WO2019154091A1 - Composé de diaminopyrimidine substituée - Google Patents

Composé de diaminopyrimidine substituée Download PDF

Info

Publication number
WO2019154091A1
WO2019154091A1 PCT/CN2019/072883 CN2019072883W WO2019154091A1 WO 2019154091 A1 WO2019154091 A1 WO 2019154091A1 CN 2019072883 W CN2019072883 W CN 2019072883W WO 2019154091 A1 WO2019154091 A1 WO 2019154091A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkoxy
halogen
mmol
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2019/072883
Other languages
English (en)
Chinese (zh)
Inventor
王义汉
李焕银
Original Assignee
深圳市塔吉瑞生物医药有限公司
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 深圳市塔吉瑞生物医药有限公司 filed Critical 深圳市塔吉瑞生物医药有限公司
Publication of WO2019154091A1 publication Critical patent/WO2019154091A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to a substituted diaminopyrimidine compound having an inhibitory effect on protein tyrosine kinase, a pharmaceutical composition comprising the same, a method of preparing the compound, and the use of the compound in therapy.
  • the compounds are useful as a new generation of ALK inhibitors, and are useful for treating ALK-mediated cancers, and these compounds have more excellent pharmacokinetic properties.
  • Anaplastic lymphoma kinase is a receptor-type protein tyrosine kinase belonging to the insulin receptor superfamily. It was discovered in 1994 by Morris and Shiota as a product of chromosomal rearrangement from Anaplastic large cell lymphoma (ALCL). The most common fusion method is the NPM (Nucleophosmin) gene on chromosome 5. ALK gene fusion on chromosome 2. NPM-ALK fusion proteins were detected in nearly 75% of ALCL-positive ALCL patients. In subsequent studies, different ALK fusion forms were found in a wide variety of cancers, including inflammatory myofibroblastic tumors. And diffuse large B-cell lymphoma.
  • EML4-ALK gene-positive patients generally do not carry the epidermal growth factor receptor (EGFR) or the Kirsten rat sarcoma virus (KRAS) mutation, which makes the EML4-ALK fusion gene A unique molecular target for non-small cell lung cancer.
  • EGFR epidermal growth factor receptor
  • KRAS Kirsten rat sarcoma virus
  • amplification or point mutations of the ALK gene have been found in Neuroblastomas, anaplastic thyroid cancer, and ovarian cancer.
  • crizotinib achieved an objective response rate of 60-74% and a good median progression-free survival (8-11 months) in ALK+NSCLC patients, most patients developed disease recurrence after 1 year of treatment. That is, acquired resistance is produced. Acquired resistance mechanisms of crizotinib have also been identified, including gains in ALK fusion genes, activation of signaling pathways, secondary mutations in the ALK kinase region, and other mechanisms.
  • second-generation ALK inhibitors have been effective in overcoming the deficiencies of resistance to crizotinib, such as ceritinib (Zykadia, Novartis) and erlotinib (Alectinib, Alecensa, Roche).
  • crizotinib such as ceritinib (Zykadia, Novartis) and erlotinib (Alectinib, Alecensa, Roche).
  • these second-generation inhibitors are effective in overcoming most of the crizotinib-resistant mutations, they are still ineffective for some mutations, such as ceratinib versus F1174C/V, erlotinib versus I1171N/T/S and They still have no effect on the G1202R.
  • ADME absorption, distribution, metabolism, and/or excretion
  • the present invention discloses a novel diaminopyrimidine compound and a composition and use thereof, which have better effectiveness and safety, lower side effects, and better pharmacodynamics/pharmacokinetics.
  • the performance can be used to treat ALK kinase-mediated cancer and has high selectivity for the resistant mutation L1196M.
  • R 1 and R 2 are independently selected from H, D, halogen, -CN, -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl ) 2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R 1 and R 2 atoms to which they are attached form a C 6-10 aryl group or a 5-10 membered heteroaryl group, preferably a pyrrolyl group; wherein the group is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 D substitution;
  • R 3 is selected from H, D, halogen, -CN or C 1-6 alkoxy; wherein said C 1-6 alkoxy is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 D substitutions;
  • R 4 is selected from H, D, halogen, -CN or C 1-6 alkoxy; wherein said C 1-6 alkoxy is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 D substitutions;
  • R 5 is selected from:
  • R 6 is selected from:
  • R 3 is a C 1-6 alkoxy group or a deuterated derivative thereof, at least one of the following options holds:
  • R 1 and R 2 and the atom to which they are attached form a C 6-10 aryl group or a 5-10 membered heteroaryl group;
  • the molecule in addition to R 3 , the molecule also has at least one D atom;
  • R 5 is formula (b);
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention provides a method of treating a cancer-related disorder resulting from an ALK mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); Forms of lymphoma, such as non-Hodgkin's lymphoma (NHL) known as anaplastic large cell lymphoma (ALCL); various forms of leukemia.
  • NHL non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • the non-small cell lung cancer is an ALK positive non-small cell lung cancer.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of ALK-mediated cancer.
