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WO2022199561A1 - Composé inhibiteur de la kinase hpk1 - Google Patents

Composé inhibiteur de la kinase hpk1 Download PDF

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Publication number
WO2022199561A1
WO2022199561A1 PCT/CN2022/082151 CN2022082151W WO2022199561A1 WO 2022199561 A1 WO2022199561 A1 WO 2022199561A1 CN 2022082151 W CN2022082151 W CN 2022082151W WO 2022199561 A1 WO2022199561 A1 WO 2022199561A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
pharmaceutically acceptable
alkylene
stereoisomer
Prior art date
Application number
PCT/CN2022/082151
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English (en)
Chinese (zh)
Inventor
陈宇锋
吕萌
杨寒
程万里
武朋
刘灿丰
陈凯旋
王友平
何南海
Original Assignee
杭州阿诺生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州阿诺生物医药科技有限公司 filed Critical 杭州阿诺生物医药科技有限公司
Priority to CN202280006669.4A priority Critical patent/CN116348117A/zh
Priority to CN202310684400.8A priority patent/CN116768888A/zh
Priority to CN202310687634.8A priority patent/CN116854687A/zh
Publication of WO2022199561A1 publication Critical patent/WO2022199561A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • HPK1 a member of the MAP4K family, is mainly expressed in cells of the hematopoietic system and acts as an intracellular negative regulator of T cell proliferation and signaling.
  • the adaptor protein SLP-76 in the cytoplasm is recruited to the lipid membrane TCR complex, providing binding sites for signal transduction-related kinases to achieve TCR-mediated signal transmission and induce T cell activation.
  • HPK1 is activated by phosphorylation by the tyrosine kinases Lck and Zap70, and is involved in the regulation of T cell receptor protein interactions.
  • suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) .
  • metal salts such as alkali metal salts (eg, sodium or potassium salts); and alkaline earth metal salts (eg, calcium or magnesium salts) .
  • pharmaceutically acceptable non-toxic acid addition salts are amino groups with inorganic acids (eg, hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (eg, acetic, oxalic, maleic, tartaric, citric acid, succinic acid or malonic acid), or by using other methods in the art such as ion exchange.
  • the precursors or metabolites described in the present invention may be those known in the art, as long as the precursors or metabolites can be metabolized in vivo to form the target compound.
  • “prodrugs” refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., Have a reasonable benefit/risk ratio and be valid for its intended use.
  • prodrug refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, eg, by in vivo metabolism, or N-demethylation of a compound of the present invention.
  • Solvate as used herein means a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of isolation. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • the present invention provides a method for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, comprising: A mammal in need thereof is administered a compound of the present invention.
  • anticancer agents for treating cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carbamide mustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin , epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxif
  • the compounds of the present invention may provide enhancement when administered in combination with additional therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases therapeutic effect.
  • compositions of the present invention may be formulated according to any of conventional methods into dosage forms such as tablets, granules, powders for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) , capsules, syrups, emulsions, microemulsions, solutions or suspensions.
  • the compounds of the present invention may exist in various tautomeric forms in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thereby rearranged. It is to be understood that all tautomeric forms that may exist are encompassed by the present invention.
  • the definitions of the substituents of the present invention are each independent rather than interrelated, for example, for R a (or R a ') in a substituent, it is independent in the definitions of different substituents .
  • selecting a definition for Ra (or Ra ') in one substituent does not mean that Ra (or Ra ') has the same definition in other substituents.
  • NR a R a ' when the definition of R a (or R a ') is selected from hydrogen, it does not mean that in -C(O)-NR In a R a ', R a (or R a ') must be hydrogen.
  • substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkane oxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (wherein the 2 amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio group, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylthiocarbonyl, alkylthiocarbonyl, alkylthiocarbonyl, alkylthio
  • alkyl or “alkylene” as used herein are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms.
  • C1 - C6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, tert-butyl) and Pentyl (eg n-pentyl, isopentyl, neopentyl).
  • Preferred alkyl groups are C1 - C6 alkyl groups.
  • Preferred alkylene groups are C 0 -C 6 alkylene groups or C 1 -C 6 alkylene groups.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length.
  • C2-C6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • Preferred alkenyl groups are (C 3 -C 6 )alkenyl groups.
  • alkoxy refers to -O-alkyl.
  • C 1 -C 6 alkoxy (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy.
  • alkylthio or “thioalkoxy” represents an alkyl group, as defined above, having the indicated number of carbon atoms attached through a sulfur bridge; eg, methyl-S- and ethyl-S-.
