WO2023103523A1 - Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de kras g12d - Google Patents

Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de kras g12d Download PDF

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WO2023103523A1
WO2023103523A1 PCT/CN2022/120295 CN2022120295W WO2023103523A1 WO 2023103523 A1 WO2023103523 A1 WO 2023103523A1 CN 2022120295 W CN2022120295 W CN 2022120295W WO 2023103523 A1 WO2023103523 A1 WO 2023103523A1
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cancer
reaction
mmol
compound
room temperature
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Chinese (zh)
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刘彬
高峰
张鹏志
郭永起
高宇
吴卓
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苏州浦合医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • 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
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, in particular to a substituted bicyclic heteroaryl compound, which can be used as a KRAS G12D inhibitor.
  • the human RAS gene family includes three types of RAS genes KRAS, NRAS and HRAS, encoding four different RAS proteins (KRAS-4A, KRAS-4B, NRAS and HRAS).
  • RAS protein belongs to the GTPase protein family, it is in an inactive state when it binds to GDP, and it is in an active state after binding to GTP, which can lead to the activation of downstream RAF-MAPK, PI3K-Akt and other signaling pathways, leading to the anti-apoptosis and anti-apoptosis of cells. Proliferation (Cell, 2017; 170(1):17-33; Cell, 2020; 183(4):850-859; Nat Rev Drug Discov, 2020; 19(8):533-552.).
  • KRAS Activating mutations in the RAS gene are the most prevalent oncogenic driver genes in human cancers, among which KRAS is the most frequent oncogenic activating mutation.
  • KRAS has a mutation rate of 86-96% in pancreatic cancer, 40-54% in colorectal cancer, and 27-39% in lung cancer (PNAS, 2019; 116(32):15823-15829 ; Pathol Res Pract, 2009; 205, 858–862; Nature, 2012; 491, 399–405; Nature, 2014; 511, 543–550).
  • Oncogenic driver mutations can occur at multiple sites in the KRAS gene, the most common mutations occur at the G12 site, including G12C, G12D, G12V, etc. These mutations can reduce the GTPase activity of the KRAS protein, resulting in a long-term Active state, leading to malignant transformation of cells and carcinogenesis (Cell, 2017; 170(1): 17-33; Nat Rev Drug Discov, 2020; 19(8): 533-552). In different cancer types, the frequently occurring KRAS mutation types are different.
  • KRAS G12D small molecule MRTX1133 for intravenous administration, but it has not yet entered clinical research.
  • the KRAS G12D-targeted small molecule drug of the present invention has excellent in vivo efficacy and greater safety, in order to solve the unmet clinical needs .
  • the invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Said compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also comprises other therapeutic agents.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating and/or preventing KRAS G12D mutein-mediated diseases.
  • the present invention provides a method for treating and/or preventing a KRAS G12D mutein-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention.
  • the present invention provides the compound of the present invention or the composition of the present invention for the treatment and/or prevention of KRAS G12D mutein-mediated diseases.
  • the diseases treated by the present invention include cancers selected from the group consisting of: acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T
  • KRAS G12D refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12.
  • the term "pharmaceutically acceptable salt” refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention, which are suitable for use in contact with patient tissues within the scope of sound medical judgment without undue toxicity, Irritation, allergic effects, etc., commensurate with a reasonable benefit/risk ratio, are valid for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.
  • Subjects for administration include, but are not limited to: human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adult, middle-aged adult or older adult)) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response.
  • an effective amount of a compound of the invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age Health conditions and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the invention may be administered with the other therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together with the other therapeutic agent in a single unit dosage form.
  • the compound of the present invention refers to the following compounds, their pharmaceutically acceptable salts, enantiomers, diastereoisomers, solvates, hydrates or isotopic variants, and their mixture.
  • the invention relates to a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Said compound is selected from:
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, eg, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereoisomers or geometric isomers (eg cis and trans isomers), or may be in the form of a mixture of stereoisomers, Racemic mixtures and mixtures enriched in one or more stereoisomers are included.
  • Isomers can be separated from mixtures by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist as tautomers.
  • a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
  • organic compounds may form complexes with solvents in which they react or from which they are precipitated or crystallized. These complexes are known as "solvates”. When the solvent is water, the complex is called a "hydrate”. The invention covers all solvates of the compounds of the invention.
  • solvate refers to a form of a compound, or a salt thereof, which is associated with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution state solvates and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that combines with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula R.x H 2 O, where R is the compound, and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R 0.5H2 O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • the compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described herein, but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replace.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • the compounds of the present invention their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms all belong to the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes (eg, 3H and14C ), are useful in drug and/or substrate tissue distribution assays. Tritium, ie3H , and carbon-14, ie14C isotopes are particularly preferred because of their ease of preparation and detection.
  • isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following Schemes and/or Examples and Preparations.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in vivo to its active form having a medical effect, for example by hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, per intro This article is for reference.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • a pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycol
  • kits eg, pharmaceutical packs.
  • kits can include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container).
  • first and second containers e.g., vials, ampoules, bottles, syringes, and/or dispersible packs or other suitable container.
  • provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention and other therapeutic agent provided in a first container and a second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal, intralesional, and intracranial injection or infusion techniques, preferably intravenously.
