WO2019223671A1 - 取代的氨基喹唑啉类化合物及其药物组合物及其用途 - Google Patents

取代的氨基喹唑啉类化合物及其药物组合物及其用途 Download PDF

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WO2019223671A1
WO2019223671A1 PCT/CN2019/087720 CN2019087720W WO2019223671A1 WO 2019223671 A1 WO2019223671 A1 WO 2019223671A1 CN 2019087720 W CN2019087720 W CN 2019087720W WO 2019223671 A1 WO2019223671 A1 WO 2019223671A1
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compound
deuterium
pharmaceutically acceptable
cancer
acceptable salt
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PCT/CN2019/087720
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English (en)
French (fr)
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王义汉
任兴业
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深圳市塔吉瑞生物医药有限公司
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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

  • the invention belongs to the technical field of medicine, and particularly relates to a substituted aminoquinazoline compound, a pharmaceutical composition containing the compound, and uses thereof. More specifically, this invention relates to certain deuterated 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazoline-6 -Yl) oxy) piperidin-1-yl) prop-2-en-1-one, these deuterium-substituted compounds and compositions thereof can be used to treat and / or prevent ErbB family tyrosine kinases (e.g.
  • Protein kinases represent a large class of proteins that play an important role in maintaining control of cell functions and regulating various cellular diseases. Protein tyrosine kinases can be classified as growth factor receptor (such as VEGFR, EGFR, PDGFR, FGFR, and erbB2) or non-receptor (such as c-src and bcr-abl) kinases. Receptor-type tyrosine kinases can be divided into 20 different subtypes; non-receptor-type tyrosine decryption also has many subtypes. Receptor tyrosine kinases are a large class of enzymes that enable growth factors to maintain extracellular binding regions across cell membranes. Transmembrane regions and intracellular parts function as kinases and phosphorylate on a specific protein tyrosine residue. Thus affecting cell proliferation. Variant or inappropriate protein kinase activity can lead to worsening of the condition.
  • growth factor receptor such as VEGFR,
  • Epidermal growth factor receptor is a receptor-type tyrosine kinase with four receptor subtypes, namely EGFR (ErbB-1), HER2 / c-neu (ErbB-2) , Her3 (ErbB-3) and Her4 (ErbB-4).
  • EGFR ErbB-1
  • HER2 / c-neu ErbB-2
  • Her3 ErbB-3
  • Her4 ErbB-4
  • Normal EGFR-activated signaling pathways can regulate cell proliferation, angiogenesis, growth, migration, and adhesion, and play an important role in organogenesis or adult-cell interactions.
  • Many molecules can lead to the continuous activation of EGFR kinase activity, continuously triggering a large number of downstream signal transduction pathways, including K-ras activation. Therefore, the EGFR family is closely related to tumor formation.
  • EGFR overexpression or mutations can be detected in a variety of cancers, including head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, and brain tumor. This poor prognosis.
  • Her2 is considered to be a strong tumor protein, and its mutations are also seen in many tumors, especially breast cancer, lung cancer and colon cancer.
  • Poziotinib (aka HM-78136, chemical name is 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl ) Oxy) piperidin-1-yl) prop-2-en-1-one, which has the following structural formula) is a new oral quinazoline broad-spectrum developed by Hanmi Pharmaceutical (Inc) of South Korea- ErbB inhibitors can irreversibly block the signaling pathways of ErbB family tyrosine kinase receptors (including EGFR, Her2, and Her4), thereby inhibiting the proliferation of tumor cells that overexpress these receptors.
  • ErbB family tyrosine kinase receptors including EGFR, Her2, and Her4
  • Poziotinib can effectively inhibit EGFR and Her2 exon 20 insertion mutations (EGFR and Her2 exon 20 mutations, That is, EGFR and Her2 Ex20Insmutants).
  • EGFR and Her2 exon 20 mutations that is, EGFR and Her2 Ex20Insmutants.
  • Poziotinib's inhibitory effect on EGFR Ex20Ins mutation is significantly better than its typical EGFR T790M mutation.
  • Poziotinib's phase II clinical research results show that it can effectively inhibit the EGFR Ex20Ins mutation, which is far more than the expected efficacy of 64%.
  • ADME absorption, distribution, metabolism, and / or excretion
  • Poziotinib as a broad-spectrum ErbB inhibitor, can effectively treat cancers mediated by ErbB family tyrosine kinase receptors, there are still serious clinical unmet needs in this field, and it is found that there is a treatment for New compounds with c-neu (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4) wild-type and mutant kinase-mediated diseases that have good oral bioavailability and are druggable are still challenging Sex work.
  • the present invention discloses a new type of deuterium substituted aminoquinazoline compound and its composition and use, which have better EGFR / ErbB1, Her-2 / ErbB2, Her-3 / ErbB3 or Her-4 / ErbB4 kinase inhibitory activity, and higher inhibitory activity and selectivity for one or more selected from T790M mutation, L858R mutation, del19 mutation, C797S mutation or Ex20Ins mutation, while having lower side effects Better pharmacokinetic properties, can be used to treat ErbB family tyrosine kinase-mediated diseases.
  • compound of the present invention refers to a compound represented by formula (I).
  • the term also includes pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants of a compound of formula (I).
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • 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 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compounds contain at least one deuterium atom
  • 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.
  • a compound of the invention is provided in a therapeutically effective amount.
  • a compound of the invention is provided in a prophylactically effective amount.
  • the pharmaceutical composition further contains another therapeutic agent selected from the group consisting of a cell signal transduction inhibitor, a mitotic inhibitor, an alkylating agent, an antimetabolite, an antibiotic, and a growth agent.
  • Factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones and antiandrogens are examples of a cell signal transduction inhibitor, a mitotic inhibitor, an alkylating agent, an antimetabolite, an antibiotic, and a growth agent.
  • the present invention provides a method for preparing 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 also relates to a method of treating and / or preventing an ErbB family tyrosine kinase-mediated disease in a subject.
  • the method includes administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the ErbB family tyrosine kinase is selected from one or more of the wild-type and mutant of EGFR, Her2, Her3 or Her4 kinase.
  • the EGFR mutant is selected from one or more of a T790M mutation, a L858R mutation, a del19 mutation, a C797S mutation, or an Ex20Ins mutation.
  • the Her2 mutant is selected from the Ex20Ins mutation.
  • the proliferative disease is metastatic cancer, epidermal cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer, pancreas Cancer, cancer of the central nervous system, malignant glioma, myelodysplastic disease, atherosclerosis or pulmonary fibrosis.
  • the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • deuterated refers to the replacement of one or more hydrogens in a compound or group with deuterium; deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuterated and “one or more deuterated” are used interchangeably.
  • non-deuterated compound refers to a compound containing a deuterium atomic proportion not higher than the natural deuterium isotope content (0.015%).
  • pharmaceutically acceptable salt means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergies, etc., and with reasonable benefits / dangers Proportion of those salts.
  • 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 salts derived from suitable inorganic and organic acids and bases.
  • the compounds of the invention may be in amorphous or crystalline form.
  • 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 different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • crystalline form refers to different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • the term "subject” includes, but is not limited to: a human (ie, a male or female of any age group, for example, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults)) and / or non-human animals, for example, mammals, for example, primates (for example, 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 specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder, or condition. Or development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest.
  • the effective amount of a compound of the present invention can vary depending on factors such as the biological objective, the pharmacokinetics of the compound, the disease to be 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 during the treatment of a disease, disorder, or condition, or one or more of which is associated with the disease, disorder, or condition. Symptoms are delayed or minimized.
  • 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” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
  • a prophylactically effective amount of a compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent a disease , The number of recurrences 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 preventative benefit in the prevention of a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the preventive efficacy of other preventive agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously in a single unit dosage form with another therapeutic agent.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • 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 is independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium in the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more Preferably it is greater than 95%, more preferably greater than 99%.
  • the deuterium isotope content in each deuteration position is at least 5%, preferably more than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25 %, More preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater 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 greater than 99%.
  • the compound of formula (I) contains at least one deuterium atom, more preferably one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, More preferably five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms, even more preferably ten deuterium atoms, more preferably Eleven deuterium atoms, more preferably twelve deuterium atoms, more preferably thirteen deuterium atoms, more preferably fourteen deuterium atoms, more preferably fifteen deuterium atoms, and more preferably sixteen deuterium atoms Atoms, preferably seventeen deuterium atoms, more preferably eighteen deuterium atoms, more preferably nineteen deuterium atoms, and more preferably twenty deuterium atoms.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl” includes Y 1 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, Y 2 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, Y 3 is selected from hydrogen, deuterium, halogen, or trifluoromethyl, and so on, until Y 8 is selected from the group consisting of hydrogen, deuterium, halogen or trifluoromethyl.
  • Y 1 is hydrogen, Y 1 is deuterium, Y 1 is halogen (F, Cl, Br, or I) or Y 1 is trifluoromethyl
  • Y 2 is hydrogen, Y 2 is deuterium, and Y 2 is Halogen (F, Cl, Br or I) or Y 2 is trifluoromethyl
  • Y 3 is hydrogen, Y 3 is deuterium, Y 3 is halogen (F, Cl, Br or I) or Y 3 is trifluoromethyl
  • Y 8 is hydrogen, Y 8 is deuterium, Y 8 is halogen (F, Cl, Br or I) or Y 8 is trifluoromethyl.
  • 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
  • R 1 It is selected from hydrogen or deuterium
  • R 2 is selected from hydrogen or deuterium
  • R 3 is selected from hydrogen or deuterium, and so on, until R 9 is selected from hydrogen or deuterium. More specifically, including R 1 is hydrogen, R 1 is deuterium, R 2 is hydrogen, R 2 is deuterium, R 3 is hydrogen, R 3 is deuterium, and so on, until R 9 is hydrogen and R 9 is deuterium.
  • Technical solutions including R 1 is hydrogen, R 1 is deuterium, R 2 is hydrogen, R 2 is deuterium, R 3 is hydrogen, R 3 is deuterium, and so on, until R 9 is hydrogen and R 9 is deuterium.
  • the technical scheme of “X is independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D” includes a technical scheme of X selected from CH 3 , CD 3 , CHD 2 or CH 2 D. More specifically, technical solutions including X is CH 3 , X is CD 3 , X is CHD 2, or X is CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 1 -Y 8 are each independently selected from hydrogen or deuterium
  • X and R 1 -R 9 are as defined above, with the additional condition that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 1 to Y 8 are each independently selected from hydrogen or deuterium
  • X is selected from CD 3 or CH 3
  • R 1 to R 9 are as defined above, with the additional condition that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 3 -Y 8 are both hydrogen
  • Y 1 and Y 2 are each independently selected from hydrogen or deuterium
  • X and R 1 -R 9 are as defined above, with the additional condition that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 3 -Y 8 are both hydrogen
  • Y 1 and Y 2 are each independently selected from hydrogen or deuterium
  • R 1 -R 9 are as defined above
  • X is selected from CD 3 or CH 3 , with the additional condition that the compound Contains at least one deuterium atom.
  • R 2 -R 5 are the same.
  • R 6 -R 9 are the same.
  • R 2 -R 9 are the same.
  • R 1 is hydrogen
  • R 1 is is deuterium
  • X is CD 3.