  • Preferred alkoxy groups are C 1 -C 6 alkoxy groups.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl or aromatic ring. For example, dashed lines drawn from a ring system indicate that the bond may be attached to any suitable ring atom. Preferred aryl groups are C6 - C10 aryl groups.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group, preferably having 3 to 8 ring members.
  • a monocyclic cyclic alkyl group refers to a C3 - C8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl".
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.
  • haloalkyl groups also include "fluoroalkyl groups" intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (preferably 1 to 6 carbon atoms) substituted with 1 or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group, as defined above, having the indicated number of carbon atoms (preferably 1 to 6 carbon atoms) attached through an oxygen bridge.
  • haloC1 - C6alkoxy is intended to include C1 , C2 , C3, C4 , C5 , C6 haloalkoxy .
  • haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • the ring atoms may be carbon atoms or heteroatoms, eg heteroatoms selected from N, O and S.
  • the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, eg selected from N, O and S of heteroatoms.
  • the one or more halogens may each be independently selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclyl groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable.
  • the nitrogens in the heterocycle may be optionally quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocycle is not greater than one.
  • heterocycle it is intended to include heteroaryl groups.
  • heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl azolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carboline, chromanyl, chromenyl, cinnoline, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-
  • heteroaryl may also include biaryl structures formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as, but not limited to, "-phenylbipyridyl-", “- Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-”, “-pyrimidinylbiphenyl-”; wherein the present invention also includes fused rings containing, for example, the above heterocycles and Spiro compounds.
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyls.
  • Monocyclic heterocycloalkyl refers to a 3-8 membered or 4-8 membered, and at least one saturated or unsaturated but non-aromatic cyclic alkyl system selected from O, N, S, P.
  • Bicyclic heterocycloalkyl systems refer to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
  • spirocycloalkyl refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings.
  • heterospirocyclyl refers to polycyclic hydrocarbons in which a single carbon atom (called a spiro atom) is shared between single rings, and the ring contains at least one atom selected from O, N and S.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and the substitution results in a stable compound.
  • nitrogen atoms eg, amines
  • these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (eg, mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention .
  • oxidizing agents eg, mCPBA and/or hydrogen peroxide
  • both shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
  • patient refers to an organism treated by the methods of the present invention.
  • organisms preferably include, but are not limited to, mammals (eg, murine, simian/monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
  • the term "effective amount” means the amount of a drug or agent (ie, a compound of the invention) that will elicit the biological or medical response of a tissue, system, animal or human, eg, sought by a researcher or clinician.
  • therapeutically effective amount means an amount that results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the incidence of a disease, as compared to a corresponding subject not receiving such amounts or the rate of progression of the disease.
  • An effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiology.
  • pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without unduly toxic, irritating sexual, allergic reactions and/or other problems or complications and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or a solvent encapsulating material which is involved in carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aid eg lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid
  • solvent encapsulating material which is involved in carrying or transporting a subject compound from one organ or part of the body to another organ or part of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • composition means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (ie) adjuvants, excipients or vehicles such as diluents, preservatives , fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating and dispersing agents, depending on The mode of administration and the nature of the dosage form.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • cancer refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
  • solid tumors eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (eg, thyroid), prostate , skin (melanoma), or blood tumor (eg, nonleukemic leukemia).
  • co-administration refers to the administration of several selected therapeutic agents to a patient, administered in the same or different administrations at the same or different times.
  • enhancing refers to the ability of a desired result to be increased or prolonged, either in potency or duration.
  • the term “enhancer” refers to the drug's ability to increase or prolong the potency or duration of the drug in the system.
  • potency value refers to the ability to maximize the ability of another therapeutic agent in an ideal system.
  • immune disease refers to a disease or condition of an adverse or deleterious response to an endogenous or exogenous antigen.
  • the result is usually the dysfunction of cells, or the destruction and dysfunction of the cells, or the destruction of organs or tissues that may produce immune symptoms.
  • subject or “patient” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; livestock such as rabbits, dogs; laboratory animals including rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, and the like.
  • the selected mammal is a human.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, Such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing and/or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or associated with the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, ear canal , nasal administration and topical administration.
  • parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal.
  • the compounds described herein are administered locally rather than systemically.
  • the depot formulation is administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered by a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed.
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally a one or more of the other therapeutic agents described above.