  • an effective amount of a compound provided herein is administered.
  • the amount of the compound actually administered can be determined by the physician according to the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • the compounds provided herein are administered to a subject at risk of developing the condition, typically on the advice and supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • Chronic administration refers to administering a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within the therapeutic window.
  • compositions may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to effective levels.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose provides slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV intravenous infusion) ) can be delivered more rapidly, so that the concentration of the active ingredient in the blood rises rapidly to effective levels.
  • the pharmaceutical compositions may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions will be presented in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful for forming the desired administration form. Carriers or excipients and processing aids.
  • a typical regimen is one to five oral dosages per day, especially two to four oral dosages, typically three oral dosages.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dosage levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given in order to achieve adequate steady state levels.
  • the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may comprise, for example, any of the following components, or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl sylate or orange flavoring.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often from about 0.05 to 10% by weight, the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active ingredients When formulated in an ointment, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream, with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other ingredients for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
  • transdermal administration can be achieved using patches of the reservoir or porous membrane type, or various solid matrices.
  • compositions for oral administration, injection or topical administration are representative only. Other materials and processing techniques, etc. are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form, or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrins composed of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, optionally including a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, eg, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the reagents used in the present invention are commercial reagents purchased directly or synthesized by common methods well known in the art.
  • Step 1 Dissolve the raw material 2-amino-3-fluoro-4-bromobenzoic acid a1-1 (15g, 64.1mmol) in 100mL DMF, slowly add N-chlorosuccinimide (8.56g, 64.1mmol) , the temperature was raised to 80° C. for 16 hours, and the reaction was stopped. The reaction solution was poured into 500 mL of ice water, filtered with suction to obtain a filter cake, and dried to obtain intermediate a1-2 (13.2 g, 49.2 mmol). Yield: 77%.
  • LC-MS: [MH] - 267.
  • Step 2 Add urea (35.3g, 588mmol) and intermediate a1-2 (10.5g, 39.2mmol) into a 200mL round bottom flask, and heat up to 200°C for 12 hours. After cooling down to 80°C, 100 mL of water was added to the system, refluxed for 10 minutes, cooled to room temperature, filtered to obtain a filter cake, washed with water, and dried in an oven to obtain intermediate a1-3 (4.0 g, 13.7 mmol). Yield: 35%.
  • LC-MS: [M+H] + 294.
  • Step 3 Dissolve the intermediate a1-3 (4.0g, 13.7mmol) and N,N-diisopropylethylamine (5.3g, 41.1mmol) in 15mL phosphorus oxychloride, and heat up to 120°C After reacting for 8 hours, stop the reaction. The solvent was evaporated under reduced pressure and separated by column chromatography to obtain intermediate a1 (1.9 g, 5.8 mmol). Yield: 42%.
  • LC-MS: [M+H] + 331.
  • Step 1 Under ice bath, dissolve 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid a4-2 (3.0g, 20.8mmol) in 60mL of dichloromethane, slowly add oxalyl chloride (10.5g, 83.3 mmol), added 5 drops of anhydrous DMF, and reacted at 0° C. for 20 minutes. The ice bath was removed, the temperature was raised to room temperature and stirring was continued for 1 hour, and the solvent was evaporated under reduced pressure.
  • Step 2 At -78°C, the intermediate a4-3 (2.6g, 13.2mmol) was dissolved in 30mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (26.4mL, 1M) was added slowly. The temperature was raised to room temperature for 2 hours, and the reaction was stopped. Slowly pour 80 mL of ice water into the reaction solution, evaporate the organic solvent under reduced pressure, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and separate by flash column chromatography to obtain intermediate a4 (900 mg, 5.8 mmol). Yield: 44%.
  • LC-MS: [M+H] + 156.
  • Step 1 Under ice bath, dissolve 6-bromo-2,3-difluorobenzaldehyde a7-1 (25g, 113mmol) in 250mL of methanol, slowly add sodium borohydride (8.54g, 226mmol), and stir for 20 minutes , the temperature was raised to room temperature and the reaction was continued for 1 hour, and the reaction was stopped. The reaction solution was slowly poured into saturated aqueous NH 4 Cl solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid a7-2 (23.9 g, 107 mmol). Yield: 95%.
  • Step 2 Dissolve intermediate a7-2 (23.9g, 107mmol) and N,N-diisopropylethylamine (20.7g, 161mmol) in 200mL anhydrous tetrahydrofuran under ice bath, and slowly add methylsulfonate Acid anhydride (20.5 g, 118 mmol), after stirring for 20 minutes, the ice bath was removed, and the reaction was continued at room temperature for 18 hours, and the reaction was stopped. The reaction solution was slowly poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain oil a7-3 (19 g, 63.1 mmol). Yield: 59%.
  • Step 3 Dissolve the above intermediate a7-3 (19g, 63.1mmol) in 240mL of a mixed solution of ethanol and water (v/v, 6/1), and add potassium cyanide (4.49g, 69mmol). React under reflux condition for 1 hour, stop the reaction. The organic solvent was evaporated under reduced pressure, the reaction solution was poured into saturated sodium carbonate solution, stirred for 20 minutes, extracted with dichloromethane, concentrated, and separated by column chromatography to obtain intermediate a7-4 (10.4g, 44.8mmol). Yield: 71%.