  • the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, neurological tumors, esophageal cancer, soft tissue cancer, lymphoma, and leukemia.
  • the non-small cell lung cancer is an ALK-positive non-small cell lung cancer; wherein the lymphoma is an anaplastic large cell lymphoma.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • the "C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, a C 1-4 alkyl group is preferred. Examples of the C 1-6 alkyl group include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C1-6 alkyl also includes heteroalkyl groups in which one or more (eg, 1, 2, 3 or 4) carbon atoms are heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) replacement.
  • the alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 2-6 alkenyl means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon to carbon double bond. In some embodiments, a C2-4 alkenyl group is preferred. Examples of the C 2-6 alkenyl group include a vinyl group (C 2 ), a 1-propenyl group (C 3 ), a 2-propenyl group (C 3 ), a 1-butenyl group (C 4 ), and a 2-butenyl group. (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
  • C 2-6 alkenyl also includes heteroalkenyl groups in which one or more (eg, 1, 2, 3 or 4) carbon atoms are bonded to a hetero atom (eg, oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) replacement.
  • the alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon radical having from 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, a C2-4 alkynyl group is preferred. Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (eg, 1, 2, 3 or 4) carbon atoms are heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) replacement.
  • the alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, -Cl or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1-6 haloalkyl group means the above "C 1-6 alkyl group” which is substituted by one or more halogen groups. Examples include monohalogen, dihalo, and perhalogenated polyhalogen.
  • a monohalogen substituent may have an iodine, bromine, chlorine or fluorine atom in the group; two halogen substituents and a plurality of halogen substituents may have two or more identical halogen atoms or a combination of different halogens.
  • haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl , dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • the haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • C 1 -C 6 alkoxy refers to the group -OR wherein R is a substituted or unsubstituted C 1 -C 6 alkyl group. In some embodiments, a C 1 -C 4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.
  • C 6-10 aryl refers to a monocyclic or polycyclic (eg, bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (eg, having a cyclic arrangement) Shared 6 or 10 ⁇ electrons) groups.
  • an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • the aryl group also includes a ring system in which the above aryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be represented.
  • the aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • 5-10 membered heteroaryl means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (eg, having a ring-like arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a 5-6 membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • the heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • amino and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectate este
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon 14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may be in amorphous or crystalline form. Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state. A drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, 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, each introduction This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, the hydroxy, thiol and amino functional acetate/amide, formate/amide and benzoate/amide derivatives of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • the invention relates to a compound of formula (I):
  • R 1 and R 2 are independently selected from H, D, halogen, -CN, -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl ) 2, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or R 1 and R 2 atoms to which they are attached form a C 6-10 aryl group or a 5-10 membered heteroaryl group, preferably a pyrrolyl group; wherein the group is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 D substitution;
  • R 3 is selected from H, D, halogen, -CN or C 1-6 alkoxy; wherein said C 1-6 alkoxy is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 D substitutions;
  • R 4 is selected from H, D, halogen, -CN or C 1-6 alkoxy; wherein said C 1-6 alkoxy is optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 D substitutions;
  • R 5 is selected from:
  • R 6 is selected from:
  • R 3 is a C 1-6 alkoxy group or a deuterated derivative thereof, at least one of the following options holds:
  • R 1 and R 2 and the atom to which they are attached form a C 6-10 aryl group or a 5-10 membered heteroaryl group;
  • the molecule in addition to R 3 , the molecule also has at least one D atom;
  • R 5 is formula (b);
  • the invention relates to a compound of formula (Ia):