  • the compounds of the present invention may be administered for any of the above uses by any suitable means, eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (eg, in sterile injectable aqueous or non-aqueous solutions or suspensions liquid); nasally, including administration to nasal membranes, such as by inhalation spray; topically, such as in cream or ointment; or rectally, such as in suppository; or by intratumoral injection.
  • suitable means eg orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions
  • Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.
  • Such carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, and the like.
  • suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources such as Allen L.V.Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.
  • dosage regimens for the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient. nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and desired effect.
  • the daily oral dose of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably, when used for the indicated effect Typically from about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are usually in the form of suitable pharmaceutical diluents, excipients or carriers (herein) appropriately selected according to the intended form of administration (eg, oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice. are administered in the form of a mixture of drug carriers).
  • a typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60 mesh screen and packaged into size 1 gelatin capsules.
  • a typical injectable formulation can be prepared by aseptically placing at least one compound of the invention (250 mg) in a vial, aseptically lyophilizing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.
  • compositions comprising, either alone or in combination with a pharmaceutical carrier, a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the present invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient, without being toxic to the patient.
  • the dose level selected will depend on a variety of factors, including the activity of the particular compound of the invention or its ester, salt or amide employed; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical arts such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition.
  • a physician or veterinarian may initiate a test of a compound of the present invention used in a pharmaceutical composition at a level below that required and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the present invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend on the factors discussed above.
  • oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.01 to about 50 mg/kg body weight/day.
  • an effective daily dose of the active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the dosing is once a day.
  • composition may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical formulation (composition).
  • the container may contain one or more of the compounds described herein, which may be present as pharmaceutical components or in admixture with other ingredients described herein.
  • the container may have a sterile outlet (eg, the container may be an IV pack or bottle, the stopper being pierced by a hypodermic needle).
  • kits may carry a compound, along with instructions for use, labeling, or operating instructions as described herein.
  • a typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, dispensers, bags, containers, vials and/or tubes, with a list of contents and/or instructions for use, as well as instructions for the inner packaging. The entire set of instructions is to be included.
  • Labels can be displayed on or closely associated with the container.
  • the appearance of a label on a container means that the letters, numbers or other features of the label are affixed, moulded, or engraved on the container; the label may also appear in a container box or shipping box containing a variety of containers, such as in product inserts.
  • a label may be used to indicate a specific therapeutic use of the contents.
  • the label may also indicate instructions for use of the contents, such as described in the above method.
  • the raw materials and reagents used in the present invention are all known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents were used without further purification.
  • Room temperature refers to 20-30°C.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L.
  • microwave reaction use Initiator+ microwave reactor.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the measurement of LC-MS was performed using a Thermo liquid mass spectrometer (UltiMate 3000+MSQ PLUS).
  • a Thermo high pressure liquid chromatograph (UltiMate 3000) was used.
  • Preparative Reversed Phase Chromatography A Thermo (UltiMate 3000) Preparative Reversed Phase Chromatograph was used.
  • Fast column chromatography uses AIJER (FS-9200T) automatic column passing machine, and silica gel prepacked column uses Santai Prepacked columns.
  • the thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • the first step 1-methyl-3,5-dinitropyridin-2-one Int-1a (1.0 g, 5.02 mmol) was dissolved in methanol (50 mL), followed by adding ammonia methanol solution (7 mol/L, 8.61 mL, 60.27 mmol) and 1-methylpiperidin-4-one Int-1b (625 mg, 5.52 mmol).
  • the reaction mixture was heated to 50°C and stirred for 5 hours. After cooling to room temperature, it was left to stand for 48 hours, the reaction solution was concentrated under reduced pressure, and the residue was added with ethyl acetate (50 mL), followed by filtration.
  • the second step The compound Int-1c (1.0 g) obtained in the previous step was dissolved in methanol (30 mL), 10% Pd-C (400 mg) was added, and the reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain Int-1d as a yellow solid (800 mg, yield 94.70%).
  • the third step Compound Int-1d (100 mg, 0.61 mmol) was dissolved in acetic acid (3 mL), N-bromosuccinimide (109 mg, 0.61 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to quench the reaction until no bubbles were generated, the aqueous phase was extracted with methanol/dichloromethane (1/20, 50 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound Int-1e (38 mg, 25% yield).
  • the first step Compound Int-1e (100 mg, 0.41 mmol) and trimethylcyclotriboroxane (148 mg, 1.19 mmol) were dissolved in dioxane (1.5 mL) and water (0.15 mL), and carbonic acid was added Potassium (171 mg, 1.24 mmol), Pd(dppf)Cl2 (30 mg , 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 140° C. with a microwave and stirred for 1 hour. The reaction was cooled to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated.
