120418247A/zh
Priority to EP23809862.8A priority patent/EP4605392A1/fr
Priority to AU2023364551A priority patent/AU2023364551A1/en
Priority to JP2025523024A priority patent/JP2025538097A/ja
Priority to IL320332A priority patent/IL320332A/en
Priority to KR1020257016596A priority patent/KR20250110370A/ko
Publication of WO2024086809A1 publication Critical patent/WO2024086809A1/fr
Priority to MX2025004532A priority patent/MX2025004532A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
  • the tumor suppressor p53 encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370).
  • TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242).
  • TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2016) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53).
  • mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254).
  • the p53 Y220C mutation occurs in ⁇ 1% of human cancers; ⁇ 100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2016) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74).
  • X 1 is CR 1 or N;
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a p53-associated cancer in a subject the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a subject the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.
  • pharmaceutically acceptable excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
  • the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents.
  • substituent(s) when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted.
  • Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl,
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • sulfhydryl refers to a –SH radical.
  • cyano refers to a -CN radical.
  • zido refers to a –N3 radical.
  • nitro refers to a –NO2 radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • Acyl groups can be substituted with cyano or with 1-3 independently selected halogens.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • heteroaryl as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam or phosphinane oxide) and one or more N or S atoms may be substituted by 1-2 oxid
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2- oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • halocycloalkyl refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
  • haloalkenyl refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • haloalkynyl refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • alkoxyalkyl refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxyethyl).
  • hydroxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy.
  • alkoxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy.
  • alkoxyamino refers to an –O-amino radical (e.g., -OCH2CH2N(CH3)2).
  • haloalkoxy refers to an -O-haloalkyl radical (e.g., -OCF3).
  • alkenoxy refers to an -O-alkenyl radical (e.g., -O-allyl).
  • haloalkenoxy refers to an -O-haloalkenyl radical.
  • alkynoxy refers to an -O-alkynyl radical (e.g., -O-propargyl).
  • haloalkynoxy refers to an -O-haloalkynyl radical.
  • cycloalkoxy refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).
  • aryloxy refers to an -O-aryl radical (e.g., phenoxy).
  • heteroaryloxy refers to an -O-heteroaryl radical (e.g., pyridinoxy).
  • heterocyclyloxy refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or –O-oxetanyl).
  • aralkyl refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).
  • cycloalkylalkyl refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).
  • heteroarylkyl refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).
  • heterocyclylalkyl refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl).
  • alkyl group e.g., methyloxetanyl.
  • aralkoxy refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyloxy).
  • cycloalkylalkoxy refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).
  • aminoalkyl refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).
  • a “sulfenyl” group refers to an -SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • a “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CF3) or –S(CHF2)).
  • a “sulfonyl” group refers to an -SO2R group in which R can be the same as defined with respect to sulfenyl.
  • R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • a “trihalomethanesulfonyl” group refers to an X3CSO2- group wherein each X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an X3CS(O)2N(R’)- group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • S-sulfonamido refers to a -SO2N(RR’) group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • N-sulfonamido refers to a RSO2N(R’)- group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • amino refers to a –NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
  • an amino group is –NH2
  • R is hydrogen and R’ is alkyl
  • a dialkylamine R and R’ are independently selected alkyl.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) ( a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., ,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, one of X 2 , X 3 , X 4 , and X 5 is N. In some embodiments, two of X 2 , X 3 , X 4 , and X 5 are N. In some embodiments, X 1 is CR 1 . In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen.
  • R 4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are the same.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are different. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are each hydrogen. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are each an independently selected C1-C6 alkyl.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 1 is an optionally substituted C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl.
  • R 1 is C2-C6 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 1 is C2-C3 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 1 is C2-C3 alkynyl. In some embodiments, R 1 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 1 is C3-C6 cycloalkyl.
  • R 1 is an optionally substituted phenyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 1 is 4-6 membered heterocyclyl. In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is 5-6 membered heteroaryl. In some embodiments, X 1 is N. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA1), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: AA2), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: , , pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is pharmaceutically acceptable salt thereof, is .
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: AA7), or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: , , , , pharmaceutically acceptable salt of any of the foregoing, wherein R 2B’ is hydrogen or an optionally substituted C1-C6 alkyl.
  • R A is hydrogen.
  • R A is –OR 6 .
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are the same.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are different. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each hydrogen. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each an independently selected C1-C6 alkyl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is an optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is substituted phenyl or optionally 5-10 membered heteroaryl.
  • R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R A is an optionally substituted C1-C6 alkyl.
  • R A is C1-C6 alkyl. In some embodiments, R A is methyl, ethyl, or n-propyl. In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is C1-C3 haloalkyl. In some embodiments, R A is trifluoromethyl. In some embodiments, R A is an optionally substituted C2-C6 alkenyl. In some embodiments, R A is C2-C6 alkenyl. In some embodiments, R A is an optionally substituted C2-C3 alkenyl. In some embodiments, R A is C2-C3 alkenyl.