  • X is CH 3.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 2 is deuterium
  • Y 1 and R 1 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 6 -R 9 are hydrogen
  • Y 1 , Y 2 and R 1 -R 5 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, with the additional condition that: These compounds contain at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • Y 2 is deuterium
  • R 6 -R 9 are hydrogen
  • Y 1 and R 1 -R 5 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 2 -R 5 are deuterium
  • Y 1 , Y 2 , R 1 and R 6 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 2 -R 5 and Y 2 are deuterium
  • Y 1 , R 1 and R 6 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 2 -R 5 is deuterium
  • R 6 -R 9 is hydrogen
  • Y 1 , Y 2 and R 1 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 2 -R 5 and Y 2 are deuterium
  • R 6 -R 9 are hydrogen
  • R 1 is selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 1 is deuterium
  • Y 1 , Y 2 and R 2 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 1 is deuterium
  • Y 2 is deuterium
  • Y 1 and R 2 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 1 is deuterium
  • R 6 -R 9 are hydrogen
  • Y 1 , Y 2 and R 2 -R 5 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 1 -R 5 are deuterium
  • Y 1 , Y 2 and R 6 -R 9 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, R 1 is deuterium, Y 2 is deuterium, R 6 -R 9 are hydrogen, and Y 1 and R 2 -R 5 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Wherein R 1 -R 5 is deuterium, Y 2 is deuterium, and Y 1 and R 6 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • R 1 -R 5 are deuterium
  • R 6 -R 9 are hydrogen
  • Y 1 and Y 2 are each independently selected from hydrogen or deuterium
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, R 1 -R 5 is deuterium, Y 2 is deuterium, R 6 -R 9 is hydrogen, Y 1 is selected from hydrogen or deuterium, and X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • X is CD 3
  • Y 1 , Y 2 and R 1 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , Y 2 is deuterium, and Y 1 and R 1 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Wherein X is CD 3 , R 6 -R 9 are hydrogen, and Y 1 , Y 2 and R 1 -R 5 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , Y 2 is deuterium, R 6 -R 9 are hydrogen, and Y 1 and R 1 -R 5 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof,
  • X is CD 3
  • R 2 -R 5 are deuterium
  • Y 1 , Y 2 , R 1, and R 6 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 2 -R 5 are deuterium, Y 2 is deuterium, and Y 1 , R 1 and R 6 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 2 -R 5 are deuterium, R 6 -R 9 are hydrogen, and Y 1 , Y 2 and R 1 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , Y 2 is deuterium, R 2 -R 5 is deuterium, R 6 -R 9 is hydrogen, and Y 1 and R 1 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 1 is deuterium, and Y 1 , Y 2 and R 2 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 1 is deuterium, Y 2 is deuterium, and Y 1 and R 2 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 1 is deuterium, R 6 -R 9 are hydrogen, and Y 1 , Y 2 and R 2 -R 5 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , Y 2 is deuterium, R 1 is deuterium, R 6 -R 9 are hydrogen, and Y 1 and R 2 -R 5 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, wherein X is CD 3 , R 1 -R 5 are deuterium, and Y 1 , Y 2 and R 6 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, Among them, X is CD 3 , R 1 -R 5 are deuterium, Y 2 is deuterium, and Y 1 and R 6 -R 9 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, wherein X is CD 3 , R 1 -R 5 are deuterium, R 6 -R 9 are hydrogen, and Y 1 and Y 2 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystalline form, stereoisomer or isotope variant thereof, wherein X is CD 3 , Y 2 is deuterium, R 1 -R 5 is deuterium, R 6 -R 9 is hydrogen, and Y 2 is selected from hydrogen or deuterium.
  • the compound has any one of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, This includes racemic mixtures and mixtures rich in one or more stereoisomers.
  • Isomers can be separated from a mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds can form complexes with solvents that react in the solvent or precipitate or crystallize from the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called a "hydrate”. The invention encompasses all solvates of the compounds of the invention.
  • solvate refers to the form of a compound or a salt thereof in combination with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • the "solvate” includes a solvate in a solution state and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than 0.
  • a given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • the compounds of the invention may be in an amorphous or crystalline form (polymorphic form).
  • 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.
  • polymorph refers to a crystalline form (or a salt, hydrate, or solvate) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the predominance of a crystalline form.
  • Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Thallium, i.e. 3 H and carbon-14, i.e. 14 C isotopes, are particularly preferred because they are easy to prepare and detect.
  • An isotope-labeled compound of the formula (I) of the present invention and a prodrug thereof can generally be prepared in such a manner that, when performing the processes disclosed in the following schemes and / or examples and preparation examples, non-isotope-labeled reagents are replaced with readily available isotopically-labeled reagents. Labeled reagent.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect in vivo by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs, 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, or drug, delivery: solubility, limitation, overcome, and use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each article introduced This article is for reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in vivo.
  • Prodrugs are usually prepared by modifying functional groups, and the modification is performed in a manner such that the modification can be performed by routine manipulation or cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxy, amino, or thiol group is bonded to an arbitrary group, and when administered to a patient, can be cleaved to form a hydroxy, amino, or thiol group.
  • prodrugs include, but are not limited to, acetate, amide, formate / amide, and benzoate / amide derivatives of hydroxyl, thiol, and amino functional groups of the compound of formula (I).
  • a carboxylic acid -COOH
  • an ester such as methyl ester, ethyl ester, or the like can be used.
  • the esters themselves can be active and / or can be hydrolyzed under conditions in the human body.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups that readily break down in the human body to release the parent acid or its salt.
  • the compounds of the invention can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic pathways, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be performed in a suitable solvent, and those skilled in the art of organic synthesis can easily select a solvent.
  • Suitable solvents may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is performed (eg, a temperature in the range of the solvent freezing temperature to the solvent boiling temperature).
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • the skilled person can select a solvent for a specific reaction step depending on the specific reaction step.
  • the preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the selection of an appropriate protecting group.
  • the chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups, Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the reaction can be monitored according to any suitable method known in the art.
  • spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry (MS)), or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the following general preparation route can be used to synthesize compounds of formula (I) of the present invention.
  • the synthetic route is as follows:
  • compositions preparations and kits
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of an active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds 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 (such as human serum albumin ), Buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embe
  • kits eg, pharmaceutical packaging.
  • the provided kits can include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other Suitable container).
  • the provided kit may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and / or other therapeutic agent.
  • a compound of the invention and other therapeutic agents are provided in a first container and a second container to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, and sternal administration , Cerebrospinal spinal membrane 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 .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically based on and under the supervision of a physician, at a dosage level as described above.
  • Subjects at risk for developing a particular disorder typically include subjects with a family history of the disorder, or those who are determined by genetic testing or screening to be particularly sensitive to the development of the disorder.
  • the pharmaceutical compositions provided herein can also be administered chronically ("long-term administration").
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the remainder of a subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • the pharmaceutical composition may be administered by bolus, for example, to rapidly 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, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, whereas a bolus delivered directly to a vein (e.g., by IV intravenous drip) can be more Rapid delivery allows the concentration of the active ingredient in the blood to rise quickly to an effective level.
  • the pharmaceutical composition can be administered in the form of a continuous infusion, e.g., by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of a liquid solution or suspension in bulk or a powder in bulk. However, more generally, to facilitate accurate dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is each useful for forming a desired administration form A carrier or excipient and processing aid.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.
  • transdermal doses are usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour.
  • a preloaded bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be given.
  • the maximum total dose cannot exceed about 2 g / day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and 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 compounds having similar properties: a binder, such as microcrystalline cellulose, tragacanth, or gelatin; an excipient, such as starch or lactose, a disintegrant, For example, alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, water Methyl salicylate or orange flavor.
  • a binder such as microcrystalline cellulose, tragacanth, or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing an active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffin or a water-miscible ointment base.
  • the active ingredient may 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 components for enhancing the 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 achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Section 8 of Remington's Pharmaceuticals, Science, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system.
  • sustained-release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to a pharmaceutically acceptable formulation of a compound of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrin consisting of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or more substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, a sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention are useful for treating human or non-human ErbB family tyrosine kinase-mediated proliferative diseases.
  • the ErbB family tyrosine kinase is selected from the group consisting of EGFR / ErbB1, Her-2 / ErbB2, Her-3 / ErbB3, or Her-4 / ErbB4.
  • the compounds of the invention are inhibitors of wild-type or at least one mutant of EGFR and are therefore suitable for treatment with one or more EGFR wild-type or mutants (e.g., deletion mutations, activation mutations, resistance mutations, or combinations thereof), Specific examples include T790M mutation, L858R mutation, del19 mutation, C797S, L858R / T790M double mutation, del19 / T790M double mutation, L858R / T790M / C797S triple mutation, del19 / T790M / C797S triple mutation, Ex20Ins mutation). One or more conditions.
  • the present invention provides a method for treating an EGFR wild-type or mutation-mediated disorder, which comprises administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, stereo Isomers, solvates, hydrates, crystalline forms, prodrugs or isotopic derivatives, or the steps of administering a pharmaceutical composition according to the invention.
  • the compounds of the invention are inhibitors of wild-type or at least one mutant of Her2 and are therefore suitable for treatment with one or more Her2 wild-type or mutants (e.g., deletion mutations, activation mutations, resistance mutations, or combinations thereof, Specific examples include one or more disorders related to the activity of the Ex20Ins mutation). Therefore, in a specific embodiment, the present invention provides a method for treating a Her2 wild-type or mutation-mediated disorder, which comprises administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt, stereo Isomers, solvates, hydrates, crystalline forms, prodrugs or isotopic derivatives, or the steps of administering a pharmaceutical composition according to the invention.
  • a pharmaceutically acceptable salt, stereo Isomers, solvates, hydrates, crystalline forms, prodrugs or isotopic derivatives or the steps of administering a pharmaceutical composition according to the invention.
  • EGFR TKIs EGFR tyrosine kinase inhibitors
  • classic mutations such as del19 mutations, L858R mutation
  • PFS progression-free survival
  • nearly 10 to 20% of EGFR-mutated non-small cell lung cancer tumors have the EGFR Ex20Ins mutation (EGFR exon20insertion mutation).
  • the EGFR Ex20Ins mutation is also the cause of resistance to existing EGFR TKIs.
  • historical clinical data shows that the response rate of approved EGFR TKIs to EGFR Ex20Ins mutations is only 8.7-11%, and progression-free survival (PFS) is only 2.4-2.7 months.
  • PFS progression-free survival
  • 3% of non-small cell lung cancers are caused by Her2 mutations, and 90% of Her2 mutations are Ex20Ins.
  • patients with EGFR and Her2 Ex20Ins mutations are excluded from clinical trials due to the lack of effective targeted drugs, which indicates the urgent need for new targeted drugs to treat these patients.
  • EGFR D770_N771insSVD InsSVD
  • HER2 A775_G776insYVMA InsYVMA
  • EGFR D770_N771insSVD is the most common mutation in EGFR Ex20Ins mutation
  • HER2AA775_G776insYVMA accounts for 80% of Hers2 Is its main mutation.
  • the test results show that the compound of the present invention can effectively inhibit EGFR and Her2 Ex20Ins mutations, and can be used to treat diseases with EGFR and Her2 Ex20Ins mutations.
  • the compounds of the present invention will be applied to, but by no means limited to, the use of an effective amount of a compound or composition of the present invention to a patient to prevent or treat a patient's proliferative disease.
  • diseases include cancer, especially metastatic cancer, non-small cell lung cancer, breast cancer, head and neck cancer, and epidermal cancer.
  • the compounds of the present invention will be applied to the treatment of tumors including cancer and metastatic cancer, further including, but not limited to, cancers such as epidermal cancer, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), Esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocytic leukemia, acute Lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia, and Burkitt's lymphoma); bone marrow system hematopoietic tumors ( Including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic le
  • the compounds of the present invention are also useful in the treatment of ophthalmic conditions such as corneal transplant rejection, neovascularization of the eye, retinal neovascularization including neovascularization after injury or infection; diabetic retinopathy; post lens lens fibrous hyperplasia, and neovascularization Glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcers; pathological but non-malignant conditions such as hemangiomas, including infant hemangioendothelial cell tumors, nasopharyngeal and angiofibromas without vascular necrosis; System disorders such as endometriosis. These compounds are also used to treat conditions such as edema and vascular permeability.
  • the compounds of the invention can be used to treat conditions associated with diabetes such as diabetic retinopathy and microangiopathy.
  • the compounds of the present invention are also useful in situations where blood flow is reduced in cancer patients.
  • the compounds of the present invention also have beneficial effects on reducing tumor metastasis in patients.
  • the compounds of the present invention can also be applied to veterinary treatment of pets, introduced animals and farm animals, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats.
  • the compound of the present invention includes a pharmaceutically acceptable derivative thereof.
  • the compounds of the invention can be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combination causes an acceptable adverse reaction, which has implications for the treatment of hyperproliferative diseases such as cancer Special meaning.
  • the compounds of the present invention can be combined with known cytotoxic agents, single transduction inhibitors or other anticancer agents, and mixtures and combinations thereof.
  • the normal administration of an additional therapeutic agent to treat a particular disease is known as "appropriate treatment of a disease.”
  • the "additional therapeutic agent" used in the present invention includes a chemotherapeutic drug or other anti-proliferative drug, which can be used in combination with the compound of the present invention to treat a proliferative disease or cancer.
  • Chemotherapy drugs or other antiproliferative drugs include histone deacetylase (HDAC) inhibitors, including, but not limited to, SAHA, MS-275, MGO103, and those compounds described in the following patents: WO2006 / 010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO00 / 71703, WO01 / 38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005 / 030705, WO 2005/092899 , And demethylation reagents include, but are not limited to, 5-azaaza-2′-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine (Decitabine) and the following Compounds described in the literature: US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US 6,020
  • chemotherapeutic drugs or other anti-proliferative drugs can be combined with compounds of the invention to treat proliferative diseases and cancer.