  • the first step Compound Int-1e (350 mg, 1.45 mmol) and potassium vinyl trifluoroborate (387 mg, 2.89 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.15 mL), Potassium carbonate (399 mg, 2.89 mmol) and Pd(dppf)Cl2 (105 mg , 0.14 mmol) were added. After the reaction system was replaced with nitrogen, it was heated to 120° C. with a microwave reactor and stirred for 1 hour.
  • the first step Compound Int-1e (100 mg, 0.41 mmol) was dissolved in a mixed solvent of toluene (3 mL) and water (0.3 mL), cyclopropylboronic acid (42 mg, 0.49 mmol), potassium phosphate (306 mg, 1.45 mmol) were added mmol), tricyclohexylphosphine (23 mg, 0.082 mmol) and palladium acetate (9 mg, 0.041 mmol). After the reaction system was replaced with nitrogen, it was heated to 100°C and stirred for 18 hours.
  • N-tert-butoxycarbonyl-4-piperidinone Int-6a (4.4 g, 22.1 mmol) and 1-methyl-3,5-dinitro-2-pyridone Int-1a (4.0 g, 20.1 mmol) was dissolved in methanol (150 mL) and ammonia in methanol (7N, 34.4 mL, 240.8 mmol) was added. Stir at 60°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and stirring was continued for 2 days.
  • the third step Compound Int-6c (3.7 g, 14.8 mmol) was dissolved in DMF (20 mL), and N-bromosuccinimide (2.78 g, 15.6 mmol) and acetic acid (370 mg) were added. The reaction mixture was stirred at room temperature for 2 hours and completed by LCMS. Water (100 mL) was added, the aqueous phase (150 mL*3) was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography to obtain a yellow solid Int- 6d (3.6 g, 74% yield). ESI-MS (m/z): 328.2 [M+H] + .
  • the fourth step Compound Int-6d (500 mg, 1.53 mmol) was dissolved in methanol (5 mL), and sodium methoxide methanol solution (5N, 0.33 mL, 1.65 mmol) was added. The reaction mixture was heated to 100°C with microwave and stirred for 3 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography to obtain Int-6 as a yellow solid (330 mg, yield 77%). ESI-MS (m/z): 280.2 [M+H] + .
  • Compound 1 was prepared by the following steps:
  • the first step Boc-3-amino-2,2-dimethyl-propionic acid 1a (50 mg, 0.23 mmol) and methylamine hydrochloride (77 mg, 1.15 mmol) were dissolved in N,N-dimethylmethane To the amide (5 mL) was added HATU (105 mg, 0.27 mmol) followed by N,N-diisopropylethylamine (297 mg, 2.30 mmol) and the reaction mixture was stirred at room temperature for 14 hours. The complete conversion of starting material 1a was detected by TLC. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of compound 1b, which was directly used in the next reaction.
  • the second step the crude product of compound 1b obtained in the previous step was dissolved in a dioxane hydrochloric acid solution (4 mol/L, 5 mL), and the reaction solution was stirred at room temperature for 2 hours. TLC showed that the reaction of compound 1b was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product of compound 1c, which was directly used in the next reaction.
  • the fourth step Compound 1e (52 mg, 0.18 mmol) and intermediate Int-1 (36 mg, 0.18 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos G3 Pd (17 mg, 0.018 mmol) was added successively ), BrettPhos (10 mg, 0.018 mmol), cesium carbonate (122 mg, 0.37 mmol). After the reaction mixture was purged with nitrogen, it was stirred at 100°C overnight. The complete reaction of compound 1e was detected by LCMS.
  • Boc-3-amino-2,2-dimethyl-propionic acid 1a in the first step of Example 1 is replaced with Boc-DL-3-aminoisobutyric acid, and compound 2 can be obtained by similar methods and reaction steps .
  • Compound 4 was prepared by the following steps:
  • the fourth step dissolve compound 4e (50mg, 0.19mmol), Int-1 (37mg, 0.19mmol), BrettPhos G3Pd (17mg, 0.019mmol), Brettphos (20mg, 0.038mmol), cesium carbonate (126mg, 0.39mmol) In dioxane (10 mL), the reaction was stirred overnight at 110°C under nitrogen atmosphere. Complete conversion of starting material was detected by LCMS. The reaction solution was filtered, spin-dried, and the crude product was purified by reverse-phase preparative HPLC to obtain compound 4 (8 mg, yield 10%).