  • R A is an optionally substituted C2-C6 alkynyl. In some embodiments, R A is C2-C6 alkynyl. In some embodiments, R A is an optionally substituted C2-C3 alkynyl. In some embodiments, R A is C2-C3 alkynyl. In some embodiments, R A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R A is C3- C10 cycloalkyl. In some embodiments, R A is C3-C6 cycloalkyl. In some embodiments, R A is an optionally substituted phenyl.
  • R A is phenyl. In some embodiments, R A is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R A is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R A is 3-12 membered heterocyclyl. In some embodiments, R A is 4-8 membered heterocyclyl. In some embodiments, R A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R A is 5-10 membered heteroaryl. In some embodiments, R A is 5-6 membered heteroaryl.
  • R A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R A is a 9-10 membered heteroaryl. In some embodiments, R A is phenyl optionally substituted with 1-3 independently selected R A1 . In some embodiments, R A is pyridinyl, pyrimidinyl, pyridizinyl, or pyrazinyl, each optionally substituted with 1-3 independently selected R A2 . In some embodiments, R A is a 9 membered heteroaryl optionally substituted with 1-3 independently selected R A3 .
  • each R A1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.
  • each R A2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
  • each R A3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
  • R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • the optionally substituted C1-C3 alkyl of R 8 is a C1-C3 haloalkyl.
  • R 8 is substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with halogen.
  • R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2, or 3 halogen (e.g., fluoro or chloro). In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogen. In some embodiments, R 8 is substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogen.
  • halogen e.g., fluoro or chloro
  • R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
  • R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are the same.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are different. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each hydrogen. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each an independently selected C1-C6 alkyl.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R B is an optionally substituted C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl, ethyl, or n-propyl. In some embodiments, R B is C1-C6 haloalkyl.
  • R B is C1-C3 haloalkyl. In some embodiments, R B is a C1-C3 fluoroalkyl. In some embodiments, R B is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, R B is 2,2,2-trifluoroethyl. In some embodiments, R B is an optionally substituted C2-C6 alkenyl. In some embodiments, R B is C2-C6 alkenyl. In some embodiments, R B is an optionally substituted C2-C3 alkenyl. In some embodiments, R B is C2-C3 alkenyl. In some embodiments, R B is an optionally substituted C2-C6 alkynyl.
  • R B is C2-C6 alkynyl. In some embodiments, R B is an optionally substituted C2-C3 alkynyl. In some embodiments, R B is C2-C3 alkynyl. In some embodiments, R B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R B is C3- C10 cycloalkyl. In some embodiments, R B is C3-C6 cycloalkyl. In some embodiments, R B is an optionally substituted phenyl. In some embodiments, R B is phenyl.
  • R B is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R B is an optionally substituted 4-8 membered heterocyclyl. In some embodiments, R B is 3-12 membered heterocyclyl. In some embodiments, R B is 4-8 membered heterocyclyl. In some embodiments, R B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R B is 5-10 membered heteroaryl. In some embodiments, R B is 5-6 membered heteroaryl. In some embodiments, R B is methyl, ethyl, or n-propyl.
  • R is hydroxyl, , or . In some embodiments, R B is or . In some embodiments, R B is , , , In some embodiments, R B is –SR 8 , where R 8 is an optionally substituted C1-C6 alkyl. In some embodiments, R B is –SR 8 , where R 8 is a C1-C6 haloalkyl. In some embodiments, R B is –SCF3. In some embodiments, each . In some embodiments, one of X 2 , X 3 , X 4 , and X 5 is CR 2 and the remaining X 2 , X 3 , X 4 , and X 5 are CH, N, or CR 3 .
  • Z 1 is C2- C6 alkenylene. In some embodiments, Z 1 is C2-C3 alkenylene. In some embodiments, Z 1 is an optionally substituted C2-C6 alkynylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkynylene. In some embodiments, Z 1 is C2- C6 alkynylene. In some embodiments, Z 1 is C2-C3 alkynylene. In some embodiments, Z 1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z 1 is C3-C4 cycloalkylene. In some embodiments, Z 2 is N. In some embodiments, Z 2 is O and R 2B is absent.
  • Z 2 is a bond. In some embodiments, Z 2 is CR 2C . In some embodiments, R 2C is hydrogen. In some embodiments, R 2C is halogen. In some embodiments, R 2C is fluoro or chloro. In some embodiments, R 2C is C1-C6 alkyl. In some embodiments, R 2C is C1-C3 alkyl. In some embodiments, R 2C is methyl. In some embodiments, when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to Formula (I) via Z 1 . In some embodiments, when Z 2 is a bond, R 2B is absent and R 2A is directly connected to Z 1 .