  • R 1 ' , R 2 ' , R 3 ' , R 4 ' , R 5 ' , R 6 ' , R 7 ' , R 8 ' and R 9 ' are each independently selected from hydrogen or deuterium;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • R 1 , R 2′ , R 3′ , R 4′ are deuterium.
  • X 1 and X 2 are each independently selected from CD 3 , CHD 2 or CH 2 D; preferably, X 1 and X 2 are CD 3 .
  • R 9 ' is deuterium
  • X 4 and X 5 are each independently selected from CD 3 , CHD 2 or CH 2 D; preferably, X 4 and X 5 are CD 3 .
  • the compound of the formula (Ia) contains at least one halogen atom, more preferably one germanium atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably more than 30%, more preferably more than 50%, more preferably more than 75%, more preferably more than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • R 1 ' , R 2 ' , R 3 ' , R 4 ' , R 5 ' , R 6 ' , R 7 ' , R 8 ' , R 9 ' , X 1 , X 2 , X 3 , X 4 and X 5 having a strontium isotope content of at least 5%, preferably more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, in each deuterated position, More preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more Preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably The ground is greater than 99%.
  • the compound of the formula (Ia) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four Helium atom.
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D; in another specific embodiment, X 1 is CH 3 ; in another embodiment In the scheme, X 1 is CD 3 ; in another specific embodiment, X 1 is CH 2 D; in another specific embodiment, X 1 is CHD 2 ; in another specific embodiment, X 2 is CH 3 ; In another specific embodiment, X 2 is CD 3 ; in another specific embodiment, X 2 is CH 2 D; in another specific embodiment, X 2 is CHD 2 ; In the scheme, X 1 is CH 3 and X 2 is CD 3 ; in another specific embodiment, X 1 is CD 3 and X 2 is CH 3 ; in another specific embodiment, X 1 is CH 3 , X 2 is CH 3 ; in another specific embodiment, X 1 is CD 3 and X 2 is CD 3 .
  • X 3 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D; in another specific embodiment, X 3 is CH 3 ; in another specific embodiment, X 3 is CD 3 ; In another specific embodiment, X 3 is CH 2 D; in another specific embodiment, X 1 is CHD 2 .
  • X 4 and X 5 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D; in another specific embodiment, X 4 is CH 3 ; In the scheme, X 4 is CD 3 ; in another specific embodiment, X 4 is CH 2 D; in another specific embodiment, X 4 is CHD 2 ; in another specific embodiment, X 5 is CH 3 ; In another specific embodiment, X 5 is CD 3 ; in another specific embodiment, X 5 is CH 2 D; in another specific embodiment, X 5 is CHD 2 ; In the scheme, X 4 is CH 3 and X 5 is CD 3 ; in another specific embodiment, X 4 is CD 3 and X 5 is CH 3 ; in another specific embodiment, X 4 is CH 3 , X 5 is CH 3 ; in another specific embodiment, X 4 is CD 3 and X 5 is CD 3 .
  • R 1 ' , R 2 ' , R 3 ' , R 4 ' , R 5 ' , R 6 ' , R 7 ' , R 8 ' and R 9 ' are each independently selected from hydrogen or
  • R 1 ' is hydrogen; in another specific embodiment, R 1 ' is hydrazine; in another specific embodiment, R 2 ' is hydrogen; in another specific embodiment Wherein R 2 ' is hydrazine; in another specific embodiment, R 3 ' is hydrogen; in another specific embodiment, R 3 ' is hydrazine; in another specific embodiment, R 4 ' is hydrogen; In another specific embodiment, R 4 ' is hydrazine; in another specific embodiment, R 5 ' is hydrogen; in another specific embodiment, R 5 ' is hydrazine; in another specific embodiment, R 6 ' is hydrogen; in another specific embodiment, R 6 ' is hydrazine; in another specific embodiment, R 7 ' is hydrogen; in another specific embodiment, R
  • the invention relates to a compound of formula (X):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen or hydrazine;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen or hydrazine;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • X 1 , X 2 , X 3 , X 4 and X 5 are both CH 3 , then R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , At least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 is ⁇ ; and if X 1 , X 2 , X 4 and X 5 are both CH 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are all hydrogen , then X 3 is selected from CHD 2 or CH 2 D;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen or deuterium.
  • Y 1 is hydrogen; in another specific embodiment, Y 1 is deuterium; in another specific embodiment, Y 2 is hydrogen; in another specific embodiment, Y 2 is In another specific embodiment, Y 3 is hydrogen; in another specific embodiment, Y 3 is deuterium; in another specific embodiment, Y 4 is hydrogen; in another specific embodiment, Y 4 is hydrazine; in another specific embodiment, Y 5 is hydrogen; in another specific embodiment, Y 5 is hydrazine; in another specific embodiment, Y 6 is hydrogen; in another specific embodiment Y 6 is hydrazine; in another specific embodiment, Y 7 is hydrogen; in another specific embodiment, Y 7 is hydrazine; in another specific embodiment, Y 8 is hydrogen; in another embodiment In the scheme, Y 8 is ⁇ .
  • R 1 -R 9 and X 1 -X 5 are as defined for R 1 ' -R 9 ' and X 1 -X 5 in the compound of formula (Ia).
  • the invention relates to a compound of formula (Ib):
  • R 1 and R 2 are independently selected from H, halogen, -CN, -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or the atom to which R 1 and R 2 are attached form a C 6-10 aryl group or 5- a 10-membered heteroaryl group, preferably a pyrrolyl group;