  • Compound 5 was prepared by the following steps:
  • the second step Compound 5b (48 mg, 0.16 mmol) and Int-1 (30 mg, 0.16 mmol) were dissolved in 1,4-dioxane (5 mL), and BrettPhos Pd G3 (14 mg, 0.016 mol) was added, BrettPhos (17 mg, 0.032 mol) and cesium carbonate (101 mg, 0.32 mol). After the reaction system was replaced with nitrogen, it was heated to 110°C and stirred for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse preparative HPLC to give compound 5 (6 mg, 8% yield).
  • the second step compound 7a (15mg, 0.036mmol) was dissolved in a mixed solvent of tetrahydrofuran (3mL) and water (3mL), then lithium hydroxide (3mg, 0.072mmol) was added to the above reaction solution, and the reaction solution Stir at room temperature for 3 hours. Complete conversion of starting material was detected by LCMS.
  • the reaction solution was concentrated to remove tetrahydrofuran, then the pH value of the solution was adjusted to 3 with 1N aqueous hydrochloric acid solution, and the aqueous solution was concentrated to obtain compound 7 (15 mg).
  • the third step Compound 7 (75mg, 187umol), ammonium chloride (142mg, 0.37mmol), HATU (142mg, 0.37mmol), DIPEA (72mg, 0.56mmol) were dissolved in DMF (8mL), and the reaction solution was Stir overnight at room temperature. Complete conversion of starting material was detected by LCMS. The reaction solution was concentrated to obtain crude product and purified by reverse-phase preparative HPLC to obtain compound 8 (10 mg, yield 14%).
  • Compound 10 was prepared by the following steps:
  • the third step compound 10c (260mg, 0.56mmol) was dissolved in a mixed solution of tetrahydrofuran (5mL) and water (5mL), lithium hydroxide (23mg, 0.56mmol) was added to the above reaction solution, and the reaction solution was in Stir at room temperature for four hours.
  • the crude product was purified by reverse phase preparative HPLC to give compound 10 (3.59 mg, 1.47% yield).
  • Test Example 1 Detection of the ability of compounds to inhibit HPK1 kinase activity (Method 1)
  • the required reagents are as follows
  • the specific operations are as follows: configure the enzymatic reaction system buffer (10mM MOPS, pH 7.2, 5mM ⁇ -glycerol-phosphate, 10mM MgCl2, 0.8mM EDTA, 2mM EGTA, 0.1mM DTT); test compounds (prepared in 1mM DMSO) Compound stock solution) was diluted with buffer to a maximum concentration of 60uM (containing 6% DMSO), and formulated at a concentration of 60 ⁇ M starting with a 5-fold dilution with a buffer containing 6% DMSO for a total of 8 point gradient concentrations; subsequently used Buffer diluted HPK1 kinase to 30 nM.
  • reaction substrate (10 ⁇ M MBP and 20 ⁇ M ATP dissolved in distilled water)
  • reaction substrate 10 ⁇ M MBP and 20 ⁇ M ATP dissolved in distilled water
  • the enzymatic reaction activity was detected by ADP-Glo Kinase Assay Kit, ADP - Glo Kinase Assay Kit assays are performed according to the kit's operating instructions. Data are described using the compound's median inhibitory concentration IC50.
  • Test Example 2 Detection of the agonistic ability of the compound to secrete cytokine interleukin-2 (IL-2) by Jurkat cells and the effect of the compound on the viability of Jurkat cells (Method 2)
  • the required reagents and cells are as follows:
  • the specific operations are as follows: dissolve the compound powder to 10 mM with DMSO, add 2 ⁇ l of the compound to 998 ⁇ l of RPMI 1640 medium (both in this test containing 10% FBS), and vortex to mix the highest concentration point.
  • the compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points.
  • the control was treated with RPMI 1640 medium solution containing 0.1% DMSO.
  • 1 ⁇ 105 Jurkat E6-1 cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound dilutions.
  • the control group was added RPMI 1640 medium containing 0.2% DMSO, and placed at 37 Incubate for 1 h in a cell incubator (Thermo Fisher Scientific, model: 3111). Subsequently, Anti-human CD3 Antibody and 1 ⁇ g/ml Anti-human CD28 Antibody were added at a final concentration of 1 ⁇ g/ml and incubated in a 37°C cell incubator for 24 h. The culture supernatant was collected and detected by Human IL-2 DuoSet ELISA KIT. IL-2 content in serum, Human IL-2 DuoSet ELISA detection was carried out according to the operating instructions of the kit.