  • Z 2 is O and R 2B is absent.
  • R 2 is –NR 2A R 2B , i.e., Z 1 is a bond and Z 2 is N.
  • R 2 is R 2B , i.e., Z 1 and Z 2 are both a bond, R 2A is absent and R 2B is directly connected to Formula (I) via Z 1 .
  • R 2A is hydrogen.
  • R 10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.
  • R 11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are the same.
  • R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are different. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each hydrogen. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each an independently selected C1-C6 alkyl.
  • one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 2A is an optionally substituted C1-C6 alkyl. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl or ethyl. In some embodiments, R 2A is C1-C6 haloalkyl.
  • R 2A is C1-C3 haloalkyl. In some embodiments, R 2A is trifluoromethyl. In some embodiments, R 2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is C2-C6 alkenyl. In some embodiments, R 2A is an optionally substituted C2- C3 alkenyl. In some embodiments, R 2A is C2-C3 alkenyl. In some embodiments, R 2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2A is C2-C6 alkynyl. In some embodiments, R 2A is an optionally substituted C2- C3 alkynyl.
  • R 2A is C2-C3 alkynyl. In some embodiments, R 2A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2A is C3-C10 cycloalkyl. In some embodiments, R 2A is C3-C6 cycloalkyl. In some embodiments, R 2A is an optionally substituted phenyl. In some embodiments, R 2A is phenyl. In some embodiments, R 2A is an optionally substituted 3-12 membered heterocyclyl.
  • R 2B is trifluoromethyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is C2-C6 alkenyl. In some embodiments, R 2B is an optionally substituted C2- C3 alkenyl. In some embodiments, R 2B is C2-C3 alkenyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is C2-C6 alkynyl. In some embodiments, R 2B is an optionally substituted C2- C3 alkynyl. In some embodiments, R 2B is C2-C3 alkynyl.
  • R 2B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2B is C3-C10 cycloalkyl. In some embodiments, R 2B is C3-C6 cycloalkyl. In some embodiments, R 2B is an optionally substituted phenyl. In some embodiments, R 2B is phenyl. In some embodiments, R 2B is an optionally substituted 3-12 membered heterocyclyl. In some embodiments, R 2B is an optionally substituted 4-8 membered heterocyclyl.
  • R 2B is 3-12 membered heterocyclyl. In some embodiments, R 2B is 4-8 membered heterocyclyl. In some embodiments, R 2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2B is 5-10 membered heteroaryl. In some embodiments, R 2B is 5-6 membered heteroaryl.
  • one of R 2A and R 2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl
  • one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is a substituted 4-12 membered heterocyclyl.
  • R 2A and R 2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.
  • optionally substituted alkylene and Z 2 is N.
  • R 2 is , , or .
  • R 2 is , , or , i.e., Z 1 is an optionally substituted alkylene, Z 2 is a bond, and R 2A is absent.
  • R 2A is hydrogen.
  • R 2B is . In some e , ,
  • R 2 as defined herein comprises an ⁇ , ⁇ -unsaturated system or an electrophilic group.
  • R 2 is selected from the group consisting of: , , ,
  • X 3 is CR 2 and R 2 as defined herein comprises an ⁇ , ⁇ -unsaturated system or an electrophilic group, as described herein.
  • one of X 2 , X 3 , X 4 , and X 5 is CR 2 , one of X 2 , X 3 , X 4 , and X 5 is CR 3 , and the remaining X 2 , X 3 , X 4 , and X 5 are CH or N.
  • one of X 2 , X 3 , X 4 , and X 5 is CR 2 , one of X 2 , X 3 , X 4 , and X 5 is CR 3 , and the remaining X 2 , X 3 , X 4 , and X 5 are CH.
  • R 3 is halogen.
  • R 12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 13 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
  • R 14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are the same.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are different. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each hydrogen. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each an independently selected C1-C6 alkyl.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are the same. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are different. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each hydrogen.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each an independently selected C1-C6 alkyl. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
  • R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
  • R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkenyl.
  • R 3 is C2-C6 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 3 is C2-C3 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 3 is C2-C3 alkynyl. In some embodiments, R 3 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is C3-C6 cycloalkyl.
  • R 3 is an optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is an optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 3 is 4-6 membered heterocyclyl. In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is 5-6 membered heteroaryl. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene.
  • L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene.
  • Non-Limiting Exemplary Compounds the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in List 2, or a pharmaceutically acceptable salt thereof.
  • List 2 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4- methoxybenzamide; azetidin-1-yl(3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro
  • the compound is selected from the group consisting of the compounds delineated in List 1 and/or List 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A
  • compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Methods of Treatment Provided herein are methods for restoring p53 function, encoded by TP53 gene.
  • compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53-associated disease), such as cancer (e.g., p53-associated cancer).
  • the terms “restore” or “restoration of” means to increase the activity and/or function of the specified target by a measurable amount.
  • restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.
  • the ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and/or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value.
  • a compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value.
  • Compounds of Formula (I), or pharmaceutically acceptable salts thereof are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
  • the p53-associated disease or disorder is Li-Fraumeni syndrome.
  • Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the cancer is a p53-associated cancer.
  • Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the p53-associated cancer harbors a Y220C mutation.
  • Some embodiments provide a method of treating a p53-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1-510, or a pharmaceutically acceptable salt thereof.
  • the p53-associated cancer harbors a Y220C mutation.
  • Some embodiments provide a method of treating cancer in a subject that has been identified or diagnosed as having a p53-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53-associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.
  • a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject with Li-Fraumeni syndrome.
  • p53-associated disease refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein).
  • Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).
  • p53-associated cancer refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein.
  • wild type or wild-type describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.
  • a method of treating cancer e.g., a p53-associated cancer
  • the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • methods for treating p53- associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions.
  • p53 protein substitutions/insertions/deletions are described in Table 1.
  • the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y.
  • the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof.
  • the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.
  • the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein.
  • the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation.
  • the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.
  • Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPN
  • methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • methods for treating a subject identified or diagnosed as having a p53-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non- limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the cancer is an p53-associated cancer.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • a regulatory agency- approved e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same
  • the test or assay is provided as a kit.
  • the cancer is an p53-associated cancer.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer.
  • an assay e.g., an in vitro assay
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53-associated cancer.
  • a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
  • a regulatory agency-approved e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
  • a p53-associated cancer includes those described herein and known in the art.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • the subject is suspected of having a p53-associated cancer.
  • methods for treating a p53-associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein.
  • the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the tumor with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
  • a method for restoring p53 function in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function.
  • the cell is a cancer cell.
  • the cancer cell is any cancer as described herein.
  • the cancer cell is a p53-associated cancer cell.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increase cell death in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increasing tumor cell death in a subject comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • the cancer e.g., p53- associated cancer
  • the cancer is selected from a hematological cancer and a solid tumor.
  • the cancer is a hematological cancer.
  • the hematological cancer is a leukemia.
  • the hematological cancer is a lymphoma.
  • the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL).
  • the hematological cancer is acute myeloid leukemia (AML).
  • the cancer e.g., p53- associated cancer
  • the cancer is a solid tumor.
  • the cancer e.g., p53- associated cancer
  • the cancer is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.
  • the cancer e.g., p53- associated cancer
  • the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.
  • the bladder cancer is bladder urothelial carcinoma.
  • the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.
  • the skin cancer is cutaneous melanoma.
  • the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.
  • the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.
  • the breast cancer is breast invasive ductal carcinoma.
  • the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.
  • the ovarian cancer is serous ovarian cancer.
  • the kidney cancer is chromophobe renal cell carcinoma.
  • the colorectal cancer is colon adenocarcinoma.
  • the liver cancer is hepatocellular carcinoma.
  • the pancreatic cancer is pancreatic adenocarcinoma.
  • the cancer is prostate cancer.
  • the p53-associated cancer is breast cancer.
  • the p53-associated cancer is colorectal cancer.
  • the p53-associated cancer is endometrial cancer.
  • the p53-associated cancer is lung cancer.
  • the p53-associated cancer is selected from the cancers described in Table 1. Table 1. p53 Protein Amino Acid Substitutions/Insertions/Deletions A
  • compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing.
  • chemotherapeutic agents such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing.
  • a surgery may be open surgery or minimally invasive surgery.
  • Compounds of Formula (I), or pharmaceutically acceptable salts thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy.
  • the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a cancer e.g., a locally advanced or metastatic tumor
  • standard therapy e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)).
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy.
  • a subject has undergone prior therapy.
  • a subject is na ⁇ ve to p53 restoration therapy. In some embodiments, a subject is not na ⁇ ve to p53 restoration therapy.
  • a subject is kinase inhibitor na ⁇ ve. In some embodiments, a subject is not kinase inhibitor na ⁇ ve.
  • the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein.
  • the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.
  • Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), anti- androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
  • EGFR inhibitors e.g., HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein)
  • PARP inhibitors e.g., CDK4/6 inhibitors,
  • the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELATM, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.
  • the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284)
  • the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440.
  • the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005)
  • the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride
  • the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).
  • the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), creartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 29
  • the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
  • HER2 inhibitors include trastuzumab (e.g., TRAZIMERATM, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSATM), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF2
  • a “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR.
  • a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator).
  • a RAS modulator is a covalent inhibitor.
  • a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.”
  • a KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation).
  • Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR.
  • a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator).
  • a KRAS modulator is a covalent inhibitor.
  • Non-limiting examples of a KRAS-targeted therapeutic agents include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849).
  • RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.
  • the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.
  • the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof.