  • R 3 is selected from H, halogen, -CN or C 1-6 alkoxy
  • R 4 is selected from H, halogen, -CN or C 1-6 alkoxy
  • R 5 is selected from:
  • R 3 is a C 1-6 alkoxy group
  • R 1 and R 2 and the atom to which they are attached form a C 6-10 aryl group or a 5-10 membered heteroaryl group;
  • R 5 is formula (b);
  • R 1 and R 2 are independently selected from H or halogen, or R 1 and R 2 and the atom to which they are attached form a pyrrolyl group;
  • R 3 is selected from H or C 1-6 alkoxy
  • R 4 is selected from H, halogen or C 1-6 alkoxy
  • R 5 is selected from:
  • R 3 is not a C 1-6 alkoxy group
  • R 1 and R 2 are independently selected from H, chloro, or the atoms to which R 1 and R 2 are attached form a pyrrole ring.
  • R 1 is chloro and R 2 is H.
  • R 1 and R 2 and the atoms to which they are attached form a pyrrole ring.
  • R 3 is selected from H, methoxy, ethoxy, isopropoxy or tert-butoxy.
  • R 3 is H.
  • R 3 is methoxy
  • R 4 is selected from H, fluoro, chloro, methoxy, ethoxy, isopropoxy or tert-butoxy.
  • R 4 is H.
  • R 4 is fluoro
  • R 4 is methoxy
  • R 1 is fluorine, chlorine, R 3 is not a methoxy, ethoxy, isopropoxy or tert-butoxy.
  • R 1 is chloro
  • R 3 is not a methoxy group.
  • the invention relates to a compound of formula (Ic):
  • R 3 is selected from H
  • R 4 is selected from H, halogen or C 1-6 alkoxy; preferably, R 4 is selected from methoxy or fluoro; preferably, R 4 is methoxy;
  • the invention relates to a compound of formula (Id):
  • R 3 is selected from H, halogen, -CN or C 1-6 alkoxy; preferably, R 3 is selected from H or C 1-6 alkoxy; preferably, R 3 is H; preferably, R 3 is C 1-6 alkoxy; preferably, R 3 is methoxy;
  • R 4 is selected from H, halogen, -CN or C 1-6 alkoxy; preferably, R 4 is selected from H, halogen or C 1-6 alkoxy; preferably, R 4 is selected from halogen or C 1- 6 alkoxy; preferably, R 4 is selected from methoxy or fluoro; preferably, R 4 is H;
  • R 3 is H, and R 4 is selected from H, halo or C 1-6 alkoxy; preferably, R 3 is H, and R 4 is selected from halo or C 1-6 alkane Alkoxy; preferably, R 3 is H, and R 4 is selected from methoxy or fluoro.
  • R 4 is H and R 3 is selected from H or C 1-6 alkoxy; preferably, R 4 is H, and R 3 is C 1-6 alkoxy; preferably R 4 is H, and R 3 is methoxy.
  • R 3 is selected from H, methoxy, ethoxy, isopropoxy or tert-butoxy.
  • R 3 is H.
  • R 3 is methoxy
  • R 4 is selected from the group consisting of H, fluorine, chlorine, bromine, methoxy, ethoxy, isopropoxy or t-butoxy.
  • R 4 is H.
  • R 4 is fluoro
  • R 4 is methoxy
  • the compound of the invention is selected from the group consisting of a compound, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, polymorph, stereoisomer or isotopic variation thereof:
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition 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 the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use 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, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • 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 provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8 - Capsules The compound of the invention in dry powder form can be combined with the starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of 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 can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided 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 ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from 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.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr 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 can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as 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 stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials as well as processing techniques and the like are set forth in Remington's Pharmaceutical Sciences, 17 th edition , 1985, Mack Publishing Company, Easton, in Section 8 Pennsylvania, herein incorporated by reference in this document.
  • 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 further 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 alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic derivative thereof, or a given to a subject in need of treatment.
  • Pharmaceutical The pharmaceutical composition of the invention is used to treat cancer.
  • the cancer is an ALK-driven cancer.
  • the cancer is non-small cell lung cancer.
  • a “therapeutically effective amount” is an amount effective to detect the growth or spread of killing or inhibiting cancer cells; the size or number of weights; or other measure of the level, stage, progression or severity of cancer. The exact amount required can vary from subject to subject, depending on the race, age and general health of the subject, the severity of the disease, the particular anticancer agent, its mode of administration, combination therapy with other therapies, and the like.
  • various compounds disclosed herein inhibit tyrosine kinase activity of ALK, fak, and c-met, particularly tyrosine kinases believed to mediate the growth, progression, and/or metastasis of cancer.