  • LC-MS: [M+H] + 233.
  • Step 4 Under ice bath, dissolve the intermediate a7-4 (10.4g, 44.8mmol) in 80mL DMF, slowly add potassium tert-butoxide (5.3g, 47.2mmol), and stir for 20 minutes, the solution turns red , DMF solution (6.2 g, 47.2 mmol, 5 mL) of ethyl isothiocyanatoformate (6.2 g, 47.2 mmol, 5 mL) prepared in advance was slowly added dropwise. After continuing to stir the reaction liquid for 1 hour, the temperature was raised to 100° C. for 30 minutes to react.
  • Step 5 The above intermediate a7-5 (6.7g, 19.5mmol) was dissolved in 30mL DMSO, and 30mL aqueous sodium hydroxide solution (5M) was added. React under reflux conditions for 4 hours, stop the reaction. After cooling to room temperature, 100 mL of ice water was slowly added to the reaction liquid to quench the reaction, and the filter cake was obtained by suction filtration, washed with water, and dried in a vacuum oven to obtain the crude intermediate a7-6 (3.8 g).
  • LC-MS: [M+H] + 272.
  • Step 6 Dissolve the above crude product a7-6 (3.8g) and DMAP (122mg, 1mmol) in a mixed solution of 30mL THF/DMF (v/v, 1/1), add Boc anhydride (4.3g, 19.5mmol ). React at room temperature for 12 hours, then stop the reaction. Add 80 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude intermediate a7-7 (3.3 g).
  • Step 7 Under the protection of nitrogen, the crude product a7-7 (3.3g) and raw material a7-8 (6.01g, 26.7mmol) were dissolved in 30mL 1,4-dioxane, and potassium acetate (2.62g, 26.7 mmol) and Pd(DPEphos)Cl 2 (643mg, 0.9mmol), the temperature was raised to 100°C for 1 hour, and the reaction was stopped. Cool to room temperature, filter, wash with saturated brine, extract with dichloromethane, dry, concentrate, and separate by flash column chromatography to obtain intermediate a7 (2.5g, 6.2mmol).
  • LC-MS: [M+H] + 405.
  • Step 1 Dissolve starting material 3-methoxy-2,2-dimethyl-3-oxalonic acid a15-1 (1.0g, 6.8mmol) and starting material a5-1 (850mg, 6.8mmol) in 20mL without Add EDCI (1.56g, 8.2mmol), N,N-diisopropylethylamine (1.77g, 13.6mmol) and HOBt (1.1g, 8.2mmol) to water dichloromethane, react at room temperature for 16h, stop reaction. Add 60 mL of ice water to the reaction solution, extract with dichloromethane, and dry over anhydrous sodium sulfate. The mixture was separated by Flash column chromatography to obtain intermediate a15-2 (1.04g, 4.6mmol) with a yield of 68%.
  • LC-MS: [M+H] + 218.
  • Step 2 At -78°C, the intermediate a15-2 (1.04g, 4.6mmol) was dissolved in 15mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (350mg, 9.2mmol) was added slowly. The temperature was raised to 0°C for 1 hour, and the reaction was stopped. Slowly add 2 mL of 10% NaOH aqueous solution to the reaction liquid, precipitate flocs, filter with suction, concentrate the filtrate under reduced pressure, and separate by flash column chromatography to obtain intermediate a15 (700 mg, 4.0 mmol). Yield: 87%.
  • LC-MS: [M+H] + 176.
  • Step 1 Add raw material 3,3-difluorocyclobutane-1-amine a24-1 (1.0g, 9.34mmol) and intermediate a19-2 (3.16g, 9.34mmol) in a 100mL reaction flask, 40mL anhydrous THF dissolves. After stirring for 5 minutes, NaBH(OAc) 3 (2.57g, 12.34mmol) and 10 drops of acetic acid were added to the reaction solution, reacted at room temperature for 10 hours, and the reaction was stopped. The reaction solution was poured into 200mL of ice water and extracted with ethyl acetate.
  • Step 2 Add intermediate a24-2 (2.62g, 5.91mmol) and aqueous formaldehyde (0.26mL) into a 100mL reaction flask, and dissolve in 40mL THF. After stirring for 5 minutes, NaBH(OAc) 3 (1.63g, 7.68mmol) and 10 drops of acetic acid were added to the reaction solution, reacted at room temperature for 2 hours, and the reaction was stopped. The reaction solution was poured into 100mL of ice water and extracted with ethyl acetate.
  • Step 3 The above intermediate a24-3 (2.0 g, 4.51 mmol) was dissolved in 20 mL of tetrahydrofuran, and tetrabutylammonium fluoride (2.2 g, 9.0 mmol) was added. The reaction was carried out at room temperature for 12 hours, and the reaction was complete as monitored by TLC.
  • Step 2 Intermediate a25-2 (1.21g, 4.13mmol) was dissolved in 25mL of anhydrous THF under ice bath, and lithium aluminum hydride (310mg, 8.3mmol) was added slowly. The temperature was raised to room temperature for 2 hours, and the reaction was stopped. Slowly add 2 mL of 10% NaOH aqueous solution to the reaction liquid, precipitate flocs, filter with suction, concentrate the filtrate under reduced pressure, and separate by flash column chromatography to obtain intermediate a25 (180 mg, 0.76 mmol). Yield: 18%.