  • the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC
  • the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-aceta), ipat
  • the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.
  • a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVEN TM ), or combinations thereof.
  • the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.
  • the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.
  • the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing.
  • the antimetabolite is methotrexate, pemetrexed, or 5-FU.
  • Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.
  • the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.
  • the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.
  • Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289.
  • LYNPARZA® olaparib
  • rucaparib rucaparib
  • niraparib niraparib
  • veliparib BGB-290 (pamiparib)
  • Non-limiting examples of selective estrogen receptor modulators or degraders include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.
  • Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).
  • Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof.
  • CTLA-4 inhibitor is ipilimumab (YERVOY®).
  • the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof.
  • pembrolizumab KYTRUDA®
  • OPDIVO® nivolumab
  • LIBTAYO® cemiplimab
  • JEMPERLI® dostarlimab
  • JTX-4014 vopratelimab
  • PDR001 camrelizumab
  • SIBI308 sintilimab
  • the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof.
  • the LAG-3 inhibitor is IMP701 (LAG525).
  • the A2AR inhibitor is CPI-444.
  • the TIM-3 inhibitor is MBG453.
  • the B7-H3 inhibitor is enoblituzumab.
  • the VISTA inhibitor is JNJ-61610588.
  • the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol.11: 39 (2016).
  • the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.
  • additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and/or as palliative therapy, for example, opioids and corticosteroids.
  • EXAMPLES Compound Preparation
  • the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.
  • the synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field.
  • the compounds described herein can also be synthesized, for example, using the following procedure, using different coupling partners from diversifiable intermediate 8 in the scheme below.
  • Step 1 Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of ethoxy(iodo)ethyne: To a stirred solution of ethoxy-ethyne (2.0 g, 28.53 mmol, 1 equiv) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 11.4 mL, 28.53 mmol, 1 equiv) dropwise at -78°C under nitrogen atmosphere.
  • Step 2 Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine
  • 3-bromopyridin-2-amine 926.9 mg, 5.36 mmol, 1.40 equiv
  • ACN 20 mL
  • ethoxy(iodo)ethyne 2.50g, 12.76 mmol, 1 equiv
  • Cu(OAc)2 463.4 mg, 2.55 mmol, 0.20 equiv
  • Step 2 Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
  • 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2- carbaldehyde 390 mg, 1.27 mmol, 1 equiv
  • MeOH 3 mL
  • dimethyl (1-diazo-2- oxopropyl)phosphonate 488 mg, 2.54 mmol, 2 equiv
  • K2CO3 526.6 mg, 3.81 mmol, 3 equiv
  • Step 3 Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide
  • DMF dimethyl sulfoxide
  • Step 3 Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline
  • a mixture of 4-(ethanesulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 equiv) and Fe (3.53 g, 63.20 mmol, 5 equiv) in EtOH (20 mL)/sat.NH4Cl (5 mL) was stirred for 1 h at 70°C.
  • the resulting mixture was filtered, the filter cake was washed with EtOH.
  • the filtrate was concentrated under reduced pressure.
  • the result mixture was extracted with EtOAc (3*100mL).
  • Step 2 Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene
  • 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene To a stirred solution of 4-(isopropylsulfanyl)-2-methoxy-1-nitrobenzene (21 g) in Acetone (100 mL)/H2O (100 mL)/MeOH (10 mL) was added Oxone (103.58 g) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature, then filtered. The filter cake was washed with MeOH.
  • reaction mixture was stirred at room temperature for 2 h under nitrogen atmosphere, followed by the addition of 8-bromo-2-ethynyl-3- [(trifluoromethyl)sulfanyl]indolizine (3.16 g, 9.87 mmol, 1.00 equiv) in toluene (1.00 mL) dropwise at room temperature.
  • the mixture was stirred at 60°C for 1 h under nitrogen atmosphere.
  • POM (1.96 g, 21.72 mmol, 2.20 equiv) at room temperature.
  • the resulting mixture was stirred at 60°C for additional 16 h under nitrogen atmosphere.
  • the resulting mixture was concentrated under reduced pressure.
  • the resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere.
  • 8-bromo-3-[(difluoromethyl)sulfanyl]-2- ethynylindolizine (1.20 g, 3.97 mmol, 1.00 equiv) at room temperature.
  • the resulting mixture was stirred at 60°C for additional 1 h.
  • POM (1.07 g, 11.91 mmol, 3.00 equiv) in one portion at room temperature.
  • the resulting mixture was stirred at 60°C for additional 1 h.
  • the resulting mixture was concentrated under reduced pressure.
  • Desired product could be detected by LCMS.
  • the reaction was quenched with Water, the organic phase was separated, washed with aqueous10% sodium thiosulfate (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 60% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 1-bromo-5- chloroindolizine-2-carboxylate (1 g, 34.51%) as a white solid.
  • Desired product could be detected by LCMS.