  • a variety of compounds as disclosed herein have also been found to have potent in vitro activity against cancer cell lines. Thus, such compounds are useful in the treatment of cancer, including solid tumors as well as lymphomas, and include cancers that are resistant to other therapies.
  • the cancer is an ALK-driven cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is an ALK positive NSCLC. In some embodiments, the cancer is a locally advanced or metastatic ALK-positive NSCLC. In some embodiments, the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • NSCLC non-small cell lung cancer
  • the cancer is an ALK positive NSCLC.
  • the cancer is a locally advanced or metastatic ALK-positive NSCLC.
  • the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • Such cancers include, but are not limited to, breast cancer, non-small cell lung cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); various forms of lymphoma, Non-Hodgkin's lymphoma (NHL) such as known as anaplastic large cell lymphoma (ALCL); various forms of leukemia; and includes cancers mediated by ALK or c-met.
  • NDL Non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • leukemia includes cancers mediated by ALK or c-met.
  • Anaplastic lymphoma kinase is a transmembrane receptor tyrosine kinase that belongs to the insulin receptor subfamily.
  • the ALK receptor tyrosine kinase was originally identified for its involvement in human non-Hodgkin's lymphoma subtypes known as anaplastic large cell lymphoma (ALCL).
  • ALK typically has a restricted distribution in mammalian cells and is found to be at a significant level in the nervous system only during embryonic development, indicating the role of ALK in brain development.
  • normal ALK In addition to its role in normal development, expression of full-length normal ALK has been detected in cell lines derived from various tumors, such as glioblastoma, neuroectodermal tumors, and glioblastoma, and breast. Cancer and melanoma lines.
  • translocations affect the ALK gene, leading to expression of the original cell fusion kinase, the most common of which is NPM-ALK.
  • NPM-ALK anaplastic large cell lymphoma
  • ACL anaplastic large cell lymphoma
  • NMP nucleolar phosphoprotein
  • This mutant protein, NPM-ALK has a constitutively active tyrosine kinase domain that is responsible for its carcinogenic properties by activating downstream effectors.
  • ALK positive lymphoid cancer cells The constitutively activated chimeric ALK has been shown to be present in approximately 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that primarily affects children and young adults. Furthermore, current reports have described the appearance of the variant ALK fusion TPM4-ALK in the case of esophageal squamous cell carcinoma (SCC).
  • IMTs myofibroblastic tumors
  • SCC esophageal squamous cell carcinoma
  • ALK is one of the few examples of RTKs involved in neoplasia in both non-hematopoietic malignancies and hematopoietic malignancies.
  • EML4 thorny animal microtubule-associated protein-like 4
  • ALK anaplastic lymphoma kinase
  • an ALK inhibitor can create a durable cure when used as a single therapeutic agent or in combination with current chemotherapy for ALCL, IMT, proliferative disorders, glioblastoma, and other possible solid tumors cited herein, Or as a single therapeutic agent can be used to prevent the maintenance of relapse in patients in need of such treatment.
  • a compound as disclosed herein can be administered as part of a therapeutic regimen wherein the compound is the only active agent, or in combination with one or more other therapeutic agents that are part of a combination therapy.
  • the therapeutic agent being administered can be formulated to simultaneously or sequentially administer separate compositions at different time points (eg, within 72 hours, 48 hours, or 24 hours of each other), Alternatively, the therapeutic agents can be formulated together as a single pharmaceutical composition and administered simultaneously.
  • administration of a compound of the invention may be mediated by at least one additional treatment known to those skilled in the art for preventing or treating cancer, such as radiation therapy or cytostatics, cytotoxic agents, other anticancer agents, and other drugs. Symptoms of cancer or any side effects of drugs.
  • additional therapeutic agents include agents suitable for immunotherapy (such as, for example, PD-1 or PDL-1 inhibitors), anti-angiogenic agents (such as, for example, bevacizumab), and/or chemotherapy.
  • such combination products employ a compound as disclosed herein in an acceptable dosage range.
  • the compounds as disclosed herein can be administered sequentially with other anticancer or cytotoxic agents.
  • the compounds as disclosed herein can be administered prior to, concurrently with, or subsequent to the administration of other anticancer or cytotoxic agents.
  • a typical chemotherapy regimen consists of a DNA alkylating agent, a DNA intercalating agent, a CDK inhibitor, or a microtubule poison.
  • the dose of chemotherapy used is just below the maximum tolerated dose, and thus dose limiting toxicity typically includes nausea, vomiting, diarrhea, hair loss, neutropenia, and the like.