  • LC-MS: [M+H] + 238.
  • Step 1 Add oxetane-3,3-diyldimethanol a26-1 (4.1g, 33.9mmol) and triethylamine (4.11g, 40.63mmol) in a 50mL reaction flask, 40mL of anhydrous dichloro Methane dissolves.
  • tert-butyldiphenylchlorosilane (7.18g, 33.86mmol) was added to the reaction liquid, reacted at room temperature for 2 hours, stopped the reaction, poured the reaction liquid into 200mL ice water, extracted with dichloromethane, organic The phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 12 g of crude intermediate a26-2.
  • Step 2 At -10°C, dissolve the crude intermediate a26-2 (12.0 g) from the previous step in 40 mL of tetrahydrofuran, add pyridine sulfur trioxide (12.8 g, 81.0 mmol), and react under ice cooling for 3 hours to stop the reaction.
  • the reaction solution was poured into 100 mL of ice water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain intermediate a26-3 (8.0 g, 22.7 mmol), two Step yield: 67%.
  • Step 1 Dissolve intermediate a1 (3.0g, 9.15mmol) and raw material 4,7-diazaspiro[2.5]octane-4-carboxylate tert-butyl a27-1 (2.12g, 10.1mmol) at room temperature
  • N,N-diisopropylethylamine (2.3 g, 17.4 mmol) was added, and reacted at room temperature for 8 hours.
  • LC-MS: [M+H] + 505.
  • Step 2 Under the protection of nitrogen, the intermediate a27-2 (3.74g, 7.4mmol) was dissolved in 75mL of anhydrous DMF, CsF (3.4g, 22.2mmol) was added, the temperature was raised to 60°C for 8h, and the reaction was stopped. The reaction solution was added to 300 mL of water, the mixture was extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain intermediate a27 with a yield of 90%.
  • LC-MS: [M+H] + 489.
  • Step 1 Dissolve 2-fluoro-3-methyl-4-bromopyridine a29-1 (4.5g, 23.9mmol) in 25mL carbon tetrachloride, slowly add N-bromosuccinimide NBS (6.35g , 35.8mmol) and azobisisobutyronitrile AIBN (390mg, 2.3mmol), reacted at room temperature for 3 hours, and stopped the reaction.
  • the reaction solution was slowly poured into 150 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE/EtOAc, 5/1) to obtain oil a29-2 (6.1 g, 22.9 mmol). Yield: 94%.
  • Step 2 Intermediate a29-2 (5.2g, 3.7mmol) and trimethylcyanosilane TMSCN (2.9g, 5.6mmol) were dissolved in 20mL of acetonitrile, and a solution of tetrahydrofuran (29mL) containing TBAF (5.5mmol) was added , reacted at room temperature for 16 hours, and stopped the reaction. The solvent was evaporated under reduced pressure and separated by column chromatography (PE/EtOAc, 5/1) to obtain oil a29-3 (3.4g, 15.9mmol). Yield: 81%.
  • Step 3 Under ice bath, dissolve the above intermediate a29-3 (3.4g, 15.9mmol) in 20mL DMF, slowly add NaH (2.9g, 19.1mmol), stir for 30 minutes, the solution turns red, slowly gradually A DMF solution of ethyl isothiocyanate (1.8 g, 15.9 mmol, 5 mL) prepared in advance was added dropwise. The reaction solution was heated up to 100° C. to react for 1 hour, and then cooled to room temperature.
  • Step 4 Dissolve the intermediate a29-4 (1.0 g, 3.1 mmol) in 10 mL of DMSO, and add 10 mL of aqueous sodium hydroxide solution (5M). React under reflux conditions for 4 hours, stop the reaction. After cooling to room temperature, 100 mL of ice water was slowly added to the reaction solution to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product was separated by column chromatography (PE/EtOAc, 1/1) to obtain a light yellow solid a29- 5 (450 mg, 1.8 mmol). Yield: 20%.
  • LC-MS: [M+H] + 254.
  • Step 5 Dissolve the intermediate a29-5 (450mg, 1.8mmol) and DMAP (5mg, 0.04mmol) in 20mL THF/DMF mixed solution (v/v, 1/1), add Boc anhydride (465mg ,2.16mmol). React at room temperature for 12 hours, then stop the reaction. Add 50 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude intermediate a29-6 (760 mg).
  • Step 2 Dissolve the above intermediate b1-2 (1.0g, 4.9mmol), palladium acetate (55mg, 0.24mmol) and NBS (0.87g, 4.87mmol) in 10mL of anhydrous acetic acid, and heat the reaction solution to 80°C The reaction was stopped for 1 hour, cooled to room temperature, the reaction liquid was poured into water, filtered, and the filter cake was dried to obtain a brown solid b1-3 (1.03 g, 3.6 mmol).
  • LC-MS: [M+H] + 284.
  • Step 3 Dissolve the intermediate b1-3 (12.5g, 43.99mmol) in the above step in a mixed solution of 60mL concentrated hydrochloric acid and 100mL 1,4-dioxane.
