WO2021113595A1 - Dérivés de phosphore utilisés comme inhibiteurs de kras - Google Patents

Dérivés de phosphore utilisés comme inhibiteurs de kras Download PDF

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Publication number
WO2021113595A1
WO2021113595A1 PCT/US2020/063242 US2020063242W WO2021113595A1 WO 2021113595 A1 WO2021113595 A1 WO 2021113595A1 US 2020063242 W US2020063242 W US 2020063242W WO 2021113595 A1 WO2021113595 A1 WO 2021113595A1
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carcinoma
c6alkyl
hydrogen
sarcoma
compound
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PCT/US2020/063242
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English (en)
Inventor
Don Zhang
Jirong Peng
Michael John COSTANZO
Michael Alan Green
Michael Nicholas Greco
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Beta Pharma, Inc.
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Publication of WO2021113595A1 publication Critical patent/WO2021113595A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is directed to inhibitors of Kirsten Rat sarcoma virus (KRAS), and more particularly to phosphorous compounds, compositions and methods for the treatment or prevention of a disease, disorder, or medical condition mediated through KRAS, especially the KRAS mutant G12C.
  • KRAS Kirsten Rat sarcoma virus
  • the diseases include various cancers.
  • Ras is a superfamily of small guanosine triphosphate (GTP) binding proteins consisting of various isoforms. Ras genes can mutate to oncogenes that are associated with numerous cancers such as lung, pancreas, and colon. Ras is one of the most frequently mutated oncogenes. KRAS, (Kirsten Rat sarcoma virus) an isoform of Ras, is one of the most frequently mutated Ras genes, comprising approximately 86% of all mutations. KRAS functions as an on/off switch in cell signaling. KRAS is a proto-oncogene that operates between inactive (GDP-bound) and active (GTP-bound) states to control a variety of functions, including cell proliferation.
  • GTP small guanosine triphosphate
  • KRAS-GTP binding represent potential therapeutic agents for the treatment of various cancers.
  • the present invention is directed to a compound of Formula I: or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A and B are each independently chosen at each occurrence from aryl, or heteroaryl optionally substituted with one or more of hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2 - C6alkenyl, C2-C6alkynyl, -(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, and C1-6alkoxy; X is hydrogen, halogen or trifluoromethyl; R 1 is hydrogen, C 1 -C 6 alkyl, C 1-6 alkoxy, -(C 0 -C 6 alkyl)cycloalkyl, C 1 -
  • the present invention is directed to a method of treating a disease, disorder, or medical condition in a patient, comprising the step of providing to a patient in need thereof a therapeutic agent, wherein the therapeutic agent comprises the compound of Formula I or salt thereof.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.
  • All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers and encompass heavy isotopes and radioactive isotopes.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 11 C, 13 C, and 14 C
  • the compounds disclosed herein may include heavy or radioactive isotopes in the structure of the compounds or as substituents attached thereto.
  • useful heavy or radioactive isotopes include 18 F, 15 N, 18 O, 76 Br, 125 I and 131 I.
  • All Formulae disclosed herein include all pharmaceutically acceptable salts of such Formulae.
  • the opened ended term “comprising” includes the intermediate and closed terms “consisting essentially of” and “consisting of.”
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
  • a dash ( ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms.
  • the term C1-C6alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. C1-C8alkyl, C1-C4alkyl, and C1-C2alkyl.
  • C0-Cn alkyl is used herein in conjunction with another group, for example, -C0-C2alkyl(phenyl), the indicated group, in this case phenyl, is either directly bound by a single covalent bond (C 0 alkyl), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms.
  • Alkyls can also be attached via other groups such as heteroatoms as in –O-C0- C 4 alkyl(C 3 -C 7 cycloalkyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.
  • Alkoxy is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-O-).
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2- butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2- hexoxy, 3-hexoxy, and 3- methylpentoxy.
  • an “Alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by a sulfur bridge (-S-).
  • alkenyloxy refers to alkenyl, alkynyl, and cycloalkyl groups, in each instance covalently bound to the group it substitutes by an oxygen bridge (-O-).