  • chemotherapeutic drugs include, but are not limited to, other therapies or anticancer agents can be combined with the anticancer agents of the present invention and include surgery, radiation therapy (a few examples such as gamma radiation, neutron beam radiation therapy, electron beam radiation therapy) , Proton therapy, brachytherapy and system radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), derivatives of platinum, biological response modifiers (interferon, interleukins, tumors Necrosis factor (TNF), TRAIL receptor targeting and vehicle), hyperthermia and cryotherapy, agents that dilute any adverse reactions (such as antiemetics), and other approved chemotherapeutic drugs, including but not limited to, alkane Drugs (nitrogen mustard, phenylbutyrate nitrogen mustard, cyclophosphamide, phen
  • Anti-angiogenic factors (Avastin and others), kinase inhibitors (Imatinib, Sutent, Nexavar, Cetuximab (Erbitux) ), Herceptin, Tarceva, Iressa and others).
  • Drugs inhibit or activate cancer pathways such as the mTOR, HIF (Hypoxia Inducible Factor) pathway and others.
  • HIF Hydrofluoxia Inducible Factor
  • the compounds of the invention can be combined with cytotoxic anticancer agents.
  • cytotoxic anticancer agents can be found in the thirteenth edition of the Merck Index (2001).
  • anticancer agents include, but are not limited to, Asparaginase, Bleomycin, Carboplatin, Carmustine, Chlorambucil, Cisplatin, L-asparaginase (Colaspase), cyclophosphamide, Cytarabine, dacarbazine, Actinomycin D (Dactinomycin), Daunorubicin, Adriamycin ( Doxorubicin), Epirubicin, Etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, cyclohexyl Nitrourea, nitrogen mustard, 6-mercaptopurine, Mesna, Methotrexate, Mitomycin C, Mitoxantrone, Prednisolone ),
  • cytotoxic drugs used in combination with the compounds of the present invention include, but are not limited to, these compounds that are generally recognized for the treatment of neoplastic diseases, as described in the following literature: Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.); these anticancer agents include, but are not limited to, Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine , Cladribine, Busulfan, Diethylstilbestrol, 2 ′, 2′-Difluorodeoxycytokine, Docetaxel, Erythrohydroxynonyladenine, Ethylestradiol Diols, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine monophosphate, Fludarabine phosphate, Fluoxymesterone, Flutamide, Hydroxyprogesterone hexanoate, Iran Idarubicin, interferon,
  • the compounds of the invention can be combined with other signal transduction inhibitors.
  • signal transduction inhibitors target the EGFR family, such as EGFR, HER-2 and HER-4 and their respective ligands.
  • Such agents include, but are not limited to, antibody therapies such as Herceptin (trastuzumab), Cetuximab (Erbitux), and Pertuzumab.
  • Such therapies also include, but are not limited to, small molecule kinase inhibitors such as Gefitinib, Erlotinib, Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788.
  • the compounds of the present invention are combined with other signal transduction inhibitors to target receptor kinases (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) in the family of division kinases. ), And their respective ligands.
  • target receptor kinases VDGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.
  • Such agents include, but are not limited to, antibodies such as bevacizumab (Avastin).
  • Such agents include, but are not limited to, small molecule inhibitors such as Gleevec / Imanitib, Sprycel (Dasatinib), Tasigna / Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787 / ZK222584), Telatinib / BAY-57-9352, BMS- 690514, BMS-540215, Axitinib / AG-013736, ZD-6474, KRN-951, CP-547,632, CP-673,451, CHIR-258, MLN-518.
  • small molecule inhibitors such as Gleevec / Imanitib, Sprycel (Dasatinib), Tasigna / Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787 / ZK222584), Telatinib / BAY-57-9352, BMS- 690514, BMS-540215, Ax
  • the compounds of the invention can bind histone deacetylase inhibitors.
  • histone deacetylase inhibitors include, but are by no means limited to, suberylanilide hydroxamic acid (SAHA), LAQ-824, LBH-589, MS-275, FR-901228, and MGCDOI03.
  • the compounds of the invention can be combined with other anticancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are not limited to, bortezomib and CCI-779.
  • the compounds of the present invention may also be combined with other anticancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.
  • Those additional therapeutic agents may be administered separately from a composition comprising a compound of the invention as part of a multiple dosing regimen.
  • those therapeutic agents may be part of a single dosage form, mixed with a compound of the invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other simultaneously or continuously over a period of time to achieve the target agent activity.
  • each reaction is usually performed in an inert solvent at room temperature to reflux temperature (for example, 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.
  • TBU deuterated chloroform
  • compound 1 10 g, 50.2 mmol
  • the reaction solution was stirred at room temperature for 24 hrs.
  • the reaction solution was neutralized with 1M dilute hydrochloric acid, and then extracted with dichloromethane.
  • the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.02 g of a yellow solid, which was directly used in the next step.
  • TsCl (3.52 g) was added to a solution of the above compound 5 (3.1 g), DMAP (62 mg) and TEA (3.23 mL) in dry dichloromethane (40 mL), and the mixture was allowed to react in a greenhouse overnight.
  • the reaction solution was extracted and washed with saturated brine (20 mL), saturated sodium carbonate solution (10 mL) and water (20 mL).
  • the organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate.
  • phosphorus oxychloride 5mL was added dropwise to a toluene (45ml) solution of compound 6 (5g) and DIPEA (4.13ml) within 20min. After the dropwise addition was completed, the reaction solution was stirred at the current temperature. 3hrs. After the reaction was completed, it was directly used in the next step.
  • Example 5 (4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1 -Base-3,3,5,5-d 4 ) Preparation of prop-2-en-1-one (compound I-1).
  • Example 7 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidine-1 -Base-3,3,4,5,5-d 5 ) Preparation of prop-2-en-1-one (compound I-3).
  • the intermediate compound B-1 in step 1 was replaced with the intermediate compound B-2, and A was replaced with N-Boc-4- (4-toluenesulfonyloxy) piperidine.
  • -1 was prepared to obtain 130 mg of a white solid compound I-4 with a yield of 51.92% and a purity of 99.15% (HPLC).
  • LC-MS (APCI): m / z 496.2 (M + 1) + .
  • Triphenyl phosphorus (26 g) and CD 3 OD (7.8 mL) were added to a solution of methyl 3,4-dimethoxybenzoate (compound 13, 15 g) in dry tetrahydrofuran (90 mL) at room temperature, respectively. Under nitrogen protection, the mixture was stirred at room temperature, and then diisopropyl azodicarboxylate (DIAD, 20 mL) was slowly added dropwise to the above reaction system, and the reaction was stirred at room temperature for 3 hrs. The THF was removed under reduced pressure, diluted with water, and extracted with ethyl acetate (150 mL x 3).
  • DIAD diisopropyl azodicarboxylate
  • phosphorus oxychloride (1.08mL) was added dropwise to a toluene (10ml) solution of compound 19 (1.1g) and DIPEA (4.130.95mL) within 20min. After the dropwise addition was completed, the reaction solution was Stir at temperature for 3hrs. After the reaction was completed, it was directly used in the next step.
  • Example 12 4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7- (methoxy-d 3 ) quinazolin-6-yl) oxy ) Piperidin-1-yl) propan-2-yl Preparation of enen-1-one (Compound I-6).
  • the intermediate compound B-1 in step 1 was replaced with the intermediate compound B-3, and 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylic acid tertiary was used.
  • Butyl ester was prepared instead of the intermediate compound A-1 in step 1 to obtain 135 mg of a white solid compound I-6 with a yield of 64.30% and a purity of 96.41% (HPLC).
  • LC-MS (APCI): m / z 494.2 (M + 1) + .
  • Example 13 4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7- (methoxy-d 3 ) quinazolin-6-yl) oxy Piperidin-1-yl-4-d) Preparation of prop-2-en-1-one (compound I-7).
  • the intermediate compound B-3 was used in place of the intermediate compound B-1 in step 1, and the intermediate compound A-2 was used in place of the intermediate compound A-1 in step 1.
  • 60 mg of a white solid was obtained with a yield of 48.89% and a purity of 98.69% (HPLC).
  • LC-MS (APCI): m / z 495.2 (M + 1) + .
  • the intermediate compound B-3 was used in place of the intermediate compound B-1 in step 1, and the intermediate compound A-3 was used in place of the intermediate compound A-1 in step 1.
  • 72 mg of white solid compound I-8 was obtained with a yield of 42.81% and a purity of 99.51% (HPLC).
  • LC-MS (APCI): m / z 499.2 (M + 1) + .
  • Example 15 4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7- (methoxy-d3) quinazolin-6-yl) oxy) Piperidin-1-yl -3,3,5,5-d4) Preparation of prop-2-en-1-one (compound 1-9).
  • the intermediate compound B-3 was used in place of the intermediate compound B-1 in step 1 to obtain 50 mg of a white solid compound I-9 with a yield of 34.29% and a purity of 99.07. % (HPLC).
  • LC-MS (APCI): m / z 498.2 (M + 1) + .
  • ADP-GloTM Kinase Assay Kit (Promega, V9102) kit was used to determine the inhibitory activity of the test substance on EGFR (D770_N771insNPG) (Signalchem, E-10-132GG) and HER2 (A775_G776insYVMA) (Signalchem, E27-13BG).
  • the final reaction concentration in the system is: 0.5nM EGFR or 10nM HER2, 10 ⁇ M ATP, 0.03mg / mL Poly (4: 1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl2 10mM, Brij35 0.01%.
  • Test compound concentration 1,0.33, 0.11,0.037, 0.0123, 0.004, 0.0014, 0.00047, 0.00015, 0.00005, 0.00017, 0nM. Then add 10 ⁇ L ADP Glo reagent and continue incubation at 25 ° C for 40 minutes.
  • the enzyme activity was measured by Envision microplate reader (Perkin Elmer 2104) to determine the enzyme activity in the presence of each concentration of compound, and the inhibitory activity of the compound at different concentrations on the enzyme activity was calculated. Then according to the four-parameter equation, according to Graphpad 5.0 software, the inhibitory activity of the enzyme activity under different concentrations of compounds was fitted to calculate the IC 50 value.
  • the compound of the present invention was tested in the above kinase inhibition experiment, and it was found that the compound of the present invention has a considerably stronger inhibitory effect on EGFR D770_N771insNPG and HER2 A775_G776insYVMA kinase than the non-deuterated parent compound Pozoitinib, indicating that the compound of the present invention has Exon 20 insertion mutations in EGFR and HER2 have more potent activity.
  • Table 1 The results for representative example compounds are summarized in Table 1 below.
  • lung cancer cells NCI-H1975 (purchased from the American Standard Biological Collection Center (ATCC)), Ba / F3 EGFR-D770_N771insSVD and Ba / F3 ERBB2-A775_G776insYVMA logarithmic growth phase cells, and trypan blue exclusion method to detect cell viability to ensure Cell viability is above 90%.
  • Cells were seeded into 96-well plates and cultured at 37 ° C, 5% CO 2 overnight. Prepare a 10-fold drug solution with a maximum concentration of 10 ⁇ M, 9 concentrations, and a 3-fold dilution. Add 10 ⁇ L of the drug solution to each well of the 96-well plate, three duplicate wells, and continue the culture for 72 hours.
  • the compound of the present invention was tested in the above kinase inhibition experiment, and it was found that the compound of the present invention has stronger resistance to NCI-H1975, Ba / F3 EGFR-D770_N771insSVD and Ba / F3 ERBB2-A775_G776insYVMA than the non-deuterated parent compound Pozoitinib.
  • the inhibitory effect indicates that the compound of the present invention has potent activity on EGFR T790M mutation, exon 20 insertion mutation of EGFR and HER2.
  • Table 2 The results of representative example compounds are summarized in Table 2 below.
  • Microsomal experiments human liver microsomes: 0.5mg / mL, Xenotech; rat liver microsomes: 0.5mg / mL, Xenotech; mouse liver microsomes: 0.5mg / mL, Xenotech; coenzyme (NADPH / NADH): 1mM , Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).
  • Preparation of the stock solution A certain amount of powder of the example compound and the reference compound was precisely weighed, and dissolved to 5 mM with DMSO, respectively.
  • phosphate buffer solution 100 mM, pH 7.4.