  • the reaction solution was heated to reflux and stirred for 1 hour, then the reaction was stopped, and concentrated under reduced pressure.
  • LC-MS: [M+H] + 255.
  • Step 4 Under nitrogen protection, the intermediate b1-4 (7.90g, 30.97mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoro Borate) salt (Selectfluor, 16.46g, 46.5mmol) was dissolved in 80mL of methanol, and 0.3mL of concentrated sulfuric acid was slowly added dropwise. The reaction solution was heated to 50° C. for 5 hours, then the reaction was stopped, and concentrated under reduced pressure.
  • Step 7 In ice bath, under the protection of nitrogen, the intermediate b1-7 (21.0 g, 77.5 mmol) and pyridine (18.38 g, 232.41 mmol) were dissolved in 200 mL of dichloromethane. Trifluoromethanesulfonic anhydride (26.2 g, 92.96 mmol) was slowly added dropwise to the reaction solution, and the mixture was slowly raised to room temperature for 1 hour to stop the reaction, and the solvent was evaporated under reduced pressure.
  • LC-MS: [M+H]+ 314.
  • Step 1 Dissolve the raw material 4-fluorophenylacetic acid b2-1 (50.0g, 324.4mmol) and cyclo(ethylene)isopropyl malonate b2-2 (51.4g, 356.8mmol) in 500mL of acetonitrile, add 4- Dimethylaminopyridine (DMAP, 3.57 g, 29.2 mmol) and DIEA (88.0 g, 681.2 mmol). After stirring for 5 minutes, pivaloyl chloride (43.0 g, 356.8 mmol) was slowly added dropwise. The reaction solution was heated to 45°C and stirred for 3 hours, then cooled to room temperature.
  • DMAP Dimethylaminopyridine
  • DIEA 88.0 g, 681.2 mmol
  • Step 2 Slowly add intermediate b2-3 (54.0 g, 192.7 mmol) in the above step into trifluoromethanesulfonic acid (228.5 g, 1.5 mol).
  • the reaction solution was stirred at room temperature for 2 hours, and the reaction was complete as monitored by LC-MS.
  • Step 3 Dissolve the intermediate b2-4 (66.0g, 295.96mmol) in the above step in a mixed solution of 660mL acetonitrile and water (v/1, 1/1), raise the temperature to 80°C for 13 hours, and stop the reaction. The solvent was evaporated under reduced pressure, washed with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain pale yellow compound b2-5 (51.8 g, 291.01 mmol), yield: 97%.
  • LC-MS: [M+H] + 179.
  • Step 6 Under nitrogen protection, at -40°C, the crude product b2-7 (58.4g, 113.43mmol) and DIEA (51.3g, 397.0mmol) were dissolved in 300mL of dichloromethane, and trifluoromethanesulfonic anhydride (54.4 g, 192.8mmol), after 3 hours of dripping, the stirring was continued for 0.5 hour, and the reaction was stopped. The reaction solution was poured into 500 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated.
  • Step 7 Under nitrogen protection, the intermediate b2-8 (61.6g, 95.2mmol), triethylamine (38.5g, 380.9mmol) and pinacol borane (48.7g, 380.9mmol) were dissolved in 600mL of acetonitrile, After stirring for 5 minutes, the catalyst Pd(dppf) Cl2 (4.2 g, 5.7 mmol) was added. The reaction solution was heated to 80°C and stirred for 4 hours, then cooled to room temperature. The mixture was slowly quenched with MeOH, keeping the temperature below 25 °C, and a solid precipitated out. After suction filtration, the filter cake was washed with MeOH and dried to obtain compound b2 (45.9 g, 73.4 mmol) as a white solid, yield: 77%.
  • LC-MS: [M+H] + 625.
  • Step 2 Dissolve the crude product c1-2 (25g, 77.3mmol) in 300mL DMF, add sodium methylthiolate (6.5g, 92.8mmol) at room temperature, raise the temperature to 90°C and stir for 16 hours to stop the reaction.
  • the reaction solution was poured into 500 mL ice water, extracted with ethyl acetate, washed with saturated brine, concentrated, and the crude product was separated by column chromatography to obtain compound c1-3 (10 g, 36.4 mmol), with a yield of 47%.
  • LC-MS: [M+H] + 275.
  • Step 3 Dissolve the intermediate c1-3 (16.5g, 51.0mmol) in 200mL of anhydrous tetrahydrofuran at -78°C under the protection of nitrogen, slowly add LDA (12.8g, 76.6mmol) dropwise, and continue stirring for 0.5 Hour.
  • Step 6 In an ice bath, dissolve the crude product c1-7 (2.1 g, 9.8 mmol) in 20 mL of tetrahydrofuran, add lithium aluminum hydride (750 mg, 19.5 mmol), and continue stirring for 1 hour to stop the reaction. Add 10 mL of methanol to the system to quench, filter, concentrate under reduced pressure, add 50 mL of water to the mixture, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain crude product c1 (directly used in the next reaction).
  • LC-MS: [M+H] + 188.
  • Step 7 Substitution of intermediate c1-5 by c1-6 yields intermediate c2.