  • Halo or “halogen” means fluoro, chloro, bromo, or iodo, and are defined herein to include all isotopes of same, including heavy isotopes and radioactive isotopes. Examples of useful halo isotopes include 18 F, 76 Br, and 131 I. Additional isotopes will be readily appreciated by one of skill in the art.
  • Haloalkyl means both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy is a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical).
  • Peptide means a molecule which is a chain of amino acids linked together via amide bonds (also called peptide bonds).
  • compositions means compositions comprising at least one active agent, such as a compound or salt of Formula II, and at least one other substance, such as a carrier.
  • Pharmaceutical compositions meet the U.S. FDA’s GMP (good manufacturing practice) standards for human or non-human drugs.
  • Carrier means a diluent, excipient, or vehicle with which an active compound is administered.
  • a “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier” includes both one and more than one such carrier.
  • a “patient” means a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder or diagnostic treatment. In some embodiments the patient is a human patient.
  • Providing means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.
  • Treatment means providing an active compound to a patient in an amount sufficient to measurably reduce any disease symptom, slow disease progression or cause disease regression. In certain embodiments treatment of the disease may be commenced before the patient presents symptoms of the disease.
  • a “therapeutically effective amount” of a pharmaceutical composition means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, decrease disease progression, or cause disease regression.
  • a “therapeutic compound” means a compound which can be used for diagnosis or treatment of a disease.
  • the compounds can be small molecules, peptides, proteins, or other kinds of molecules.
  • a significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s T-test, where p ⁇ 0.05.
  • Compounds of the Formulae disclosed herein may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms including atropisomers.
  • these compounds with two or more asymmetric elements these compounds can additionally be mixtures of diastereomers.
  • all optical isomers in pure form and mixtures thereof are encompassed. In these situations, the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates.
  • Racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All forms are contemplated herein regardless of the methods used to obtain them.
  • chiral refers to molecules, which have the property of non- superimposability of the mirror image partner.
  • Stepoisomers are compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • a “diastereomer” is a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Enantiomers refer to two stereoisomers of a compound, which are non- superimposable mirror images of one another. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereo specificity in a chemical reaction or process. [0038] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a “racemic mixture” or “racemate” is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity.
  • a racemic mixture may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • a “chelating group” or “chelator” is a ligand group which can form two or more separate coordinate bonds to a single central atom, which is usually a metal ion. Chelating groups as disclosed herein are organic groups which possess multiple N, O, or S heteroatoms, and have a structure which allows two or more of the heteroatoms to form bonds to the same metal ion.
  • “Pharmaceutically acceptable salts” include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non- toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable.
  • Salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non- toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, n
  • the compounds of the present invention relate to phosphorus-containing 4-(4- acryloylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one derivatives, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the compound of Formula I is capable of forming an irreversible covalent bond with a cysteine residue within the active site of the KRAS mutant G12C, and inactivating it.
  • One aspect of the present invention is directed to a phosphorus-containing-derivative of Formula I: or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A and B are each independently chosen at each occurrence from aryl, or heteroaryl optionally substituted with one or more of hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2 - C6alkenyl, C2-C6alkynyl, -(C0-C6alkyl)cycloalkyl, C1-C6haloalkyl, and C1-6alkoxy; X is hydrogen, halogen or trifluoromethyl; R 1 is hydrogen, C 1 -C 6 alkyl, C 1-6 alkoxy, -(C 0 -C 6 alkyl)cycloalkyl, C
  • A is heteroaryl optionally substituted with one or more of hydrogen, C1-6alkyl, and -(C0-C6alkyl)cycloalkyl;
  • B is aryl optionally substituted with one or more of hydrogen, halogen, and hydroxyl;
  • X is hydrogen, halogen or trifluoromethyl;
  • R 1 is C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)CN or -(C 1 -C 6 alkyl)P(O)R 2 R 3 ;
  • R 2 and R 3 are C 1 -C 6 alkyl or C 1 -C 6 alkoxyl and n is 1.