  • IL-2 secretion data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO; cells were harvested, using The Luminescent Cell Viability Assay Kit detects cell viability, and the cell viability data is described by the half inhibitory concentration IC50 of the compound.
  • NA indicates that no enhanced release of IL-2 was detected.
  • Test Example 3 Detection of agonistic ability of compounds on human PBMC cells to secrete cytokine interleukin-2 (IL-2) Effects of compounds on human PBMC cell viability (Method 3)
  • IL-2 cytokine interleukin-2
  • the required reagents are as follows
  • human PBMCs are taken out from liquid nitrogen according to standard operations, thawed and thawed in a 37°C water bath, resuspended in RPMI 1640 medium (both containing 10% FBS in this test), and washed twice by centrifugation. ; Human PBMC cells were then resuspended in RPMI 1640 medium for use.
  • Compound powder was dissolved to 10 mM with DMSO, 2 ⁇ l of compound was added to 998 ⁇ l of RPMI 1640 medium, and the highest concentration point was obtained after vortexing and mixing. The compound solution was gradually diluted 3-fold with 0.2% DMSO medium for a total of 8 concentration points.
  • the control was treated with RPMI 1640 medium solution containing 0.1% DMSO.
  • 1 ⁇ 105 human PBMC cells were added to each well of a Corning 96-well cell culture plate (Cat. No. 3599), followed by an equal volume of compound diluents.
  • RPMI1640 medium containing 0.2% DMSO was added, and the cells were placed at 37°C.
  • Incubator (Thermo Fisher Scientific, model: 3111) was incubated for 1 h.
  • Anti-human CD3 Antibody and 1 ⁇ g/ml Anti-human CD28 Antibody were added at a final concentration of 0.01 ⁇ g/ml, and incubated in a 37°C cell incubator for 24 h.
  • Human IL-2 DuoSet ELISA KIT was used to detect the IL-2 content in the cell supernatant, and Human IL-2 DuoSet ELISA was performed according to the operating instructions of the kit. Data are described as the highest fold ratio of the stimulation signal of the compound to the signal of 0.1% DMSO. cells were collected, using The Luminescent Cell Viability Assay Kit detects cell viability, and the cell viability data is described by the half inhibitory concentration IC50 of the compound.
  • NA indicates that no enhanced release of IL-2 was detected.

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Abstract

L'invention concerne un composé de formule (I) ayant une activité d'inhibition de la kinase HPK1 et une composition pharmaceutique le comprenant. L'invention concerne également une utilisation du composé dans la prévention et/ou le traitement du cancer, de tumeurs, de maladies inflammatoires, de maladies auto-immunes ou de maladies à médiation immunitaire.
PCT/CN2022/082151 2021-03-23 2022-03-22 Composé inhibiteur de la kinase hpk1 WO2022199561A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056786A2 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Composes pour traiter le developpement anormal de cellules
WO2005111016A1 (fr) * 2004-05-14 2005-11-24 Pfizer Products Inc. Derives de pyrimidine pour le traitement d'une croissance cellulaire anormale
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
WO2009122180A1 (fr) * 2008-04-02 2009-10-08 Medical Research Council Dérivés de pyrimidine capables d’inhiber une ou plusieurs kinases
CN103003264A (zh) * 2010-05-21 2013-03-27 切米利亚股份公司 新型嘧啶衍生物
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
CN112451526A (zh) * 2020-11-30 2021-03-09 深圳市人民医院 MRT68921 HCl的应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056786A2 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Composes pour traiter le developpement anormal de cellules
WO2005111016A1 (fr) * 2004-05-14 2005-11-24 Pfizer Products Inc. Derives de pyrimidine pour le traitement d'une croissance cellulaire anormale
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
WO2009122180A1 (fr) * 2008-04-02 2009-10-08 Medical Research Council Dérivés de pyrimidine capables d’inhiber une ou plusieurs kinases
CN103003264A (zh) * 2010-05-21 2013-03-27 切米利亚股份公司 新型嘧啶衍生物
WO2018102366A1 (fr) * 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines en tant qu'inhibiteurs de kinase 1 progénitrices hématopoïétiques (hpk1)
CN112451526A (zh) * 2020-11-30 2021-03-09 深圳市人民医院 MRT68921 HCl的应用

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