  • NADPH regeneration system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U / mL G-6-PD, 3.3mM magnesium chloride), and place on wet ice before use.
  • stop solution an acetonitrile solution containing 50ng / mL propranolol hydrochloride and 200ng / mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer solution (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.
  • phosphate buffer solution pH 7.4
  • phosphate buffer solution (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L SD rat liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.
  • phosphate buffer solution (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of mouse liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.
  • Determination of metabolic stability 300 ⁇ L of pre-cooled stop solution was added to each well of a 96-well deep well plate, and placed on ice as a stop plate. Place the 96-well incubation plate and NADPH regeneration system in a 37 ° C water bath, shake at 100 rpm, and pre-incubate for 5 minutes. Take 80 ⁇ L of the incubation solution from each well of the incubation plate and add it to the termination plate, mix well, and add 20 ⁇ L of NADPH regeneration system solution as a 0min sample. Add 80 ⁇ L of NADPH regeneration system solution to each well of the incubation plate, start the reaction, and start timing.
  • the reaction concentration of the corresponding compound was 1 ⁇ M, and the protein concentration was 0.5 mg / mL.
  • 100 ⁇ L of each reaction solution was taken, added to the stop plate, and the reaction was stopped by vortexing for 3 minutes.
  • the stop plate was centrifuged at 5000 ⁇ g for 10 min at 4 ° C. Take 100 ⁇ L of the supernatant into a 96-well plate pre-added with 100 ⁇ L of distilled water, mix well, and use LC-MS / MS for sample analysis.
  • the compounds of the present invention and their non-deuterated compounds were tested and compared simultaneously to evaluate their metabolic stability in human and rat liver microsomes.
  • the non-deuterated compound Poziotinib was used as a control.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Poziotinib.
  • Table 3 The results for the representative example compounds are summarized in Table 3 below.
  • Rats were raised on a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide.
  • Orbital blood was collected at 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 anesthetized briefly after inhaling ether, and 300 ⁇ L of blood samples were collected in test tubes from the orbit.
  • the test tube contained 30 ⁇ L of a 1% heparin salt solution. Before use, test tubes were dried at 60 ° C overnight. After blood samples were collected at the last time point, rats were sacrificed after ether anesthesia.
  • the blood sample was centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate the plasma from the red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube with the name and time point of the compound. Plasma was stored at -80 ° C before analysis. LC-MS / MS was used to determine the concentration of a compound of the invention in plasma. Pharmacokinetic parameters were calculated based on the blood drug concentration of each animal at different time points.

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Abstract

涉及一种取代的氨基喹唑啉类化合物及药物组合物及其用途，所述的氨基喹唑啉类化合物如式(I)所示化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。化合物和组合物可用于治疗和/或预防ErbB家族酪氨酸激酶介导的疾病。

Description

取代的氨基喹唑啉类化合物及其药物组合物及其用途 技术领域
本发明属于医药技术领域，尤其涉及一种取代的氨基喹唑啉类化合物及包含该化合物的药物组合物及其用途。更具体而言，本发明涉及某些氘取代的1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮，这些氘取代的化合物及其组合物可用于治疗和/或预防ErbB家族酪氨酸激酶(例如EGFR(ErbB-1)、Her2/c-neu(ErbB-2)、Her3(ErbB-3)和Her4(ErbB-4)激酶)介导的相关疾病，且这些氘取代的化合物具有更优良的药代动力学性质。
背景技术
蛋白激酶代表了一大类在对细胞功能保持控制和各种细胞病变的调控中起重要作用的蛋白质。蛋白酪氨酸激酶可以归类于生长因子受体(如VEGFR、EGFR、PDGFR、FGFR和erbB2)或非受体(如c-src和bcr-abl)激酶。受体类型的酪氨酸激酶又可分为20中不同的亚型；而非受体类型的酪氨酸解密也有很多种亚型。受体酪氨酸激酶是一大类酵素，能使生长因子跨越细胞膜保持细胞外结合区域，跨膜区和细胞内部分作为具有激酶的功能，磷酸化作用于一个具体蛋白酪氨酸残基，从而影响细胞增殖。变体的或不恰当的蛋白激酶活性能导致病情的恶化。
表皮生长因子受体(epidermal growth factor receptor，EGFR)是一种受体型酪氨酸激酶，具有4种受体亚型，即EGFR(ErbB-1)、HER2/c-neu(ErbB-2)、Her3(ErbB-3)和Her4(ErbB-4)。正常的EGFR激活的信号通路能够调节细胞的增殖、成血管、生长、迁移和粘附，在器官发生过程或成体的细胞与细胞间的相互作用中起着重要作用。许多分子能够导致EGFR激酶活性的持续激活，不断的触发大量的下游信号转导通路，包括K-ras激活。因此EGFR家族与成瘤密切相关。EGFR的过表达或突变在头颈癌、卵巢癌、膀胱癌、宫颈癌、食道癌、胃癌、乳腺癌、内膜癌、结肠癌、肺癌和脑瘤等多种癌症中都能检测到，通常预示这不良的预后。另外，Her2被认为是一种较强的肿瘤蛋白，其突变也在多种肿瘤中可见，尤其是乳腺癌、肺癌和结肠癌等。
Poziotinib(又名HM-78136，化学名称为1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮，其具有以下结构式)是韩国韩美制药公司(Hanmi pharmaceutical,Inc)研发的一种新型口服喹唑啉广谱-ErbB抑制剂，能不可逆地阻断ErbB家族酪氨酸激酶受体(包括EGFR、Her2和Her4)的信号通路，从而抑制过度表达这些受体的肿瘤细胞的增殖。该药物目前 正在肺癌、乳腺癌、胃癌和头颈癌患者中进行研究。临床前的数据表明：相比第一代至第三代EGFR抑制剂(例如Gefitinib、Erlotinib或Osimertinib)，Poziotinib可有效的抑制EGFR和Her2外显子20插入突变(EGFR and Her2 exon 20 insertion mutants,即EGFR and Her2 Ex20Ins mutants)，同时，Poziotinib对EGFR Ex20Ins突变的抑制作用明显优于其对典型的EGFR T790M突变的抑制作用。Poziotinib的II期临床研究结果显示可有效抑制EGFR Ex20Ins突变，远超预期疗效达64％。
Figure PCTCN2019087720-appb-000001
已知较差的吸收、分布、代谢和/或排泄(ADME)性质是导致许多候选药物临床试验失败的主要原因。当前上市的许多药物也由于较差的ADME性质限制了它们的应用范围。药物的快速代谢会导致许多本来可以高效治疗疾病的药物由于过快的从体内代谢清除掉而难以成药。频繁或高剂量服药虽然有可能解决药物快速清除的问题，但该方法会带来诸如病人依从性差、高剂量服药引起的副作用及治疗成本上升等问题。另外，快速代谢的药物也可能会使患者暴露于不良的毒性或反应性代谢物中。
虽然Poziotinib作为广谱ErbB抑制剂能有效治疗ErbB家族酪氨酸激酶受体介导的癌症，但是该领域仍存在严重的临床未满足需求，而且发现具有治疗由EGFR(ErbB-1)、Her2/c-neu(ErbB-2)、Her3(ErbB-3)和Her4(ErbB-4)野生型和突变体激酶介导疾病且具有很好的口服生物利用度且有成药性的新型化合物还是具有挑战性的工作。因此，本领域仍需开发对适用作治疗剂的ErbB家族酪氨酸激酶介导疾病具有选择性抑制活性和/或更好地药效学/药代动力学的化合物，本发明提供了这样的化合物。
发明内容
针对以上技术问题，本发明公开了一种新型的氘取代的氨基喹唑啉类化合物及其组合物和用途，其具有更好地EGFR/ErbB1、Her-2/ErbB2、Her-3/ErbB3或Her-4/ErbB4激酶抑制活性，以及对于选自T790M突变、L858R突变、del19突变、C797S突变或Ex20Ins突变中的一个或多个具有的更高的抑制活性和选择性，同时具有更低的副作用、更好地药代动力学性能，可用于治疗ErbB家族酪氨 酸激酶介导的疾病。
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体。
对此，本发明采用以下技术方案：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2019087720-appb-000002
其中，
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢或氘；
X选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子；
或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。在具体实施方案中，所述的药物组合物还含有另外的治疗药物，所述的另外的治疗药物选自细胞信号转导抑制剂、有丝分裂抑制剂、烷化剂、抗代谢药、抗生素、生长因子抑制剂、细胞周期抑制剂、拓扑异构酶抑制剂、生物反应调节剂、抗激素药和抗雄激素。
在另一方面，本发明提供了一种如上所述的药物组合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物进行混合，从而形成药物组合物。
在另一方面，本发明还涉及提供一种在受试者中治疗和/或预防ErbB家族酪氨酸激酶介导的疾病的方法。该方法包括向该受试者给药治疗有效量的本发明化合物或药物组合物。在具体实施方案 中，ErbB家族酪氨酸激酶选自EGFR、Her2、Her3或Her4激酶的野生型和突变体中的一个或多个激酶。在具体实施方案中，EGFR突变体选自T790M突变、L858R突变、del19突变、C797S突变或Ex20Ins突变中的一个或多个。在具体实施方案中，Her2突变体选自Ex20Ins突变。在具体实施方案中，所述的增殖性疾病是转移癌、表皮癌、结肠癌、胃腺癌、膀胱癌、乳癌、肾癌、肝癌、肺癌、甲状腺癌、脑瘤、颈癌、前列腺癌、胰腺癌、中枢神经系统的癌症、恶性胶质瘤、骨髓增生病、动脉粥样硬化或肺纤维化。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
由随后的具体实施方式、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。
本发明化合物可以是无定形或结晶形式。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
如本文所用，术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人)) 和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在另一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可以互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗有益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其他疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其他治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