  • the mixture was allowed to cool down to room temperature.
  • the reaction was quenched by the addition of sat. NH4Cl (aq.) (10mL) at 0°C.
  • the resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3x10 mL).
  • the filtrate was concentrated under reduced pressure.
  • the resulting mixture was extracted with CH2Cl2 (3 x 10 mL).
  • the combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 35 min; detector, UV 254 nm(80%). This resulted in 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1- [(trifluoromethyl)sulfanyl]indolizine (130 mg, 35.94%) as a black oil.
  • the crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford (3S,4R)-3-fluoro-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1- methylpiperidin-4-amine (5.9 mg, 5.24%) as a white solid.
  • Example 114 Synthesis of N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn- 1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]heptan-6- amine
  • N- ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2- yn-1-yl ⁇ -4-methanesulfonyl-2-methoxyaniline 120 mg, 0.23 mmol, 1 equiv
  • 2-methyl-2- azaspiro[3.3]heptan-6-amine dihydrochloride 50.9 mg, 0.25 mmol, 1.1 equiv
  • t-BuONa 89.3 mg, 0.93 mmol, 4 equiv
  • Example 116 Synthesis of methyl 4-[(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)amino]piperidine-1-carboxylate
  • methyl 4- aminopiperidine-1-carboxylate 31 mg, 0.20 mmol, 2 equiv
  • tBuXPhos Pd G3 8 mg, 0.01 mmol, 0.1 equiv
  • t-BuONa 28 mg,
  • Example 7 Synthesis of 1-cyclopropyl-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
  • 1- cyclopropylpiperidin-4-amine 55 mg, 0.38 mmol, 2 equiv
  • t-BuXPhos Pd G3 (16 mg, 0.02 mmol, 0.1 equiv) and t-BuONa (56 mg, 0.
  • Example 9 Synthesis of 1-isopropyl-N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8- yl)piperidin-4-amine
  • the reaction mixture was heated at 100°C for 5 h under nitrogen atmosphere.
  • the resulted solution was purified using C18 chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm).
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 20% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.25) to afford 4- ⁇ [3-(3-ethoxy-8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide (15.1 mg, 9.05%) as a yellow solid.
  • Example 19 Synthesis of 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
  • 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 4; 45 mg, 0.14 mmol, 1 equiv) in dioxane (3 mL) were added 1- methylpiperidin-4-amine (24.3 mg, 0.21 mmol, 1.5 equiv), RuPhos (13.2 mg, 0.02 mmol, 0.2 equiv), Cs2CO3 (228.2 mg, 0.70 mmol, 5 equiv) and RuPhos Palladacycle Gen.4 (11.9 mg, 0.01 mmol, 0.1 equiv).
  • Example 22 Synthesis of (3S,4R)-N-[3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2- a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
  • a solution of 8-bromo-3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Intermediate 6; 100 mg, 0.38 mmol, 1 equiv), t-BuONa (73.6 mg, 0.77 mmol, 2 equiv) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 equiv) in THF (2 mL) was stirred for 1 h at 65°C under nitrogen atmosphere.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.1) to afford (3S,4R)-N- [3-ethenyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (3.1 mg, 2.59%) as a off-white solid.
  • Example 23 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide Step 1.
  • Example 25 Synthesis of tert-butyl N-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino ⁇ -2-(3- ⁇ [2-methoxy-4-(methylcarbamoyl) phenyl] amino ⁇ prop-1-yn-1-yl) imidazo[1,2- a] pyridin-3-yl)-N-methylcarbamate Step 1.
  • Example 27 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl ⁇ -8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6- ol, TFA salt trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl ⁇ -4-methanesulfonyl-2-methoxyaniline
  • 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2- a]pyridine (Intermediate 8; 760 mg, 1.63 mmol, 1 equiv), 4-methanesulfonyl-2-methoxy-N- (prop-2-yn-1-yl)
  • Example 28 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ - 3-methoxy-N-methylbenzamide, formic acid salt Step 1.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 30% B in 8 min; Wave Length: 254nm/220nm; RT(min): 7.68) to afford 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ -3- [(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy-N- methylbenzamide (22.3 mg, 13.52%) as a light yellow solid.
  • Example 29 Synthesis of 4- ⁇ [3-(3-cyclopropyl-8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-methoxy- N-methylbenzamide Step 1.
  • Step 1 Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridine
  • 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (Intermediate 11; 230.0 mg, 0.52 mmol, 1 equiv) in DMSO (5 mL) was treated with 3-methoxy- N-methyl-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 14; 227.7 mg, 1.04 mmol, 2 equiv), i-Pr2NH (527.8 mg, 5.22 mmol, 10 equiv), Pd(PPh3)4 (120.6 mg, 0.10 mmol, 0.20 equiv) and CuI (49.7 mg, 0.26 mmol, 0.50 equiv).