  • A is pyridyl, pyrimidinyl, pyrazolyl, or thiazolyl optionally substituted with one or more of hydrogen, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(C 0 -C 6 alkyl)cycloalkyl, C 1 -C 6 haloalkyl, and C 1-6 alkoxy;
  • B is aryl optionally substituted with one or more of hydrogen, halogen, hydroxyl, and cyano;
  • X is hydrogen, halogen or trifluoromethyl;
  • R1 is C1-C6alkyl, -(C1-C6alkyl)CN or -(C 1 -C 6 alkyl)P(O)R 2 R 3 ;
  • R 2 and R 3 are C 1 -C 6 alkyl or C 1 -C 6 alkoxyl; and
  • n is 1.
  • A is pyridyl, pyrimidinyl, pyrazolyl, or thiazolyl optionally substituted with one or more of hydrogen, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(C 0 -C 6 alkyl)cycloalkyl, C 1 -C 6 haloalkyl, and C 1-6 alkoxy;
  • B is aryl optionally substituted with one or more of hydrogen, halogen, hydroxyl, and cyano;
  • X is hydrogen, halogen or trifluoromethyl;
  • R1 is -(C1-C6alkyl)P(O)R2R3R2 and R3 are C1-C6alkyl or C1-C6alkoxyl; and n is 0.
  • ring A is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or thiazolyl optionally substituted with one or more of hydrogen, C1-C4 alkyl, C1-C4 alkoxyl;
  • ring B is a phenyl ring optionally substituted with one or more of hydrogen, halogen, hydroxyl, or cyano;
  • X is hydrogen, halogen or trifluoromethyl;
  • R 1 is hydrogen, C 1 -C 6 alkyl, -(C1-C6alkyl)CN or -(C1-C6alkyl)P(O)R2R3;
  • R2 and R3 are the same or different and are selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, or hydroxyl; and
  • n is 1.
  • Examples of particularly preferred embodiments of Formula I include the following, or pharmaceutically acceptable salts, solvates, or prodrugs thereof: ⁇
  • compositions comprising a compound or pharmaceutically acceptable salt of a compound, such as a compound of Formula I, together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain a compound or salt of Formula I as the only active agent, but is preferably contains at least one additional active agent.
  • the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of a compound of Formula I and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • the pharmaceutical composition may also include a molar ratio of a compound, such as a compound of Formula I, and an additional active agent.
  • the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an additional active agent to a compound of Formula I.
  • Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • compositions / combinations can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a compound of Formula III and usually at least about 5 wt.% of a compound of Formula I. Some embodiments contain from about 25 wt% to about 50 wt % or from about 5 wt% to about 75 wt% of the compound of Formula I.
  • the compounds of Formula I are useful for diagnosis or treatment of a disease, disorder, or medical condition mediated through KRAS, especially the KRAS mutant G12C, and including various cancers, such as glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non- small cell lung cancer, cholangiocarcinomas, chondrosarcoma, colon cancer or pancreatic cancer.
  • Additional cancers that can be treated or diagnosed using the compounds of the invention include the following:
  • sarcoma angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastri
  • a method of KRAS-mediated diseases or conditions comprises providing to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I.
  • the patient is a mammal, and more specifically a human.
  • the invention also encompasses methods of treating non-human patients such as companion animals, e.g. cats, dogs, and livestock animals.
  • a therapeutically effective amount of a pharmaceutical composition is preferably an amount sufficient to reduce or ameliorate the symptoms of a disease or condition.
  • a therapeutically effective amount may be an amount sufficient to reduce or ameliorate cancer.
  • a therapeutically effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient concentration of a compound of Formula I when administered to a patient.
  • a sufficient concentration is preferably a concentration of the compound in the patient’s body necessary to prevent or combat the disorder. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability.
  • the methods of treatment disclosed herein include providing certain dosage amounts of a compound of Formula I to a patient.