具体实施方式
化合物
本发明提供式(I)化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体：
Figure PCTCN2019087720-appb-000003
其中，
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢或氘；
X独立地选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
作为本发明的具体实施方案，氘在氘代位置中的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和X，各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
作为本发明的具体实施方案，式(I)化合物至少含有一个氘原子，更佳地一个氘原子，更佳地二个氘原子，更佳地三个氘原子，更佳地四个氘原子，更佳地五个氘原子，更佳地六个氘原子，更佳地七个氘原子，更佳地八个氘原子，更佳地九个氘原子，更佳地十个氘原子，更佳地十一个氘原子，更佳地十二个氘原子，更佳地十三个氘原子，更佳地十四个氘原子，更佳地十五个氘原子，更佳地十六个氘原子，更佳地十七个氘原子，更佳地十八个氘原子，更佳地十九个氘原子，更佳地二十个氘原子。
在具体实施方案中，“Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基”的技术方案包括Y 1选自氢、氘、卤素或三氟甲基，Y 2选自氢、氘、卤素或三氟甲基，Y 3选自氢、氘、卤素或三氟甲基，以此类推，直至Y 8选自氢、氘、卤素或三氟甲基的技术方案。更具体地， 包括Y 1为氢、Y 1为氘、Y 1为卤素(F、Cl、Br或I)或Y 1为三氟甲基，Y 2为氢、Y 2为氘、Y 2为卤素(F、Cl、Br或I)或Y 2为三氟甲基，Y 3为氢、Y 3为氘、Y 3为卤素(F、Cl、Br或I)或Y 3为三氟甲基，以此类推，直至Y 8为氢、Y 8为氘、Y 8为卤素(F、Cl、Br或I)或Y 8为三氟甲基的技术方案。
在另一具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢或氘”的技术方案包括R 1选自氢或氘，R 2选自氢或氘，R 3选自氢或氘，以此类推，直至R 9选自氢或氘的技术方案。更具体地，包括R 1为氢、R 1为氘，R 2为氢、R 2为氘，R 3为氢、R 3为氘，以此类推，直至R 9为氢、R 9为氘的技术方案。
在另一具体实施方案中，“X独立地选自CH 3、CD 3、CHD 2或CH 2D”的技术方案包括X选自CH 3、CD 3、CHD 2或CH 2D的技术方案。更具体地，包括X为CH 3、X为CD 3、X为CHD 2或X为CH 2D的技术方案。
在另一个具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 1-Y 8各自独立地选自氢或氘，且X和R 1-R 9如上所定义，附加条件是所述化合物至少含有一个氘原子。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 1-Y 8各自独立地选自氢或氘，且X选自CD 3或CH 3，R 1-R 9如上所定义，附加条件是所述化合物至少含有一个氘原子。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 3-Y 8同时为氢，且Y 1和Y 2各自独立地选自氢或氘，X和R 1-R 9如上所定义，附加条件是所述化合物至少含有一个氘原子。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 3-Y 8同时为氢，且Y 1和Y 2各自独立地选自氢或氘，R 1-R 9如上所定义，X选自CD 3或CH 3，附加条件是所述化合物至少含有一个氘原子。
在另一具体实施方案中，R 2-R 5是相同的。
在另一具体实施方案中，R 6-R 9是相同的。
在另一具体实施方案中，R 2-R 9是相同的。
在另一具体实施方案中，R 1是氢。
在另一具体实施方案中，R 1是氘。
在另一具体实施方案中，X是CD 3。
在优选的实施方案中，X是CH 3。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 2是氘，Y 1和R 1-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 6-R 9是氢，Y 1、Y 2和R 1-R 5各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，Y 2是氘，R 6-R 9是氢，Y 1和R 1-R 5各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 2-R 5是氘，Y 1、Y 2、R 1和R 6-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 2-R 5和Y 2是氘，Y 1、R 1和R 6-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 2-R 5是氘，R 6-R 9是氢，Y 1、Y 2和R 1各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 2-R 5和Y 2是氘，R 6-R 9是氢，R 1选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1是氘，Y 1、Y 2和R 2-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1是氘，Y 2是氘，Y 1和R 2-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1是氘，R 6-R 9是氢，Y 1、Y 2和R 2-R 5各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1-R 5是氘，Y 1、Y 2和R 6-R 9各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1是氘，Y 2是氘，R 6-R 9是氢，Y 1和R 2-R 5各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1-R 5是氘，Y 2是氘，Y 1和R 6-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1-R 5是氘，R 6-R 9是氢，Y 1和Y 2各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，R 1-R 5是氘，Y 2是氘，R 6-R 9是氢，Y 1选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 1、Y 2和R 1-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 2是氘，Y 1和R 1-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 6-R 9是氢，Y 1、Y 2和R 1-R 5各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 2是氘，R 6-R 9是氢，Y 1和R 1-R 5各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 2-R 5是氘，Y 1、Y 2、R 1和R 6-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 2-R 5是氘，Y 2是氘，Y 1、R 1和R 6-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 2-R 5是氘，R 6-R 9是氢，Y 1、Y 2和R 1各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 2是氘，R 2-R 5是氘，R 6-R 9是氢，Y 1和R 1各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1是氘，Y 1、Y 2和R 2-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1是氘，Y 2是氘，Y 1和R 2-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1是氘，R 6-R 9是氢，Y 1、Y 2和R 2-R 5各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 2是氘，R 1是氘，R 6-R 9是氢，Y 1和R 2-R 5各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1-R 5是氘，Y 1、Y 2和R 6-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1-R 5是氘，Y 2是氘，Y 1和R 6-R 9各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，R 1-R 5是氘，R 6-R 9是氢，Y 1和Y 2各自独立地选自氢或氘。
在另一具体实施方案中，本发明涉及一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，X是CD 3，Y 2是氘，R 1-R 5是氘，R 6-R 9是氢，Y 2选自氢或氘。
作为本发明的具体实施方案，所述化合物为如下任一结构，或其药学上可接受的盐，但不限于下列结构：
Figure PCTCN2019087720-appb-000004
Figure PCTCN2019087720-appb-000005
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2H 2O)和六水合物(R·6H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位 素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
合成
本发明化合物(包括其盐)可使用已知有机合成技术来制备，且可按照多种可能合成途径中的任一种(诸如下文方案中的那些)来合成。用于制备本发明化合物的反应可在合适的溶剂中进行，有机合成领域的技术人员可容易地选择溶剂。合适的溶剂可在进行反应的温度(例如，在溶剂结冻温度至溶剂沸点温度范围内的温度)下与起始物质(反应物)、中间体或产物实质上不反应。既定反 应可在一种溶剂或一种以上溶剂的混合物中进行。技术人员可依据具体反应步骤来选择用于具体反应步骤的溶剂。
本发明化合物的制备可涉及不同化学基团的保护和去除保护。本领域技术人员可容易地判定是否需要保护和去除保护以及适当保护基的选择。保护基的化学性质可参见例如Wuts和Greene，Protective Groups in Organic Synthesis，第4版，John Wiley&Sons：New Jersey，(2006)，其通过引用整体并入本文中。
可按照本领域已知任何合适的方法来监测反应。例如，可通过光谱手段(诸如核磁共振(NMR)光谱法(例如 1H或 13C)、红外(IR)光谱法、分光光度法(例如，UV-可见光)、质谱(MS))或通过色谱方法(诸如高效液相色谱法(HPLC)或薄层色谱法(TLC))来监测产物形成。
下面的通用制备路线可用于合成本发明式(I)结构的化合物。合成路线如下所示：
Figure PCTCN2019087720-appb-000006
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨 酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度快速提高至有效水平。推注剂量取决于活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而 在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤 渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
适应症
本发明化合物可用于治疗人类或非人类ErbB家族酪氨酸激酶介导的增殖性疾病。在具体的实施方案中，所述的ErbB家族酪氨酸激酶选自EGFR/ErbB1、Her-2/ErbB2、Her-3/ErbB3或Her-4/ErbB4。
本发明化合物是EGFR的野生型或至少一种突变体的抑制剂并且因此适用于治疗与一种或一种以上EGFR野生型或突变体(例如缺失突变、活化突变、抗性突变或其组合，具体实例包括T790M突变、L858R突变、del19突变、C797S、L858R/T790M双突变、del19/T790M双突变、L858R/T790M/C797S三突变、del19/T790M/C797S三突变、Ex20Ins突变)的活性相关的一种或一种以上病症。因此，在具体实施方案中，本发明提供一种治疗EGFR野生型或突变型介导的病症的方法，其包含向有需要的患者给药本发明化合物，或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物的步骤。
本发明化合物是Her2的野生型或至少一种突变体的抑制剂并且因此适用于治疗与一种或一种以上Her2野生型或突变体(例如缺失突变、活化突变、抗性突变或其组合，具体实例包括Ex20Ins突变)的活性相关的一种或一种以上病症。因此，在具体实施方案中，本发明提供一种治疗Her2野生型或突变型介导的病症的方法，其包含向有需要的患者给药本发明化合物，或其药学上可接受的 盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物的步骤。
大约10-15％的非小细胞肺癌是由于EGFR突变导致的。目前已批准的EGFR酪氨酸激酶抑制剂(EGFR TKIs)例如吉非替尼(gefitinib)、厄洛替尼(erlotinib)和阿法替尼(afatinib)，可以治疗有经典突变(例如del19突变、L858R突变)的非小细胞肺癌；相比化疗，接受这些EGFR TKIs治疗的70％的病人都有更长的无进展生存期(PFS)和更好的生活质量。但是，将近10～20％的EGFR突变的非小细胞肺癌肿瘤有EGFR Ex20Ins突变(EGFR exon20 insertion mutation)，同时EGFR Ex20Ins突变也是现有EGFR TKIs产生耐药的原因。然而，历史临床数据表明，已批准的EGFR TKIs对EGFR Ex20Ins突变的响应率只有8.7-11％，无进展生存期(PFS)只有2.4-2.7个月。此外，3％的在非小细胞肺癌是由Her2突变导致的，而90％的Her2突变是Ex20Ins。目前，由于缺乏有效靶向药物，带有EGFR和Her2 Ex20Ins突变的病人被排除在临床实验之外，这表明亟需新的靶向药物来治疗这些病人。