  • antineoplastic agents are available for commercial use, clinical evaluation, and preclinical development, which can be selected for treatment of cancer by combination chemotherapy.
  • antineoplastic agents There are several major classes of such antineoplastic agents, namely, antibiotic agents, alkylating agents, antimetabolites, antihormonal agents, immunizing agents, interferon-type agents, and a class of confounding agents.
  • an anticancer alkylating agent or an intercalating agent eg, nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, and ifosfamide
  • Antimetabolites eg methotrexate
  • anti-caking agents or pyrimidine antagonists eg 5-fluorouracil, cytarabine and gemcitabine
  • spindle inhibitors eg vinblastine, vincristine, vinorelbine
  • podophyllotoxin eg etoposide, irinotecan, topotecan
  • antibiotics eg doxorubicin, bleomycin and mitomycin
  • nitrosoureas eg Camo) Statin, lomustine
  • inorganic ions such as cisplatin, carboplatin, oxaliplatin or oxiplatin
  • enzymes such as asparaginase
  • Proteasome inhibitors such as sputum, other proteasome inhibition and (such as Src, Bcr / Abl, kdr, flt3, aurora-2, glycogen synthase kinase 3 (GSK-3), EGFR) Enzymes (such as Iressa, Tarceva, etc.), VEGF-R kinases, inhibitors of PDGF-R kinase, etc.; antibodies, soluble receptors or other receptor antagonists that are resistant to receptors or hormones involved in cancer ( Including receptors such as EGFR, ErbB2, VEGFR, PDGFR and IGF-R; and drugs such as Herceptin, Avastin, Erbitux, etc.) Examples of other therapeutic agents include, but are not limited to, sterol, alemtuzmab, hexa Melamine, amifostine, nastrozole, antibodies against prostate-specific membrane antigens (eg MLN-591,
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • the compounds of the invention were evaluated in a number of tests to determine their biological activity. For example, the ability of a compound of the invention to inhibit a variety of protein kinases of interest can be tested. Some of the compounds tested showed potent inhibitory activity against ALK kinase.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • A represents an IC 50 of 1-2.5 nM
  • B represents an IC 50 of 2.5-5 nM
  • C represents an IC 50 of 5-10 nM
  • D represents an IC 50 of 10-15 nM
  • E represents an IC 50 of 15-30 nM.
  • the compound of the present invention and the positive control were tested in the above kinase inhibition assay, and the compound of the present invention was found to have more potent activity against ALK and ALK [L1196M].
  • the results for the representative example compounds are summarized in Table 1 below.
  • the in vitro antiproliferative activity of the compounds of the present invention against three cells cultured in vitro was examined by the CellTiter-Glo method.
  • the experimental results show that the compound of the present invention has a strong inhibitory effect on the in vitro proliferation of EML4-ALK and EML4-ALK L1196M mutant cells cultured in vitro.
  • BaF3 parental contains 10 ng/ml IL-3, 0% fetal calf Serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin in RPMI1640 medium
  • Reagents and consumables RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin, liquid ( GIBCO, Cat. No. 15140-122); DMSO (Sigma, Cat. No. D2650); CellTiter-Glo Test Kit (Promega, Cat. No. G7572), 96-well plate (Coming, Cat. No. 3365).
  • the cells in the logarithmic growth phase were diluted with the culture medium to a specific cell concentration, and 90 ⁇ l of the cell suspension was added to the 96-well plate to bring the cell density to the specified concentration. Incubate overnight at 37 ° C in a 5% carbon dioxide gas incubator.
  • the compounds of the present invention were tested in the above cytotoxicity assay and found to have potent activity against Ba/F3ALK and Ba/F3ALK [L1196M].
  • the results of the inhibition of the in vitro proliferation of cancer cells by representative examples are summarized in Table 2 below, wherein A represents IC 50 ⁇ 15 nM, B represents an IC 50 of 15-50 nM, and C represents an IC 50 of 50-500 nM, and D represents The IC 50 is 500-1000 nM, and E indicates an IC 50 of IC 50 >1000 nM.
  • the compounds of the invention are also selective for Ba/F3 ALK and Ba/F3 ALK [L1196M] compared to Ba/F3 parental.
  • compound T-1 has a Ba/F3 ALK/BaF3 parental selectivity greater than 400 and a Ba/F3 ALK [L1196M]/Ba/F3 parental selectivity greater than 200.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de diaminopyrimidine substituée tel que représenté par la formule (I), ou un sel pharmaceutiquement acceptable, une forme cristalline, un promédicament, un métabolite, un hydrate, un solvate, un stéréoisomère ou un dérivé isotopique de celui-ci, et une composition pharmaceutique et son utilisation. Le composé peut être utilisé pour traiter des maladies associées à médiation par ALK telles que le cancer du poumon non à petites cellules, le cancer du sein, les tumeurs neurales, le cancer de l'oesophage, le cancer du tissu mou, le lymphome et la leucémie.
PCT/CN2019/072883 2018-02-07 2019-01-24 Composé de diaminopyrimidine substituée WO2019154091A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201810121641.0 2018-02-07
CN201810121641 2018-02-07
CN201810204028.5 2018-03-13
CN201810204146.6 2018-03-13
CN201810204146 2018-03-13
CN201810204028 2018-03-13