  • Step 2 In an ice bath, the intermediate c9-2 (12.0 g, 56.3 mmol) and triethylamine (17.3 g, 170.5 mmol) were dissolved in 120 mL of dichloromethane. After stirring for 5 minutes, a dichloromethane solution (20 mL) of methanesulfonic anhydride (14.9 g, 85.2 mmol) was added dropwise to the reaction liquid, and the stirring was continued for 1 hour after the dropping was complete. Stop the reaction, add 200 mL of ice water to the system, extract with dichloromethane, and concentrate under reduced pressure to obtain the crude product to c9-3.
  • Step 3 The crude product c9-3 and potassium thioacetate (9.4 g, 82.4 mmol) were dissolved in 150 mL of DMF, and the temperature was raised to 60° C. for 15 hours to stop the reaction. Add 300mL ice water to the system, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, the crude product is separated by column chromatography to obtain intermediate c9-4 (15g, 55.4 mmol), two-step yield: 10%.
  • LC-MS: [M+H] + 272.
  • Step 4 In ice bath, the intermediate c9-4 (15g, 55.4mmol) of the previous step was dissolved in 300mL of anhydrous tetrahydrofuran, and lithium aluminum tetrahydride (5.2g, 138mmol) was added. After stirring for 5 minutes, the ice bath was removed, and the temperature was raised to 60° C. to react for 2 hours. Stop responding. Dilute hydrochloric acid was added to the system to quench the reaction, and the pH was adjusted to about 7. A solid was precipitated, filtered with suction, and the filter cake was washed with ethyl acetate to obtain intermediate c9.
  • LC-MS: [M+H] + 174.
  • LC-MS: [M+H] + 214.
  • Step 3 Dissolve P1-3 (120 mg, 0.15 mmol) in 4 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling.
  • the reaction solution was placed under nitrogen protection to continue the reaction for 1 hour, and then the reaction was stopped.
  • the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC chromatography to obtain the target compound P1 (10.2 mg).
  • LC-MS: [M+H] + 607.
  • Step 3 Dissolve H1-2 (80 mg, 0.10 mmol) in 3 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice-cooling. Under the protection of nitrogen, the reaction solution was reacted at room temperature for 0.5 hours, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by preparative SFC (Xselect CSH C18OBD) to give target compounds H1a (4.0 mg) and H1b (4.1 mg).
  • Step 1 Dissolve intermediate a5 (420 mg, 2.42 mmol) in 10 mL of anhydrous THF in a 50 mL reaction flask, add potassium tert-butoxide (340 mg, 3.64 mmol), and stir at room temperature for 30 minutes to obtain solution S1.
  • the intermediate a2 1.0g, 2.0mmol was dissolved in 10mL of anhydrous THF, and the prepared solution S1 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction.
  • the reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Step 1 Dissolve intermediate a5 (170 mg, 0.94 mmol) in 10 mL of anhydrous THF in a 50 mL reaction flask, add potassium tert-butoxide (180 mg, 1.56 mmol), and stir at room temperature for 30 minutes to obtain solution S2.
  • the intermediate a17 400mg, 0.78mmol was dissolved in 10mL of anhydrous THF, and the prepared solution S2 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction.
  • the reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Step 1 In a 50 mL reaction flask, the intermediate a19 (150 mg, 0.55 mmol) was dissolved in 5 mL of anhydrous THF, potassium tert-butoxide (93 mg, 0.82 mmol) was added, and stirred at room temperature for 30 minutes to obtain solution S3.
  • the intermediate a2 280mg, 0.58mmol was dissolved in 5mL of anhydrous THF, and the prepared solution S3 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction.
  • the reaction solution was poured into 50 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Step 1 Dissolve intermediate a5 (142mg, 0.82mmol) in 5mL anhydrous THF in a 20mL reaction flask, add potassium tert-butoxide (138mg, 2.34mmol), and stir at room temperature for 30 minutes to obtain solution S4.
  • the intermediate a27 400mg, 0.82mmol was dissolved in 5mL of anhydrous THF, and the prepared solution S4 was slowly added under ice cooling, and the stirring was continued for 1 hour to stop the reaction.
  • the reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Step 2 Under nitrogen protection, 2,2-diethoxyethanol (33.8g, 252mmol) was dissolved in 450mL of anhydrous DMF, NaH (10.08g, 252mmol) was slowly added at 0°C, and after stirring for 1 hour, The intermediate P14-2 (45 g, 210 mmol) of the previous step was added. The ice bath was removed, and the temperature was raised to 50° C. to react for 2 hours. The reaction was stopped, cooled to room temperature, 1 L of water was added to the system, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Step 3 Add 100 mL of toluene to polyphosphoric acid (10.42 g), raise the temperature to 100°C, add the intermediate P14-3 (10.0 g, 30.4 mmol) in the previous step, continue to react at this temperature for 2 hours, and stop the reaction.
  • the reaction solution was slowly poured into a large amount of ice water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether/ethyl acetate, 10/1) to obtain yellow solid P14-4 (1.04 g, 4.4 mmol), yield: 14%.
  • LC-MS: [M+H] + 236.