通过激酶和细胞的增殖试验，我们评价了本发明化合物抗EGFR和Her2 Ex20Ins突变的活性。我们选用了EGFR D770_N771insSVD(InsSVD)和HER2 A775_G776insYVMA(InsYVMA)激酶和Ba/F3细胞来进行增殖试验，其中EGFR D770_N771insSVD是EGFR Ex20Ins突变中最常见的突变，HER2 A775_G776insYVMA约占Her2 Ex20Ins突变的50-80％，是其最主要的突变。试验结果表明：本发明化合物能有效抑制EGFR和Her2 Ex20Ins突变，可用于治疗带有EGFR和Her2 Ex20Ins突变的疾病。
本发明的化合物将应用于，但绝不限于，使用本发明的化合物或组合物的有效量对患者给药来预防或治疗患者增殖性疾病。这样的疾病包括癌症，尤其是转移癌，非小细胞肺癌、乳腺癌、头颈癌及表皮癌。
本发明的化合物将应用于瘤的治疗包括癌症和转移癌，进一步包括但并不限于，癌症如表皮癌，膀胱癌，乳腺癌，结肠癌，肾癌，肝癌，肺癌(包括小细胞肺癌)，食道癌，胆囊癌，卵巢癌，胰腺癌，胃癌，宫颈癌，甲状腺癌，前列腺癌，和皮肤癌(包括鳞状细胞癌)；淋巴系统造血肿瘤(包括白血病，急性淋巴囊肿性白血病，急性成淋巴细胞性白血病，B细胞淋巴瘤，T细胞淋巴瘤，何杰金(氏)淋巴瘤，非何杰金(氏)淋巴瘤，多毛细胞白血病和伯基特淋巴瘤)；骨髓系统造血肿瘤(包括急慢性骨髓性粒细胞性白血病，骨髓增生异常综合症，和前髓细胞白血病)；间充质细胞起源的肿瘤(包括纤维肉瘤和横纹肌肉瘤，和其他肉瘤，如软组织和软骨)；中枢末梢神经系统瘤(包括星形细胞瘤，成神经细胞瘤，神经胶质瘤，和神经鞘瘤)；和其他肿瘤(包括黑素瘤，精原细胞瘤， 畸胎癌，骨肉瘤，xenoderoma pigmentosum，keratoctanthoma，甲状腺滤泡瘤和卡波济(氏)肉瘤)。
本发明的化合物还可用于治疗眼科病症例如角膜移植排斥，眼的新生血管形成，视网膜新生血管形成包括损伤或感染后的新生血管形成；糖尿病性视网膜病；晶状体后纤维组织增生症，和新生血管性青光眼；视网膜缺血；玻璃体出血；溃疡性疾病如胃溃疡；病理学的但非恶性状况如血管瘤，包括婴儿血管内皮细胞瘤，鼻咽和无血管性骨坏死的血管纤维瘤；雌性生殖系统紊乱如子宫内膜异位。这些化合物同样也用于治疗水肿和脉管通透性过高的状况。
本发明的化合物可以用于处理与糖尿病相关的情况如糖尿病性视网膜病和微血管病。本发明的化合物同样用于癌症患者血流量减少的情况。本发明的化合物对患者肿瘤转移减少也有有益效果。
本发明的化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
联合疗法
本发明的化合物可以以仅有的药学试剂或结合一个或多个其他附加治疗(药学的)剂来给药，其中联合用药引起可接受的不良反应，这对于高增生性疾病如癌症的治疗具有特殊的意义。在这种情况下，本发明的化合物可以结合已知的细胞毒素剂，单个转导抑制剂或其他抗癌试剂，以及它们的混合物和组合。像本发明所使用的，附加治疗剂正常给药治疗特殊的疾病，就是已知的“合适地治疗疾病”。本发明所使用的“附加治疗剂”包括化学治疗药物或其他抗增殖的药物可以结合本发明的化合物治疗增殖性疾病或癌症。
化学治疗药物或其他抗增殖药物包括组蛋白去乙酰化酶(HDAC)抑制剂，包括但并不限于，SAHA，MS-275，MGO103，以及那些以下专利所描述的化合物：WO 2006/010264,WO 03/024448,WO 2004/069823,US 2006/0058298,US 2005/0288282,WO00/71703,WO01/38322,WO 01/70675,WO 03/006652,WO 2004/035525,WO2005/030705,WO 2005/092899,和脱甲基化试剂包括，但并不限于，5-杂氮-2′-脱氧胞苷(5-aza-dC)、阿扎胞苷(Vidaza)、地西他滨(Decitabine)和以下文献所描述的化合物：US 6,268137,US5,578,716,US5,919,772,US 6,054,439,US 6,184,211,US 6,020,318,US6,066,625,US 6,506,735,US 6,221,849,US 6,953,783,US 11/393,380。
另外一些实施例是，化学治疗药物或其他抗增殖药物可以结合本发明的化合物治疗增殖性疾病和癌症。已知的化学治疗药物包括，但并不限于，其他疗法或抗癌剂可以联合本发明的抗癌剂与包括外科，放射疗法(少许例子如γ辐射，中子束放射疗法，电子束放射疗法，质子疗法，近距离放 射疗法和系统放射性同位素疗法)，内分泌疗法，紫杉烷类(紫杉醇，多西紫杉醇等等)，铂的衍生物，生物反应调节剂(干扰素，白细胞间素，肿瘤坏死因子(TNF)，TRAIL受体靶向作用和媒介物)，过热和冷冻疗法，稀释任何不良反应的试剂(如止吐药)，和其他认可的化学治疗药物，包括但并不限于，烷化药物(氮芥，苯丁酸氮芥，环磷酰胺，苯丙氨酸氮芥，异环磷酰胺)，抗代谢物(甲氨蝶呤，培美曲塞(Pemetrexed)等等)，嘌呤拮抗剂和嘧啶拮抗剂(6-巯嘌呤(6-Mercaptopurine)，5-氟尿嘧啶，Cytarabile，吉西他滨(Gemcitabine))，纺锤体抑制剂(长春碱，长春新碱，长春瑞滨，紫杉醇)，鬼臼毒素(依托泊苷，伊立替康(Irinotecan)，托泊替康(Topotecan))，抗生素(多柔比星(Doxorubicin)，博莱霉素(Bleomycin)，丝裂霉素(Mitomycin))，亚硝基脲(卡莫司汀(Carmustine)，洛莫司汀(Lomustine))，无机离子(顺铂，卡铂)，细胞分裂周期抑制剂(KSP通过有丝分裂驱动蛋白抑制剂，CENP-E和CDK抑制剂)，酵素(天门冬酰胺酶)，荷尔蒙(它莫昔芬(Tamoxifen)，亮丙瑞林(Leuprolide)，氟他胺(Flutamide)，甲地孕酮(Megestrol))，格列卫(Gleevec)，阿霉素(Adriamycin)，地塞米松(Dexamethasone)，和环磷酰胺。抗血管生成因子(阿瓦斯丁(Avastin)及其他)，激酶抑制剂(伊马替尼(Imatinib)，舒尼替尼(Sutent)，索拉非尼(Nexavar)，西妥昔单抗(Erbitux)，赫赛汀(Herceptin)，它赛瓦(Tarceva)，易瑞沙(Iressa)及其他)。药物抑制或激活癌症的途径如mTOR，HIF(缺氧诱导因子)途径及其他。癌症治疗较广泛的论坛见http://www.nci.nih.gov，FAD认可的肿瘤学药物清单见http://www.fda.gov/cder/cancer/druglist-rame.htm，和默克手册，第十八版.2006，所有的内容都是结合了参考文献。
另外一些实施例是，本发明的化合物可以结合细胞毒素抗癌剂。这样的抗癌剂可以在第十三版默克索引(2001)里找到。这些抗癌剂包括，但绝不限于，门冬酰胺酶(Asparaginase)，博来霉素(Bleomycin)，卡铂，卡莫司汀(Carmustine)，苯丁酸氮芥(Chlorambucil)，顺铂，L-天冬酰胺酶(Colaspase)，环磷酰胺，阿糖胞苷(Cytarabine)，达卡巴嗪(Dacarbazine)，放线菌素D(Dactinomycin)，柔红霉素(Daunorubicin)，阿霉素(多柔比星)，表柔比星(Epirubicin)，依托泊苷(Etoposide)，5-氟脲嘧啶，六甲基三聚氰胺，羟基脲，异环磷酰胺，伊立替康，亚叶酸，环己亚硝脲，氮芥，6-巯基嘌呤，美司钠(Mesna)，甲氨蝶呤(Methotrexate)，丝裂霉素C(Mitomycin C)，米托蒽醌(Mitoxantrone)，泼尼松龙(Prednisolone)，泼尼松(Prednisone)，丙卡巴肼(Procarbazine)，雷洛昔芬(Raloxifen)，链唑霉素(Streptozocin)，他莫昔芬(Tamoxifen)，硫鸟嘌呤(Thioguanine)，托泊替康，长春碱，长春新碱，长春地辛。
与本发明的化合物联合用药的其他合适的细胞毒类药物包括，但并不限于，这些公认地应用于 肿瘤性疾病治疗的化合物，如以下文献中所描述的：Goodman and Gilman′s The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；这些抗癌剂包括，但绝不限于，氨鲁米特(Aminoglutethimide)，L-门冬酰胺酶，硫唑嘌呤，5-氮杂胞苷，克拉屈滨(Cladribine)，白消安(Busulfan)，己烯雌酚，2′，2′-二氟去氧胞二磷胆碱，多西紫杉醇，赤羟基壬烷基腺嘌呤(Erythrohydroxynonyladenine)，乙炔雌二醇，5-氟尿嘧啶脱氧核苷，5-氟脱氧尿苷单磷酸，磷酸氟达拉滨(Fludarabine phosphate)，氟甲睾酮(Fluoxymesterone)，氟他胺(Flutamide)，己酸羟孕酮，伊达比星(Idarubicin)，干扰素，醋酸甲羟孕酮，醋酸甲地孕酮，美法仑(Melphalan)，米托坦(Mitotane)，紫杉醇，喷司他丁(Pentostatin)，N-磷酸乙酰基-L-天冬氨酸(PALA)，普卡霉素(Plicamycin)，甲基环己亚硝脲(Semustine)，替尼泊苷(Teniposide)，丙酸睾丸酮，塞替派(Thiotepa)，三甲基三聚氰胺，尿核苷和长春瑞滨。
其他合适的与本发明的化合物联合应用的细胞毒素类抗癌剂包括新发现的细胞毒素物质，其中包括，但并不限于，奥沙利铂(Oxaliplatin)，吉西他滨(Gemcitabine)，卡培他滨(Capecitabine)，大环内酯类抗肿瘤药及其天然或合成的衍生物，替莫唑胺(Temozolomide)，托西莫单抗(Bexxar)，Trabedectin，和驱动蛋白纺锤体蛋白抑制剂Eg5。
另外一些实施例是，本发明的化合物可以结合其他信号转导抑制剂。有趣的是信号转导抑制剂把EGFR家族作为目标，如EGFR，HER-2和HER-4和它们各自的配体。这样的试剂包括，但绝不限于，抗体疗法如赫赛汀(曲妥单抗)，西妥昔单抗(Erbitux)，和帕妥珠单抗(Pertuzumab)。这样的疗法也包括，但绝不限于，小分子激酶抑制剂如易瑞沙(Gefitinib)，它赛瓦(Erlotinib)，Tykerb(Lapatinib)，CANERTINIB(CI1033)，AEE788。
另外一些实施例是，本发明的化合物结合其他信号转导抑制剂靶向作用于分裂激酶领域家族的受体激酶(VEGFR,FGFR,PDGFR,flt-3,c-kit,c-fins,等等)，和它们各自的配体。这样的试剂包括，但并不限于，抗体如贝伐单抗(Avastin)。这样的试剂包括，但绝不限于，小分子抑制剂如Gleevec/Imanitib,Sprycel(Dasatinib),Tasigna/Nilotinib,Nexavar(Vandetanib),Vatalanib(PTK787/ZK222584),Telatinib/BAY-57-9352,BMS-690514,BMS-540215,Axitinib/AG-013736,ZD-6474,KRN-951,CP-547,632,CP-673,451,CHIR-258,MLN-518。
另外一些实施例是，本发明的化合物可以结合组蛋白脱乙酰基酶抑制剂。这样的试剂包括，但绝不限于，辛二酰苯胺氧肟酸(SAHA)，LAQ-824,LBH-589,MS-275,FR-901228和MGCDOI03。
另外一些实施例是，本发明的化合物可以结合其他抗癌剂如蛋白酶体抑制剂和m-TOR抑制剂。这些包括，但绝不限于，硼替佐米和CCI-779。本发明的化合物还可以结合其他抗癌剂如拓扑异构 酶抑制剂，包括但绝不限于喜树碱。
那些附加治疗剂可以与包含本发明的化合物的组合物分开给药，作为多给药方案的一部分。或者，那些治疗剂可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。
实施例
下面结合具体实施例，作进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。
本文所用的缩写具有以下含义：
APCI 大气压力化学游离法
DIPEA N,N-二异丙基乙胺
POCl 3 三氯氧磷
TBU 1,5,7-三氮杂二环[4.4.0]癸-5-烯
CDCl 3 氘代氯仿
NaBH 4 硼氢化钠
EtOH 乙醇
TEA 三乙基胺
TsCl 4-甲苯磺酰氯
DMAP 4-二甲氨基吡啶
DCM 二氯甲烷
Na 2CO 3 碳酸钠
K 2CO 3 碳酸钾
DMF N,N-二甲基甲酰胺
HCl 盐酸
DMSO 二甲基亚砜
MeOD 氘代甲醇
Boc 叔丁氧碳基
Tol 甲苯
DIDA 偶氮二甲酸二异丙酯
MeSO 3H 甲基磺酸
L-Methionine L-甲硫氨酸
实施例1 4-(对甲苯磺酰氧基)哌啶-1-羧酸叔丁酯-3,3,5,5-d 4(中间体A-1)的制备。
Figure PCTCN2019087720-appb-000007
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000008
步骤1化合物2的合成
将TBU加入到化合物1(10g,50.2mmol)的氘代氯仿(100mL)，反应液在室温下搅拌24hrs。反应液用1M的稀盐酸中和，再用二氯甲烷萃取，合并有机层，用无水硫酸钠干燥，过滤，减压浓缩滤液得到10.02g黄色固体，直接用于下一步。
步骤2化合物3的合成
冰浴下，将硼氢化钠(200mg)分批加入到化合物2(2.0g)的无水甲醇(10mL)中，升至室温下反应4hrs。加入饱和的氯化铵溶液淬灭反应，减压除去甲醇。用乙酸乙酯(50mL x 3)萃取，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩滤液得到2.5g油状物直接用于下一步反应。
步骤3中间体A-1的合成
在冰浴下，将TsCl加入到化合物3，DMAP(50mg)和TEA(2.60mL)的无水二氯甲烷(30mL) 溶液中，升至温室下反应过夜。反应液用饱和的食盐水(20mL)，饱和碳酸钠溶液(10mL)和水(20mL)萃取洗涤，有机层再用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩，浓缩液柱层析纯化(石油醚/甲乙酸乙酯＝10％)得到3g白色固体，收率：83.2％。 1H NMR(300MHz,CDCl 3)δ7.81(d,J＝8.0Hz,2H),7.36(d,J＝8.1Hz,2H),4.67(s,1H),3.60(d,J＝13.7Hz,2H),3.25(d,J＝13.7Hz,2H),1.45(s,9H).
实施例2 4-(对甲苯磺酰氧基)哌啶-1-羧酸叔丁酯-4-d(中间体A-2)的制备。
Figure PCTCN2019087720-appb-000009
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000010
步骤1化合物4的合成
冰浴下，将氘代硼氢化钠(300mg)分批加入到化合物1(2.0g)的氘代甲醇(15mL)中，升至室温下反应4hrs。加入饱和的氯化铵溶液淬灭反应，减压除去氘代甲醇。用乙酸乙酯(50mL x 3)萃取，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩滤液得到油状物直接用于下一步反应。
步骤2中间体化合物A-2的合成
在冰浴下，将TsCl加入到上述化合物4，DMAP(75mg)和TEA(3.75mL)的无水二氯甲烷(45mL)溶液中，升至温室反应过夜。反应液用饱和的食盐水(20mL)，饱和碳酸钠溶液(10mL)和水(20mL)萃取洗涤，有机层再用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩，浓缩液柱层析纯化(石油醚/甲乙酸乙酯＝10％)得到2.29g白色固体，收率：83.2％。 1H NMR(400MHz,CDCl 3)δ7.80(d,J＝8.3Hz,2H),7.35(d,J＝8.0Hz,2H),3.64-3.52(m,2H),3.31-3.19(m,2H),2.46(s,3H),1.82-1.73(m,2H),1.72-1.63(m,2H),1.44(s,9H).