Publications (1)

Publication Number Publication Date
WO2019154091A1 true WO2019154091A1 (fr) 2019-08-15

Family

ID=66895834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/072883 WO2019154091A1 (fr) 2018-02-07 2019-01-24 Composé de diaminopyrimidine substituée

Country Status (2)

Country Link
CN (1) CN109851638B (fr)
WO (1) WO2019154091A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110467637B (zh) * 2018-05-09 2022-02-18 北京赛特明强医药科技有限公司 一种含有氧化膦类取代苯胺的双氨基氯代嘧啶类化合物、制备方法及其应用
CN111836819A (zh) * 2018-05-24 2020-10-27 北京赛特明强医药科技有限公司 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
CN110526915B (zh) * 2018-05-25 2022-02-01 首药控股(北京)股份有限公司 一种间变性淋巴瘤激酶抑制剂的制备方法
CN112239422B (zh) * 2020-10-16 2022-07-22 河北化工医药职业技术学院 一种布格替尼中间体、其盐、其制备方法以及布格替尼的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016410A1 (fr) * 2015-07-27 2017-02-02 苏州明锐医药科技有限公司 Procédé de préparation d'un médicament antitumoral ap26113
WO2018018986A1 (fr) * 2016-07-25 2018-02-01 安润医药科技（苏州）有限公司 Composé de diphénylaminopyrimidine et de triazine, composition pharmaceutique et utilisation de celui-ci
WO2018028721A1 (fr) * 2016-08-09 2018-02-15 厦门大学 Composé thiénopyrimidine, son procédé de préparation, composition pharmaceutique et applications associées