  • Dosage levels of each compound of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of each active compound. In certain embodiments 25 mg to 500 mg, or 25 mg to 200 mg of a compound of Formula I are provided daily to a patient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most KRAS-mediated diseases and disorders, a dosage regimen of 4 times daily or less can be used and in certain embodiments a dosage regimen of 1 or 2 times daily is used.
  • a compound of Formula I may be administered singularly (i.e., sole therapeutic agent of a regime) to treat or prevent KRAS-mediated diseases and conditions such as various canders, or may be administered in combination with another active agent.
  • One or more compounds of Formula I may be administered in coordination with a regime of one or more other active agents such as anticancer cytotoxic agents.
  • a method of treating or diagnosing KRAS-mediated cancer in a mammal includes administering to said mammal a therapeutically effective amount of a compound of Formula I, optionally in combination with one or more additional active ingredients.
  • the methods of treatment provided herein are also useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock, e.g. cattle, sheep, cows, goats, swine and the like, and pets (companion animals) such as dogs and cats.
  • a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.
  • rodents e.g. mice, rats, hamsters
  • rabbits e.g. primates, and swine
  • primates e.g. a human monocyte
  • swine e.g. swine
  • body fluids e.g. blood, plasma, serum, cellular interstitial fluid, saliva, feces, and urine
  • cell and tissue samples e.g. cell and tissue samples of the above subjects will be suitable for use.
  • the invention provides a method of treating a disease, disorder, or medical condition mediated through KRAS, especially the KRAS mutant G12C, including various cancers, in a patient identified as in need of such treatment, the method comprising providing to the patient an effective amount of a compound of Formula I.
  • the compounds of Formula I provided herein may be administered alone, or in combination with one or more other active agents.
  • the method of treating or diagnosing KRAS-mediated diseases or conditions may additionally comprise administering the compound of Formula I in combination with one or more additional compounds, wherein at least one of the additional compounds is an active agent, to a patient in need of such treatment.
  • the one or more additional compounds may include additional therapeutic compounds, including anticancer therapeutic compounds such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, avastin, Herceptin, Erbitux, and the like.
  • anticancer therapeutic compounds such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, avastin, Herceptin, Erbitux, and the like.
  • anticancer therapeutic compounds such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, avastin, Herceptin, Erbitux, and the like.
  • Scheme 1 begins with the reaction of either an aromatic amine or a heteroaromatic amine A1 with bromine to afford the corresponding bromide B1.
  • the reaction of commercially available 2,6-dichloro-5-fluoronicotinamide (C1) with oxalyl chloride generates an acyl isocyanate D1 that is not isolated, which after treatment with intermediate B1 furnishes the corresponding N-acylurea E1.
  • E1 with a strong base such as KHMDS results in cyclization to the pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione F1.
  • Reaction of F1 with phosphorus oxychloride provides the chloro compound G1, which is subsequently reacted with ⁇ N-Boc-piperazine H1 to yield intermediate I1.
  • the Suzuki-Miyaura cross-coupling reaction of I1 with boron derivative such as potassium trifluoroborate salt J1 results in the coupled product K1.
  • Palladium-mediated coupling of K1 with phosphine oxide L1 followed by deprotection with trifluoracetic acid yields the P-arylated amine derivative M1.
  • Reaction of M1 with acryloyl chloride N1 provides a compound of the formula 1.
  • Example 1 4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-1-(4-(dimethylphosphoryl)-2-isopropyl-6- methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (1).
  • Example 1 was prepared as shown below in Scheme 2.
  • reaction mixture was concentrated under a stream of nitrogen, diluted with THF (5.0 mL) and then cooled to 5 °C.
  • a solution of 4-bromo-2-methyl-6-(1-methylethyl)benzenamine (1b; CAS# 773887-07-3; 1.70 g, 7.45 mmol) in THF (2.0 mL) was added dropwise over 5 min to reaction and stirred at 5 °C for 2 h.
  • the crude reaction mixture was concentrated in vacuo and the residue was partitioned between 10% aq. citric acid (80 mL; w/v) and EtOAc (30 mL).