实施例3 4-(对甲苯磺酰氧基)哌啶-1-羧酸叔丁酯-3,3,4,5,5-d 5(中间体A-3)的制备。
Figure PCTCN2019087720-appb-000011
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000012
步骤1化合物5的合成
冰浴下，将氘代硼氢化钠(300mg)分批加入到化合物2(3.0g)的氘代甲醇(15mL)中，升至室温反应4hrs。加入饱和的氯化铵溶液淬灭反应，减压除去甲醇。用乙酸乙酯(50mL x 3)萃取，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩滤液得到3.1g油状物直接用于下一步反应。
步骤2中间体A-3的合成
在冰浴下，将TsCl(3.52g)加入到上述化合物5(3.1g)，DMAP(62mg)和TEA(3.23mL)的无水二氯甲烷(40mL)溶液中，升至温室反应过夜。反应液用饱和的食盐水(20mL)，饱和碳酸钠溶液(10mL)和水(20mL)萃取洗涤，有机层再用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩，浓缩液柱层析纯化(石油醚/甲乙酸乙酯＝10％)得到2.8g白色固体，两步收率：51.85％。 1H NMR(300MHz,CDCl 3)δ7.79(d,J＝8.3Hz,2H),7.34(d,J＝8.0Hz,2H),3.58(M,2H),3.24(M,2H),2.45(s,3H),1.43(s,9H).
实施例4 4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-醇(中间体B-1)的制备。
Figure PCTCN2019087720-appb-000013
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000014
步骤1化合物7的合成
在75℃下，将三氯氧磷(5mL)在20min内滴加到化合物6(5g)和DIPEA(4.13ml)的甲苯(45ml)溶液中，滴加完毕后，反应液在当前温度下搅拌3hrs。反应完毕后直接投入下一步。
步骤2化合物8的合成
将3,4-二氯-2-氟苯胺(3.84g)的甲苯(25mL)溶液缓慢滴加到上一步反应液中，滴加完毕后，反应继续搅拌2hrs。冷却至室温，固体过滤，用甲苯(30mL)洗涤，固体再用异丙醇(100mL)搅拌打浆2hrs。固体过滤，用异丙醇(30mL)洗涤固体。固体真空下干燥得到6.8g，收率：80.40％。LC-MS(APCI):m/z＝397.2(M+1) +。
步骤3中间体化合物B-1的合成
在10℃下将氨水(4.6mL)加入到化合物8(1g)的甲醇(10mL)中，室温下搅拌3hrs。固体过滤，用H 2O(20mL)和甲醇(20mL)的混合液洗涤固体。真空下50℃下干燥过夜到得到灰白色固体(790mg)，收率：88.38％。LC-MS(APCI):m/z＝354.1(M+1) +。
实施例5 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基-3,3,5,5-d 4) 丙-2-烯-1-酮(化合物I-1)的制备。
Figure PCTCN2019087720-appb-000015
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000016
步骤1 化合物9的合成
将碳酸钾(830mg)加入到中间体化合物B-1(706mg)和中间体化合物A-1(1.43g)的DMF(7mL)溶液中，氮气保护下，反应液在70℃下反应过夜。反应液冷却至室温，加水(20mL)稀释反应液，用乙酸乙酯萃取(50mL x 3)，合并有机层，用饱和食盐水(30mL x 3)洗涤，无水硫酸钠干燥。减压浓缩，浓缩液柱层析纯化(二氯甲烷/甲醇＝2％)得到1.00g黄白色固体，产率：92.65％。LC-MS(APCI):m/z＝541.1M+1) +。 1H NMR(300MHz,CDCl 3)δ9.64(s,1H),8.39(s,1H),7.85(s,1H),7.63–7.54(m,2H),7.24(s,1H),4.69(s,J＝3.4Hz,1H),3.95(s,3H),3.77–3.58(m,J＝13.4Hz,2H),3.30–3.16(m,2H),1.41(s,9H).
步骤2 化合物10的合成
将浓盐酸(1.6mL)缓慢加入到化合物9(1.0g)的丙酮(10ml)溶液中，反应液在室温下搅拌反应5hrs。固体过滤，用丙酮(2mL)洗涤固体。固体在真空下30℃下干燥过夜得到白色固体(620mg)，收率：65.28％。LC-MS(APCI):m/z＝441.1M+1) +。
步骤3 化合物I-1的合成
在-20℃下，将丙烯酰氯(0.47mL,0.618mmol/mL)缓慢滴加到化合物10(150mg)和TEA(0.75mL)的无水二氯甲烷(30mL)溶液中，滴加完毕后，在-20℃继续搅拌1hrs。加水(20mL)稀释反应液，用二氯甲烷萃取(30mL x 3)，合并有机层，用饱和食盐水(30mL x 1)洗涤，无水硫酸钠干燥。减压浓缩，浓缩液柱层析纯化(二氯甲烷/甲醇＝5％)得到110mg白色固体，产率：74.74％。纯度：99.14％(HPLC)；LC-MS(APCI):m/z＝495.2(M+1) +。 1H NMR(300MHz,DMSO-d 6)δ9.65(s,1H),8.38(s,1H),7.86(s,1H),7.70–7.50(m,2H),7.23(s,1H),6.83(dd,J＝16.6,10.5Hz,1H),6.10(dd,J＝16.6,1.8Hz,1H),5.67(dd,J＝10.4,1.8Hz,1H),4.75(s,1H),3.93(s,3H),3.90–3.79(m,2H),3.53–3.41(m,2H).
实施例6 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基-4-d)丙-2-烯 -1-酮(化合物I-2)的制备。
Figure PCTCN2019087720-appb-000017
根据实施例5中所述的合成方法，用中间体化合物A-2替代步骤1中的中间体化合物A-1来进行制备，得到90mg的白色固体化合物I-2，产率为58.41％，纯度为98.41％(HPLC)，LC-MS(APCI):m/z＝492.2(M+1) +。 1H NMR(300MHz,DMSO-d 6)δ9.66(s,1H),8.38(s,1H),7.87(s,1H),7.69–7.48(m,2H),7.23(s,1H),6.83(dd,J＝16.7,10.5Hz,1H),6.10(dd,J＝16.7,2.2Hz,1H),5.67(dd,J＝10.4,2.2Hz,1H),3.93(s,3H),3.91–3.77(m,2H),3.58–3.41(m,2H),2.11–1.95(m,2H),1.77–1.59(m,2H).
实施例7 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基-3,3,4,5,5-d 5) 丙-2-烯-1-酮(化合物I-3)的制备。
Figure PCTCN2019087720-appb-000018
根据实施例5中所述的合成方法，用中间体化合物A-3替代步骤1中的中间体化合物A-1来进行制备，得到62mg的白色固体化合物I-3，产率为36.78％，纯度为99.01％(HPLC)，LC-MS(APCI):m/z＝496.2(M+1) +。 1H NMR(300MHz,DMSO-d 6)δ9.65(s,1H),8.38(s,1H),7.86(s,1H),7.68–7.46(m,2H),7.23(s,1H),6.83(dd,J＝16.7,10.5Hz,1H),6.10(dd,J＝16.7,2.4Hz,1H),5.67(dd,J＝10.5,2.4Hz,1H),3.93(s,3H),3.90–3.79(m,2H),3.53–3.40(m,2H).
实施例8 4-((3,4-二氯-2-氟苯基-6-d)氨基)-7-甲氧基喹唑啉-6-醇(中间体B-2)的制备
Figure PCTCN2019087720-appb-000019
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000020
步骤1 化合物11的合成
将DCl(0.84mL,12M,)加入到3,4-二氯-2-氟苯胺(1.8g)的D 2O(25mL)溶液中，反应在微波下180℃下搅拌反应60min。冷却至室温，用饱和的碳酸氢钠溶液调pH为碱性，二氯甲烷(50mL x 3)，有机层用饱和的食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到棕色固体1.8g。LC-MS(APCI):m/z＝181.1(M+1) +  1H NMR(400MHz,DMSO-d 6)δ7.11(d,J＝1.7Hz,1H),5.61(s,2H).
步骤2 中间体B-2的合成
根据实施例4中所述的合成方法，用化合物11替代步骤2中的3,4-二氯-2-氟苯胺来进行制备。LC-MS(APCI):m/z＝355.1(M+1) +， 1H NMR(300MHz,DMSO-d 6)δ9.77(s,1H),9.56(s,1H),8.36(s,1H),7.65(s,1H),7.56(d,J＝1.3Hz,1H),7.23(s,1H),3.98(s,3H).
实施例9 1-(4-((4-((3,4-二氯-2-氟苯基-6-d)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯 -1-酮(化合物I-4)的制备
Figure PCTCN2019087720-appb-000021
根据实施例5中所述的合成方法，用中间体化合物B-2替代步骤1中的中间体化合物B-1，用N-Boc-4-(4-甲苯磺酰氧基)哌啶替代A-1来进行制备，得到130mg的白色固体化合物I-4，产率为51.92％，纯度为99.15％(HPLC)，LC-MS(APCI):m/z＝496.2(M+1) +。 1H NMR(300MHz,DMSO-d 6): δ9.67(s,1H),8.40(s,1H),7.89(s,1H),7.58(s,1H),7.25(s,1H),6.85(dd,J＝16.7,10.4Hz,1H),6.12(dd,J＝16.7,1.8Hz,1H),5.69(dd,J＝10.4,1.9Hz,1H),4.86–4.69(m,1H),3.95(s,3H),3.93–3.82(m,2H),3.56–3.43(m,2H),2.13–1.93(m,2H),1.81–1.61(m,2H).
实施例10 1-(4-((4-((3,4-二氯-2-氟苯基-6-d)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基-4-d)丙 -2-烯-1-酮(化合物I-5)的制备
Figure PCTCN2019087720-appb-000022
根据实施例5中所述的合成方法，用中间体化合物B-2替代步骤1中的中间体化合物B-1，用A-2替代A-1来进行制备，得到150mg的白色固体化合物I-5，产率为51.91％，纯度为98.72％(HPLC)，LC-MS(APCI):m/z＝496.2(M+1) +。 1H NMR(300MHz,DMSO-d 6):δ9.66(s,1H),8.40(s,1H),7.89(s,1H),7.58(s,1H),7.25(s,1H),6.85(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,1.9Hz,1H),5.69(dd,J＝10.5,1.9Hz,1H),3.95(s,3H),3.93–3.81(m,2H),3.59–3.42(m,2H),2.12–1.94(m,2H),1.81–1.59(m,2H).
实施例11 4-((3,4-二氯-2-氟苯基)氨基)-7-(甲氧基-d 3)喹唑啉-6-醇(中间体B-3)的制备
Figure PCTCN2019087720-appb-000023
采用以下路线进行合成：
Figure PCTCN2019087720-appb-000024
步骤1 化合物14的合成
室温下将三苯基磷(26g)和CD 3OD(7.8mL)分别加入到3,4-二甲氧基苯甲酸甲酯(化合物13，15g)的无水四氢呋喃(90mL)溶液中。氮气保护下，室温搅拌，然后将偶氮二甲酸二异丙酯(DIAD，20mL)缓慢滴加到上述反应体系中，反应在室温下搅拌反应3hrs。减压除去THF，加水稀释，用乙酸乙酯(150mL x 3)萃取，合并有机层，无水硫酸钠干燥，减压浓缩，浓缩液加入到石油醚(400mL)中，打浆搅拌过夜，固体过滤，用石油醚洗涤，滤液减压浓缩得到白色固体17.8g。 1H NMR(300MHz,CDCl 3):δ7.69(dd,J＝8.4,2.0Hz,1H),7.55(d,J＝2.0Hz,1H),6.89(d,J＝8.4Hz,0H),3.94(s,3H),3.90(s,3H).
步骤2 化合物15的合成
冰浴下将硝酸(20mL,70％)缓慢滴加到化合物14(17.8g)的乙酸(60mL)溶液中，反应在室温下搅拌过夜。将反应液加入到冰水(120mL)中，搅拌30min。固体过夜，用冰水洗涤，固体在65℃下真空干燥得到黄色固体17.8g，两步收率：88.52％。 1H NMR(300MHz,CDCl 3)δ7.47(s,1H),7.10(s,1H),4.00(s,3H),3.93(s,3H).
步骤3 化合物16的合成
将10％Pd/C(1.2g)加入到化合物15(5.5g)的甲醇(100mL)溶液中，反应在氢气下反应3hrs。硅藻土过滤，滤液减压浓缩，浓缩液柱层析纯化(石油醚/乙酸乙酯＝25％)得到4.4黄色固体， 1H NMR(300MHz,DMSO-d 6):δ7.13(s,1H),6.45(s,2H),6.36(s,1H),3.75(s,3H),3.64(s,3H).
步骤4 化合物17的合成
化合物16(2.6g，12.14mmol)的甲酰胺(26mL)的溶液在回流下搅拌反应12hrs。冷却至室温，加水稀释，固体过滤，固体在65℃下真空干燥。LC-MS(APCI):m/z＝210.2(M+1) +: 1H NMR(300MHz,DMSO-d 6)δ12.08(s,1H),7.99(s,1H),7.44(s,1H),7.13(s,1H),3.87(s,3H).