  • Step 4 Dissolve the intermediate P14-4 (8.3g, 35.0mmol) in 150mL of ethanol, add KOH aqueous solution (7.94g, 50mL), heat up to 90°C for 4 hours, and stop the reaction.
  • the organic solvent was evaporated under reduced pressure, 100 mL of ice water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The residue was separated by flash column chromatography (petroleum ether/dichloromethane, 2/1) to obtain yellow solid P14-5 (4.0 g, 15.7 mmol), yield: 45%.
  • LC-MS: [M+H] + 256.
  • Step 5 Under the protection of nitrogen, the intermediate P14-5 (3.3g, 13.0mmol) in the previous step was dissolved in 33mL of anhydrous THF, and a tetrahydrofuran solution containing triphosgene (3.6g, 12.4mmol) was slowly added dropwise at 0°C (20mL). The temperature was raised to room temperature for 2 hours, and the reaction was stopped. 100 mL of water was added to the system, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to obtain crude product P14-6 (2.8 g).
  • LC-MS: [M+H] + 282.
  • Step 7 At room temperature, intermediate P14-7 (1.0g, 3.15mmol) and raw material 3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl a2-1 (670mg, 3.15mmol) was dissolved in 20mL 1,4-dioxane, N,N-diisopropylethylamine (1.7mL, 9.5mmol) was added, and the reaction was carried out at 50°C for 2 hours. Add 60 mL of water to the system, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography to obtain white solid P14-8 (900 mg, 1.82 mmol). Yield: 58%.
  • LC-MS: [M+H] + 495.
  • Step 8 Under nitrogen protection, dissolve intermediate P14-8 (520mg, 1.05mmol) and cesium carbonate (684mg, 2.10mmol) in 5mL DMF, add intermediate a5 (363mg, 2.10mmol), and heat up to 140°C React for 2 hours. Cool to room temperature, add 60 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (petroleum ether/ethyl acetate, 1/1) to obtain a yellow solid P14-9 (155 mg, 0.25 mmol). Yield: 23%.
  • LC-MS: [M+H] + 630.
  • Step 9 Under the protection of nitrogen, the intermediate P14-9 (155mg, 0.25mmol) and cesium carbonate (200mg, 0.62mmol) were dissolved in 5mL of toluene, and the intermediate a7 (139mg, 0.34mmol) and Pd(DPEPhos)Cl were added 2 (52mg, 0.074mmol), heated to 105°C and reacted for 3 hours.
  • Step 10 Dissolve P14-10 (65 mg, 0.077 mmol) in 3 mL of a mixed solution of trifluoroacetic acid and dichloromethane (v/v, 1/1) under ice cooling. Under the protection of nitrogen, the reaction liquid was reacted at room temperature for 1 hour, the reaction was stopped, and saturated sodium bicarbonate solution was slowly added to the system to adjust the pH to about 8, extracted with ethyl acetate, and concentrated under reduced pressure.
  • Step 1 In ice bath, dissolve intermediate c1 (330 mg, 1.76 mmol) in 1 mL of anhydrous THF, add NaH (85 mg, 3.52 mmol), warm to room temperature and stir for 0.5 hours, and the reaction solution is set aside.
  • Intermediate a3 350mg, 0.82mmol was dissolved in 1mL of anhydrous tetrahydrofuran, added to the above reaction solution, reacted at room temperature for 1 hour, and stopped the reaction. Concentrated under reduced pressure, the crude product was separated by flash column chromatography to obtain compound P18-1 (240mg, 0.42mmol), with a yield of 24%.
  • LC-MS: [M+H] + 579.
  • Step 2 Under nitrogen protection, compound P18-1 (240mg, 0.42mmol), intermediate b2 (270mg, 0.44mmol), cesium carbonate (270mg, 0.83mmol) and methanesulfonic acid [n-butylbis(1-adamantine Alkyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (Pd-G3,10mg,0.014mmol) was dissolved in a mixed solution of 2mL1,4-dioxane and water ( v/v, 5/1), the temperature was raised to 95° C. for 1 hour, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the crude product was separated by flash column chromatography to obtain compound P18-2 (300 mg, 0.29 mmol), with a yield of 70%.
  • LC-MS: [M+H] + 1041.
  • Step 3 Compound P18-2 (270 mg, 0.26 mmol) and cesium fluoride (80 mg, 0.52 mmol) were dissolved in 1 mL of DMF, heated to 50° C. for 1 hour, and the reaction was stopped. Add 5 mL of water to the system, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product P18-3.
  • LC-MS: [M+H] + 729.
  • Step 4 Dissolve the crude product P18-3 from the previous step in 1 mL of hydrogen chloride in 1,4-dioxane solution (4M concentration), react at room temperature for 1 hour, and slowly add saturated aqueous sodium bicarbonate solution to the system to adjust the pH to 8 Left and right, extracted with ethyl acetate, concentrated under reduced pressure, and purified by TLC thin layer chromatography to obtain compound P18 (50 mg).
  • LC-MS: [M+H] + 629.
  • the compound P29-3 (450mg, 0.91mmol) and the raw material P9-1 (560mg, 1.1mmol) were dissolved in 10mL of 1,4-dioxane and 2mL of water, and the catalyst XPhos Pd G2 (215mg, 0.3 mmol) and cesium carbonate (1.18g, 3.64mmol).