  • Example 31 Synthesis of tert-butyl N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl ⁇ -8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl) carbamate Step 1.
  • Example 32 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl ⁇ -N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8- diamine
  • the reaction mixture was concentrated in vacuo.
  • the resulting crude material was purified by Pre-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 62 mL/min mL/min; Gradient: 71% B to 76% B in 9 min; Wave Length: 254nm/220nm nm; RT1(min): 8.9) to afford 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1-yl ⁇ - N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine (5.9 mg, 6.95%) as yellow solid.
  • Example 33 Synthesis of 2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop- 1-yn-1-yl ⁇ -N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine-6,8-diamine Step 1.
  • reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted with EA (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1%TFA, 20% to 40% gradient in 10 min; detector, UV 220 nm) to afford tert-butyl N-(2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl) amino] prop-1-yn-1- yl ⁇ -8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl)-N- methylcarbamate (130 mg, 67.01%) as black oil.
  • Example 34 Synthesis of N-(2- ⁇ 3-[(4-methanesulfonyl-2- methoxyphenyl)amino]prop-1-yn-1-yl ⁇ -6-phenyl-3-(2,2,2-trifluoroethyl)imidazo [1,2- a]pyridin-8-yl)-1-methylpiperidin-4-amine, formic acid salt
  • a mixture of N-(6-bromo-2- ⁇ 3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1- yn-1-yl ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine 100 mg, 0.15 mmol, 1 equiv), phenyl boronic acid (29 mg, 0.23 mmol, 1.50 equiv), Pd(dppf)Cl2 .
  • Example 35 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Example 36 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ 3-methoxy-N- methylbenzamide Step 1.
  • Example 37 and 38 Synthesis of 4- ⁇ [3-(8- ⁇ [(4R)-3,3-difluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N-methylbenzamide (37) and 4- ⁇ [3-(8- ⁇ [(4S)-3,3-difluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N-methylbenzamide (38) Step 1.
  • Example 39 Synthesis of tert-butyl N-[2-(3- ⁇ [2-methoxy-4-(methylcarbamoyl) phenyl] amino ⁇ prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-6-yl] carbamate Step 1.
  • Example 40 Synthesis of 4-[(3- ⁇ 6-amino-8-[(1-methylpiperidin-4-yl) amino]-3- (2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop-2-yn-1-yl) amino]-3-methoxy-N- methylbenzamide
  • Example 43 Synthesis of 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1- methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-ylamino)-3-methoxy-N-methylbenzamide, formic acid salt
  • Example 44 Synthesis of 3-methoxy-N-methyl-4-[(3- ⁇ 6-[(methylcarbamoyl)amino]-8- [(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop- 2-yn-1-yl) amino] benzamide
  • a mixture of 4-[(3- ⁇ 6-bromo-8-[(1-methylpiperidin-4-yl) amino]-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl ⁇ prop-2-yn-1-yl) amino]-3-methoxy-N-methylbenzamide 200 mg, 0.33 mmol, 1 equiv), methylurea (48.8 mg, 0.66 mmol, 2 equiv), XantPhos (38.1 mg, 0.07 mmol, 0.2 equiv), Cs2CO3 (32
  • Example 46 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxy-N,N-dimethylbenzamide Step 1.
  • Example 47 Synthesis of N-ethyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3- methoxybenzamide Step 1.
  • Example 48 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N-isopropyl-3- methoxybenzamide Step 1.
  • the reaction mixture was stirred at 65°C for 30 min under nitrogen atmosphere. After removal of solvent, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 0% to 30% gradient in 20 min; detector, UV 254 nm.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 .
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-N-cyclopropyl-3-methoxybenzamide
  • 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.49 mmol, 1 equiv) in DMSO (10 mL) were added N-cyclopropyl- 3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (Intermediate 18; 241.3 mg, 0.99 mmol, 2 equiv), iPr2NH (499.8 mg, 4.94 mmol, 10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv) and Cu
  • Example 50 Synthesis of (3S,4R)-3-fluoro-N-[2-(3- ⁇ [2-methoxy-4-(pyrrolidine-1- carbonyl)phenyl]amino ⁇ prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]- 1-methylpiperidin-4-amine Step 1.
  • Step 1 Synthesis of 4-(azetidine-1-carbonyl)-N- ⁇ 3-[8-bromo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl ⁇ -2-methoxyaniline
  • 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 200.0 mg, 0.50 mmol, 1 equiv) in DMSO (5 mL) was treated with 4-(azetidine- 1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (Intermediate 20; 132.7 mg, 0.54 mmol, 1.10 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.20 equiv), CuI (38.1 mg, 0.20 mmol, 0.40 equiv) and i- Pr
  • the crude product was purified using prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.05% NH3H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min mL/min; Gradient: 54% B to 68% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.42; Number Of Runs: 6.