  • Tetrakis(triphenylphosphine)palladium(0) 38 mg, 0.033 mmol was added and the reaction mixture was heated at 60 °C in a microwave reactor while stirring over 17 h. The resulting mixture was cooled to RT, concentrated in vacuo and partitioned between EtOAc (30 mL) and water (25 mL). The aqueous layer was extracted twice with EtOAc (2 x 20 mL) and the combined EtOAc extracts were dried, filtered and concentrated in vacuo.
  • Example 1 The biological activity of Example 1 was determined in a KRAS G12C/SOS1 Nucleotide Exchange Assay that was performed by Reaction Biology Corporation (RBC, 1 Great Valley Parkway, Suite 2 Malvern, PA 19355, USA). The assay evaluates the SOS1-mediated Bodipy- GDP to GTP exchange observed with KRAS G12C.
  • the compounds were tested in 10 concentration IC50 mode with 3-fold serial dilution at a starting concentration of 10 ⁇ M for Example 1 and 5 ⁇ M for the reference standard (ARS-1620).
  • the compound pre-incubation time was 30 min at RT and the curve fits were performed when the activities at the highest concentration of compounds were less than 65%.
  • Reaction Buffer 40 mM HEPES 7.4, 10 mM MgCl 2 , 1 mM DTT 0.002% Triton X100, 0.1% DMSO (final).
  • Enzyme SOS1 (RBC cat# MSC-11-502).
  • KRAS G12C Recombinant human KRAS (Genbank accession# NM_033360.3; aa 2- 169, expressed in E. coli with N-terminal TEV cleavable his-tag.
  • KRAS is pre- loaded with Bodipy-GDP.
  • the final assay volume was 15 ⁇ L.
  • the background subtracted signals (no SOS1 protein wells were used as background) were converted to % activity relative to DMSO controls. Data was analyzed using GraphPad Prism 4 with “sigmoidal dose-response (variable slope)”; 4 parameters with Hill Slope. The constraints were bottom (constant equal to 0) and top (must be less than 1).

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Abstract

La présente invention concerne des inhibiteurs du virus du sarcome de Kirsten du rat (KRAS), et plus particulièrement des composés représentés par la formule (I), ainsi que des compositions comprenant la formule (I) et des procédés d'utilisation du composé représenté par la formule (I) pour le traitement ou la prévention d'une maladie, d'un trouble ou d'un état médical à médiation par KRAS, en particulier le mutant KRAS G12C.
PCT/US2020/063242 2019-12-06 2020-12-04 Dérivés de phosphore utilisés comme inhibiteurs de kras WO2021113595A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
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WO2021249563A1 (fr) * 2020-06-12 2021-12-16 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidone aryle ou hétéroaryle, son procédé de préparation et son utilisation
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022111521A1 (fr) * 2020-11-24 2022-06-02 杭州多域生物技术有限公司 Composé aromatique, son procédé de préparation et son utilisation
WO2022135591A1 (fr) * 2020-12-25 2022-06-30 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024127214A1 (fr) * 2022-12-15 2024-06-20 Pillai Universal Llc Nouvel inhibiteur de kras à petites molécules ciblant des cibles non traitables pour thérapies anti-cancéreuses
US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations

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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2021249563A1 (fr) * 2020-06-12 2021-12-16 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidone aryle ou hétéroaryle, son procédé de préparation et son utilisation
WO2021257736A1 (fr) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Méthodes de retardement, de prévention et de traitement de la résistance acquise aux inhibiteurs de ras
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022111521A1 (fr) * 2020-11-24 2022-06-02 杭州多域生物技术有限公司 Composé aromatique, son procédé de préparation et son utilisation
WO2022135591A1 (fr) * 2020-12-25 2022-06-30 苏州泽璟生物制药股份有限公司 Dérivé de pyridone ou de pyrimidone arylique ou hétéroarylique, et son procédé de préparation ainsi que son application
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024127214A1 (fr) * 2022-12-15 2024-06-20 Pillai Universal Llc Nouvel inhibiteur de kras à petites molécules ciblant des cibles non traitables pour thérapies anti-cancéreuses
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations

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