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0321710D0 (en) * 2003-09-16 2003-10-15 Novartis Ag Organic compounds
HUE035029T2 (en) * 2008-05-21 2018-03-28 Ariad Pharma Inc Kinase inhibitor phosphorus derivatives
CN102020522A (zh) * 2009-09-21 2011-04-20 陈松源 氘代药物的制备方法和应用
CN103664726A (zh) * 2012-08-31 2014-03-26 南京华狮化工有限公司 氘代比马前列素或其衍生物、它们的制备方法及其应用
CN104109149B (zh) * 2013-04-22 2018-09-28 苏州泽璟生物制药有限公司 氘代的二氨基嘧啶化合物以及包含该化合物的药物组合物
US10717753B2 (en) * 2015-11-27 2020-07-21 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Deuterium-modified brigatinib derivatives, pharmaceutical compositions comprising same, and use thereof
CN106188138B (zh) * 2015-12-02 2018-07-24 深圳市塔吉瑞生物医药有限公司 一种二氨基嘧啶化合物及包含该化合物的组合物
CN110818690B (zh) * 2016-07-26 2021-08-10 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017016410A1 (fr) * 2015-07-27 2017-02-02 苏州明锐医药科技有限公司 Procédé de préparation d'un médicament antitumoral ap26113
WO2018018986A1 (fr) * 2016-07-25 2018-02-01 安润医药科技（苏州）有限公司 Composé de diphénylaminopyrimidine et de triazine, composition pharmaceutique et utilisation de celui-ci
WO2018028721A1 (fr) * 2016-08-09 2018-02-15 厦门大学 Composé thiénopyrimidine, son procédé de préparation, composition pharmaceutique et applications associées

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof

Also Published As

Publication number Publication date
CN109851638B (zh) 2022-05-31
CN109851638A (zh) 2019-06-07

Similar Documents

Publication Publication Date Title
WO2019154091A1 (fr) Composé de diaminopyrimidine substituée
WO2021057877A1 (fr) Dérivé cyclique condensé aromatique substitué et composition le comprenant et utilisation associée
WO2020114388A1 (fr) Composé pyrazolo[1,5-a]pyridine substitué, composition le contenant et utilisation associée
US11254696B2 (en) Dianilinopyrimidine compound for inhibiting kinase activity
WO2019201194A1 (fr) Composé de pyrrolotriazine substitué, composition pharmaceutique et utilisation associées
WO2019201131A1 (fr) Composé macrocyclique di(hétéro)aryle pour inhiber l'activité de la protéine kinase
EP3560921B1 (fr) Composé de quinazoline et procédé de préparation, utilisation en tant qu'inhibiteur de pi3k pour le traitement des maladies de cancer et composition pharmaceutique correspondantes
US20220194946A1 (en) Fgfr inhibitors and methods of making and using the same
EP3715350B1 (fr) Oxydes d'arylphosphine agissant en tant qu'inhibiteurs de l'activité kinase
WO2019134573A1 (fr) Procédé de préparation d'un composé de diphénylaminopyrimidine deutéré et forme cristalline de celui-ci
WO2022242712A1 (fr) Composé macrocyclique substitué, composition comprenant le composé et son utilisation
WO2020073862A1 (fr) Composé de dihydroimidazopyrazinone, composition le comprenant et son utilisation
WO2019042187A1 (fr) Composé aminopyrimidine, composition le comprenant et utilisation associée
WO2021057796A1 (fr) Dérivé tricyclique condensé substitué et composition et utilisation associées
WO2019228330A1 (fr) Composé de benzo[d]imidazole substitué et composition pharmaceutique associée
WO2021164697A1 (fr) Dérivé d'amide substitué et composition de celui-ci et son utilisation
WO2019001307A1 (fr) Composé amide, composition le contenant, et utilisation associée
WO2017092523A1 (fr) Composé de pyrimidine condensée, composition le comprenant et son utilisation
WO2021185348A1 (fr) Dérivé d'acrylamide substitué et composition et utilisation associée
EP3816162A1 (fr) Composé diarylpyrazole, composition le comprenant et utilisation associée
WO2020168963A1 (fr) Dérivé de cycle aromatique fusionné substitué, composition et utilisation de celui-ci
WO2023216910A1 (fr) Composé hétéroaryle bicyclique substitué utile en tant qu'inhibiteur d'usp1
WO2014154026A1 (fr) Promédicament inhibiteur de pi3k et/ou mtor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19750526

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19750526

Country of ref document: EP

Kind code of ref document: A1