  • Example 52 Synthesis of 5- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylpyridine-2-carboxamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn- 1-yl ⁇ amino)-N-methyl-3-(trifluoromethoxy)benzamide
  • a mixture of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide (Intermediate 22; 300 mg, 1.10 mmol, 1.30 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridine (Intermediate 1; 344 mg, 0.85 mmol, 1 equiv), i-Pr2NH (858 mg, 8.47 mmol, 10 equiv), CuI (162 mg, 0.84 mmol, 1 equiv) and Pd(PPh3)4 (392 mg, 0.33 mmol, 0.40
  • Example 54 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N-methyl-3- (trifluoromethyl)benzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-3-chloro-N-methylbenzamide
  • Example 56 Synthesis of 3-cyano-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Example 57 Synthesis of 3-cyclopropyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino ⁇ -N-methylbenzamide Step 1.
  • Example 58 Synthesis of 3-ethyl-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) prop-2-yn-1-yl]amino ⁇ -N- methylbenzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl) imidazo[1,2-a] pyridin-2-yl] prop-2-yn-1-yl ⁇ amino)-3-ethoxy-N-methylbenzamide
  • Example 60 Synthesis of 3-(difluoromethoxy)-4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino ⁇ -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl]amino ⁇ -N-methylbenzamide Step 1.
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-N-methyl-3-(2,2,2-trifluoroethoxy) benzamide
  • a solution of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (Intermediate 30; 200 mg, 0.70 mmol, 1 equiv), 8-bromo-2-iodo-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 424 mg, 1.05 mmol, 1.5 equiv), DIEA (90 mg, 0.70 mmol, 1 equiv), CuI (133 mg, 0.70 mmol, 1 equiv) and Pd(PPh3)4 (161 mg, 0.14 m
  • Example 62 Synthesis of 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ - 3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-(2- methoxyethoxy)-N-methylbenzamide Step 1.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05%NH3H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 44% B to 69% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.9; Number Of Runs: 3) to afford 4- ⁇ [3-(8- ⁇ [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino ⁇ -3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino ⁇ -3-(2-methoxyethoxy)-N- methylbenzamide (6.3 mg, 6.78%) as a white solid
  • Step 1 Synthesis of 4-( ⁇ 3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-2- yl]prop-2-yn-1-yl ⁇ amino)-3-methoxy-N,N-bis( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) benzenesulfonamide
  • a mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (Intermediate 1; 50 mg, 0.12 mmol, 1 equiv), 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )benzenesulfonamide (Intermediate 32; 74.2 mg, 0.15 mmol, 1.2 equiv), CuI (23.5 mg, 0.12 mmol, 1 equiv),
  • the resulting mixture was stirred at 65 o C for 1h, then cooled down to room temperature, diluted with ethyl acetate (30 mL) and washed with 3*30 mL of brine. The resulting mixture was dried with anhydrous sodium sulfate and concentrated under vacuum.

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Abstract

La présente invention concerne des composés de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci, qui restaurent la fonction p53. Ces composés sont utiles, par exemple, pour traiter une maladie dans laquelle une fonction p53 réduite contribue à la pathologie et/ou aux symptômes et/ou à la progression de la maladie (par exemple, le cancer) chez un sujet (par exemple, un être humain).
PCT/US2023/077441 2022-10-21 2023-10-20 Méthodes de traitement du cancer Ceased WO2024086809A1 (fr)

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CN202380088588.8A CN120418247A (zh) 2022-10-21 2023-10-20 用于治疗癌症的方法
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AU2023364551A AU2023364551A1 (en) 2022-10-21 2023-10-20 Methods for treating cancer
JP2025523024A JP2025538097A (ja) 2022-10-21 2023-10-20 がんを処置するための方法
IL320332A IL320332A (en) 2022-10-21 2023-10-20 Cancer treatment methods
KR1020257016596A KR20250110370A (ko) 2022-10-21 2023-10-20 암 치료 방법
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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2024187153A1 (fr) * 2023-03-08 2024-09-12 Merck Sharp & Dohme Llc Composés ciblant des mutations dans p53 et leurs utilisations
WO2025011684A3 (fr) * 2023-10-20 2025-03-06 上海宇道生物技术有限公司 Composé hétérocyclique fusionné contenant de l'azote de n-sulfonamide, et son application
WO2025077778A1 (fr) * 2023-10-12 2025-04-17 上海宇道生物技术有限公司 Composé d'acide carboxylique et son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018055316A1 (fr) * 2016-09-26 2018-03-29 Centre National De La Recherche Scientifique Composes pour leur utilisation en imagerie et notamment pour le diagnostic de maladies neuro-degeneratives
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WO2025011684A3 (fr) * 2023-10-20 2025-03-06 上海宇道生物技术有限公司 Composé hétérocyclique fusionné contenant de l'azote de n-sulfonamide, et son application

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