步骤5 化合物18的合成
将化合物17(2.3g)和L-Methionine(1.80g)加入到甲基磺酸(60mL)中，反应在回流下搅拌反应4hrs。冷却至室温，往体系中加入碎冰，缓慢用NaOH(40％)水溶液调pH为7。固体过滤，用甲醇重结晶，滤液减压浓缩得到白色固体1.7g。LC-MS(APCI):m/z＝196.1(M+1) +。
步骤6 化合物19的合成
室温下将催化量的DMAP加入到化合物18(1.70g，8.71mmol)和吡啶(1.70mL)的醋酸酐(12mL)中，体系升温至100℃，氮气保护下反应6hrs。冷却至室温，往体系中加入碎冰。固体过滤，用冷水洗涤，固体在65℃下真空干燥得到黄色固体1.20g，收率：58.08％。LC-MS(APCI):m/z＝238.0(M+1) +。 1H NMR(500MHz,DMSO-d 6)δ12.19(s,1H),8.07(s,1H),7.74(s,1H),7.27(s,1H),3.91(s,3H),2.29(s,3H).
步骤7 化合物20的合成
在75℃下，将三氯氧磷(1.08mL)在20min内滴加到化合物19(1.1g)和DIPEA(4.130.95mL)的甲苯(10ml)溶液中，滴加完毕后，反应液在当前温度下搅拌3hrs。反应完毕后直接投入下一步。
将3,4-二氯-2-氟苯胺(960mg)的甲苯(5mL)缓慢滴加到上述反应液中，滴加完毕后，反应继续搅拌2hrs。反应冷却至室温，固体过滤，用甲苯(6mL)洗涤，固体再用异丙醇(20mL)搅拌打浆2hrs。固体过滤，用异丙醇(5mL)洗涤固体。固体真空下干燥。LC-MS(APCI):m/z＝399.2(M+1) +。
步骤8 中间体化合物B-3的合成
在10℃下将氨水(4.5mL)加入到上述所得化合物20的甲醇(9mL)中，反应在室温下搅拌3hrs。固体过滤，用H 2O(5mL)和甲醇(5mL)的混合液洗涤固体。真空下50℃下干燥过夜到得到灰白色固体(620mg)，三步收率：36.3％。LC-MS(APCI):m/z＝357.1(M+1) +。
实施例12 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(甲氧基-d 3)喹唑啉-6-基)氧基)哌啶-1-基)丙-2- 烯-1-酮(化合物I-6)的制备。
Figure PCTCN2019087720-appb-000025
根据实施例5中所述的合成方法，用中间体化合物B-3替代步骤1中的中间体化合物B-1，用4-(甲苯-4-磺酰氧)哌啶-1-羧酸叔丁酯来替代步骤1中的中间体化合物A-1进行制备，得到135mg的白色固体化合物I-6，产率为64.30％，纯度为96.41％(HPLC)，LC-MS(APCI):m/z＝494.2(M+1) +。 1H NMR(500MHz,DMSO-d 6):δ9.64(s,1H),8.39(s,1H),7.88(s,1H),7.65–7.54(m,2H),7.24(s,1H),6.84(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.7,2.4Hz,1H),5.68(dd,J＝10.5,2.4Hz,1H),4.87–4.69(m,1H),3.93–3.80(m,2H),3.55–3.40(m,J＝31.1Hz,2H),2.09–1.97(m,2H),1.75–1.64(m,2H)。
实施例13 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(甲氧基-d 3)喹唑啉-6-基)氧基)哌啶-1-基-4-d) 丙-2-烯-1-酮(化合物I-7)的制备。
Figure PCTCN2019087720-appb-000026
根据实施例5中所述的合成方法，用中间体化合物B-3替代步骤1中的中间体化合物B-1，中间体化合物A-2来替代步骤1中的中间体化合物A-1进行制备，得到60mg白色固体，产率为48.89％，纯度为98.69％(HPLC)，LC-MS(APCI):m/z＝495.2(M+1) +。 1H NMR(500MHz,DMSO-d 6):δ9.63(s,1H),8.39(s,1H),7.88(s,1H),7.68–7.54(m,2H),7.24(s,1H),6.84(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.7,2.4Hz,1H),5.68(dd,J＝10.5,2.4Hz,1H),3.96–3.79(m,2H),3.57–3.39(m,2H),2.12–1.92(m,2H),1.78–1.59(m,2H).
实施例14 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(甲氧基-d 3)喹唑啉-6-基)氧基)哌啶-1-基 -3,3,4,5,5-d 5)丙-2-烯-1-酮(化合物I-8)的制备。
Figure PCTCN2019087720-appb-000027
根据实施例5中所述的合成方法，用中间体化合物B-3替代步骤1中的中间体化合物B-1，中间体化合物A-3来替代步骤1中的中间体化合物A-1进行制备，得到72mg白色固体化合物I-8，产率为42.81％，纯度为99.51％(HPLC)。LC-MS(APCI):m/z＝499.2(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.39(s,1H),7.87(s,1H),7.66–7.50(m,2H),7.23(s,1H),6.84(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.7,2.2Hz,1H),5.68(dd,J＝10.4,2.2Hz,1H),3.96–3.76(m,2H),3.60–3.39(m,2H).
实施例15 1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(甲氧基-d3)喹唑啉-6-基)氧基)哌啶-1-基 -3,3,5,5-d4)丙-2-烯-1-酮(化合物I-9)的制备。
Figure PCTCN2019087720-appb-000028
根据实施例5中所述的合成方法，用中间体化合物B-3替代步骤1中的中间体化合物B-1进行制备，得到50mg白色固体化合物I-9，产率为34.29％，纯度为99.07％(HPLC)。LC-MS(APCI):m/z＝498.2(M+1) +。 1H NMR(300MHz,DMSO-d 6)δ9.67(s,1H),8.40(s,1H),7.89(s,1H),7.73–7.52(m,2H),7.25(s,1H),6.86(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.2Hz,1H),5.69(dd,J＝10.5,2.1Hz,1H),4.77(s,1H),3.98–3.81(m,2H),3.56–3.42(m,2H).
生物活性测试。
(1)激酶抑制作用
使用ADP-GloTM Kinase Assay kit(Promega，V9102)试剂盒，测定待测物对EGFR(D770_N771insNPG)(Signalchem，E-10-132GG)和HER2(A775_G776insYVMA)(Signalchem，E27-13BG)的抑制活性。
用DMSO(MP，196055)分别将化合物按3倍浓度梯度稀释，各12个剂量。化合物的起始浓度为0.1mM。384孔板(Perkin Elmer，6007290)每孔加入100nl化合物稀释液与5μL EGFR(D770_N771insNPG)或HER2(A775_G776insYVMA)，双复孔。25℃孵育15分钟后，加入5μL底物启动反应，25℃孵育60分钟。体系中最终反应浓度为：0.5nM EGFR或10nM HER2,10μM ATP,0.03mg/mL Poly(4:1Glu,Tyr)Peptide,HEPES 50mM,EGTA 1mM,MgCl2 10mM,Brij35 0.01％。待测化合物浓度:1,0.33,0.11,0.037,0.0123,0.004,0.0014,0.00047,0.00015,0.00005,0.000017,0nM。然后加入10μL ADP Glo reagent，25℃继续孵育40分钟。再加入20μL检测试剂，25℃孵育40分钟后，通过Envision酶标仪(Perkin Elmer 2104)检测，测定在各浓度化合物存在下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性。之后根据四参数方程，根据Graphpad 5.0软件对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC 50值。
在上述激酶抑制实验中测试了本发明化合物，发现与非氘代的母型化合物Pozoitinib相比，本发明化合物对EGFR D770_N771insNPG和HER2 A775_G776insYVMA激酶具有相当甚者更强的抑制作用，表明本发明化合物对EGFR和HER2的外显子20插入突变具有更强效的活性。代表性的实施例化合物的结果归纳于下表1中。
表1：
Figure PCTCN2019087720-appb-000029
Figure PCTCN2019087720-appb-000030
(2)细胞毒性测试
取肺癌细胞NCI-H1975(购自美国标准生物品收藏中心(ATCC))、Ba/F3 EGFR-D770_N771insSVD及Ba/F3 ERBB2-A775_G776insYVMA对数生长期细胞，用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。将细胞接种到96孔板中，37℃、5％CO 2培养过夜。配制10倍药物溶液，最高浓度为10μM，9个浓度，3倍稀释。96孔板中每孔加入10μL药物溶液，三个复孔，继续培养72小时。每孔加入等体积的CTG溶液，定轨摇床上振动5分钟使细胞裂解，室温放置20分钟稳定冷光信号后，在SpectraMax多标记微孔板检测仪(MD，2104-0010A)上读取冷光值。使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。
在上述激酶抑制实验中测试了本发明化合物，发现与非氘代的母型化合物Pozoitinib相比，本发明化合物对NCI-H1975、Ba/F3 EGFR-D770_N771insSVD和Ba/F3 ERBB2-A775_G776insYVMA具有更强的抑制作用，表明本发明化合物对EGFR T790M突变、EGFR和HER2的外显子20插入突变具有强效的活性。代表性的实施例化合物的结果归纳于下表2中。
表2
Figure PCTCN2019087720-appb-000031
(3)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；小鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物和对照品化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL小鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体或者小鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int， 其中V/M即等于1/蛋白浓度。
Figure PCTCN2019087720-appb-000032
t 1/2(min)；CL int(μL/min/mg)。
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定性。采用未经氘代的化合物Poziotinib作为对照品。在人、大鼠和小鼠肝微粒体实验中，通过与未经氘代的化合物Poziotinib对照，本发明化合物可以明显改善代谢稳定性。代表性实施例化合物的结果归纳于下表3中。
表3：
Figure PCTCN2019087720-appb-000033
(4)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治疗效果。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (15)

  1. 一种式(I)化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体：
    Figure PCTCN2019087720-appb-100001
    其中，
    Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢或氘；
    X选自CH 3、CD 3、CHD 2或CH 2D；
    附加条件是，上述化合物至少含有一个氘原子。
  2. 根据权利要求1所述的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，其中，
    Y 1、Y 2、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢或氘；
    X选自CH 3、CD 3、CHD 2或CH 2D；
    Y 3、Y 4、Y 5、Y 6、Y 7和Y 8为氢；
    附加条件是，上述化合物至少含有一个氘原子。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，Y 2是氘。
  4. 根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐，其中，R 6、R 7、R 8和R 9是氢。
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐，其中，R 2、R 3、R 4、R 5是氘。
  6. 根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐，其中，R 1是氘。
  7. 根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐，其中，X是CD 3。
  8. 根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐，其中所述化合物可选自如下任一结构：
    Figure PCTCN2019087720-appb-100002
    Figure PCTCN2019087720-appb-100003
  9. 一种药物组合物，其含有药学上可接受的赋形剂和权利要求1-8中任一项所述的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。
  10. 根据权利要求9所述的药物组合物，其还包含其它治疗药物，其中所述其它治疗药物选自细胞信号转导抑制剂、有丝分裂抑制剂、烷化剂、抗代谢药、抗生素、生长因子抑制剂、细胞周期抑制剂、拓扑异构酶抑制剂、生物反应调节剂、抗激素药和抗雄激素。
  11. 权利要求1-10中任一项所述的化合物或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，或权利要求9或10的药物组合物在制备用于治疗和/或预防ErbB家族酪氨酸激酶介导的疾病的药物中的用途。
  12. 一种在受试者中治疗和/或预防ErbB家族酪氨酸激酶介导的疾病的方法，包括给药有效量的权利要求1-8中任一项所述的化合物或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体，或权利要求9或10的药物组合物。
  13. 根据权利要求11的用途或权利要求12的方法，其中所述的ErbB家族酪氨酸激酶选自EGFR、Her2、Her3或Her4激酶的野生型和突变体中的一个或多个激酶。
  14. 根据权利要求13的用途或方法，其中，所述的EGFR和Her2突变体选自Ex20Ins突变。
  15. 根据权利要求11的用途或权利要求12的方法，其中所述的增殖性疾病是转移癌、表皮癌、结肠癌、胃腺癌、膀胱癌、乳癌、肾癌、肝癌、肺癌、甲状腺癌、脑瘤、颈癌、前列腺癌、胰腺癌、中枢神经系统的癌症、恶性胶质瘤、骨髓增生病、动脉粥样硬化或肺纤维化。
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