  • the reaction solution was reacted at 95° C. for 2 hours, and the reaction was stopped.
  • the compound is tested for the inhibition of p-ERK mediated by KRAS G12D (directly reflecting the inhibitory effect of the test compound on the cellular level). details as follows:
  • AGS cells cultured in F-12K medium (Gibco, Cat.No.30-2004) containing 10% fetal calf serum and 1% penicillin were seeded on 384-well microplates at 37°C, 5% Incubate overnight under carbon dioxide conditions. 200 microliters of compounds at different concentrations (0.5% dimethyl sulfoxide final concentration) were added to each well and incubated at 37°C for 3 hours. Then, the cells were fixed in 8% fixative solution (Solarbio, Cat. No. P1112) and washed once with phosphate buffered saline (PBS). After washing, a blocking solution (LI-COR, Cat. No. 927-40000) was added to each well to block for 1 hour at room temperature.
  • F-12K medium Gibco, Cat.No.30-2004
  • Example 15 Inhibitory activity of compounds against GTP-KRAS
  • KRAS-G12D were all from the commercially available kit KRAS-G12D/cRAF BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB21PEG); in the detection of KRAS-WT, GTP was purchased from Sigma (Cat. No.V900868), GST-cRAF was prepared by Beijing Pharmaron (Cat.No.20190718), MAb Anti GST-Tb cryptate was purchased from Cisbio (Cat.No.61GSTTLA), and other key reagents were from the commercially available kit KRAS- WT/SOS1BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB15PEH).
  • Relative ratio (relative ratio, RR) (Ratio 665/615 -Ratio background )
  • Inhibition percentage [1-(RR compound -RR positive control well average value)/(RR negative control well average value-RR positive control well average value)] ⁇ 100
  • IC 50 calculation: Y lower plateau signal+(upper plateau signal-lower plateau signal)/(1+10 ⁇ (LogIC 50 -X) ⁇ Hill slope).
  • X logarithmic value of compound concentration; Y: inhibition percentage.
  • the compound to be tested (1 ⁇ M as the initial concentration, diluted 3 times, a total of 10 concentrations) was co-incubated with the cells for 7 days, and added to each well 3D reagent (Promega, catalog number G9683), read the luminescence value with Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104), the light signal is directly proportional to the amount of ATP in the system, and the content of ATP directly characterizes the amount of ATP in the system Viable cell count. Finally, XLFIT software was used to obtain the IC 50 (half inhibitory concentration) of the compound with a nonlinear fitting formula.
  • Inhibition rate (%) 100 ⁇ (negative control average value-compound reading value)/(negative control average value-positive control average value)
  • Negative control DMSO.
  • Positive control culture medium.
  • the compound to be tested is co-incubated with liver microsomes of different species with or without adding NADPH, the final concentration of the compound to be tested in the test system is 1 ⁇ M, and the final concentration of NADPH 1mM, the final concentration of liver microsomes is 0.5mg/ml. Detect the concentration of the compound in the incubation supernatant at different time points within 60 minutes and calculate the pharmacokinetic parameters (such as clearance rate Clint).
  • Some molecules (such as H1b, H10b, P20, P24, etc.) have a lower clearance rate and slower metabolism in humans than the control MRTX1133.
  • Colorectal cancer tumor cell GP2D with KRAS G12D mutation was cultured, and the tumor cells were inoculated into 6-8 week old female BALB/c nude mice (body weight about 20 g), and all mice were inoculated subcutaneously. Mice were raised in an SPF-grade experimental environment, and all mice had free access to commercially certified standard diets.
  • Daily intraperitoneal (ip) administration of the test compound began when the average tumor volume of the mice had grown to approximately 150 mm 3 .
  • the dosage is: blank group vehicle (10% Captisol in 50mM citrate buffer pH 5.0).
  • the dosage of the administration group was 10mg/kg, twice a day.
  • Tumor volumes were measured with two-dimensional calipers three times a week, and animals were weighed daily. After 10 days of continuous administration, the inhibition rate (TGI/100%) was calculated according to the final tumor volume.
  • Qualified healthy ICR mice (aged 6-8 weeks, body weight 18-20g) were selected, 3 in each group, for single intravenous administration respectively.
  • a single intravenous administration test was carried out, and the dose was explored from 2mg/kg. If no death was observed, the dose was increased, and if death occurred, the increase would be stopped.
  • the intravenous administration solution of MRTX1133 and the compound P20 intravenous administration vehicle are: DMSO/Tween80/Solutol/normal saline (the volume ratio of the four is 5/3/10/82), vortex ultrasonic to make it fully dissolved, and carry out administration disposal .
  • MRTX1133 infusion administration solution and compound P20 infusion administration vehicle are: DMSO/Tween80/Solutol/normal saline (the volume ratio of the four is 5/3/10/82), vortex ultrasonic to make it fully dissolved, then administer Drug disposal.

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Abstract

La présente invention concerne un composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de KRAS G12D. La présente invention concerne en outre une composition pharmaceutique contenant ce composé et son utilisation dans le traitement de cancers.
PCT/CN2022/120295 2021-12-09 2022-09-21 Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur de kras g12d WO2023103523A1 (fr)

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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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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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