WO2019184966A1 - 取代的二氨基杂环甲酰胺化合物及包含该化合物的组合物及其用途 - Google Patents

取代的二氨基杂环甲酰胺化合物及包含该化合物的组合物及其用途 Download PDF

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WO2019184966A1
WO2019184966A1 PCT/CN2019/080011 CN2019080011W WO2019184966A1 WO 2019184966 A1 WO2019184966 A1 WO 2019184966A1 CN 2019080011 W CN2019080011 W CN 2019080011W WO 2019184966 A1 WO2019184966 A1 WO 2019184966A1
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compound
hydrogen
chd
pharmaceutically acceptable
prodrug
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PCT/CN2019/080011
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English (en)
French (fr)
Inventor
王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to JP2020552408A priority Critical patent/JP7492742B2/ja
Priority to CN201980014848.0A priority patent/CN111788197B/zh
Priority to US16/971,128 priority patent/US11512074B2/en
Priority to EP19775720.6A priority patent/EP3741753A4/en
Publication of WO2019184966A1 publication Critical patent/WO2019184966A1/zh
Priority to US17/973,182 priority patent/US20230138863A1/en
Priority to JP2022184693A priority patent/JP2023015343A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a substituted diaminoheterocyclic carboxamide compound and a composition comprising the same and use thereof. More specifically, the present invention relates to certain anthracene substituted 6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- Phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide, these hydrazine-substituted compounds are shown to inhibit tyrosine kinases of AXL and FLT3 proteins And can be used to treat AXL and/or FLT3 mediated related diseases, and these quinone substituted compounds have more excellent pharmacokinetic properties and pharmacodynamic properties.
  • AML Acute Myeloid Leukemia
  • Myelocytic Leukemia is a disease caused by the malignant proliferation of bone marrow hematopoietic progenitor cells. As poorly differentiated progenitor cells lose their normal function, they disrupt the normal hematopoietic process, leading to infection, bleeding and dysfunction of multiple organs.
  • the overall incidence of AML is 3.4/100,000, and the median age of patients is 67 years, while more than half of the patients are ill before the age of 65.
  • the prognosis of patients with AML is generally poor, especially in elderly and poorly ill patients.
  • FMS-like tyrosine kinase 3 is a type III receptor tyrosine kinase that plays a key role in the proliferation, differentiation and apoptosis of hematopoietic cells and lymphocytes.
  • Abnormal activation of FLT3 is closely related to the occurrence and development of AML. Studies have shown that more than one-third of AML patients are accompanied by abnormal activation of FLT3.
  • the structure of FLT3 includes a cell extramembranous domain composed of five immunoglobulin-like forms, a transmembrane domain, and an intracellular membrane tyrosine kinase domain.
  • FLT3 is mainly expressed on the cell surface of normal hematopoietic hepatocytes and hematopoietic progenitor cells, and its ligand is mainly expressed in bone marrow stromal cells.
  • the ligand When the ligand binds to the extramembrane domain of FLT3 cells, it promotes the dimerization of the FLT3 receptor, and autophosphorylation of the tyrosine kinase domain in the cell membrane activates a series of downstream signaling pathways, such as Ras/MAPK, PI3K/Akt/ mTOR and STAT5 thereby regulate cell proliferation and differentiation.
  • FLT3 mutations usually lead to abnormal activation. In the absence of binding to ligands, autophosphorylation activates downstream signaling pathways, leading to abnormal proliferation of hematopoietic cells and lymphocytes, leading to a variety of malignant blood diseases.
  • ITD mutation refers to the insertion of repeated tandem amino acid sequences in the membrane proximal domain of FLT3, which is associated with approximately 17% to 34% of AML patients, as well as in Myelodysplastic Syndrome (MDS).
  • MDS Myelodysplastic Syndrome
  • the ITD mutation destroys the autoinhibitory activity of the juxtamembrane domain, causing the autoinhibition to be lost, and FLT3 is therefore in a sustained activation conformation.
  • Patients with AML with ITD mutations are often accompanied by clinical manifestations such as an increase in the number of white blood cells and an increase in the percentage of primitive bone marrow cells and blood cells. Because of the high recurrence rate and adverse reactions of patients with AML after ITD mutation, the poor prognosis of patients with ITD mutations is worse than that of patients with common A ML.
  • the point mutation of FLT3 occurs mainly on the activation loop of TKD. Insertion or deletion of the 20th exon of the FLT3 gene can mutate the 835 aspartate residue at the C-terminus of TKD in FLT3. This mutation is present in approximately 7% of AML patients. The most common mutation is Asp835Tyr, along with other mutations such as Asp835Val, Asp835Glu and Asp835Asn. These point mutations stabilize the activation in the conformation upon binding to ATP, thereby allowing FLT3 to be continuously activated.
  • FLT3 targeted therapy has become the focus of research on anti-AML drugs.
  • AXL is a receptor-type tyrosine kinase, and is a protein having a cell transmembrane region at the center, a tyrosine kinase domain on its carboxy terminal side, and an extracellular region on the amino terminal side. So far, reports on acute leukemia, astrocytoma, breast cancer, colorectal cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, hepatocellular carcinoma, Kaposi's sarcoma, lung cancer, melanoma, ovarian cancer, flesh Overexpression of AXL in tumor, pancreatic ductal adenocarcinoma, renal cell carcinoma, prostate cancer, thyroid cancer, and endometrial cancer.
  • AXL overexpression was also shown in cells that were resistant to chemotherapy, and AXL cell lines stably expressed by AXL also showed chemoresistance, so AXL was considered to be the cause of drug resistance.
  • Gilteritinib (chemical name 6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- 5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide, which has the following structural formula) is a FLT3 inhibitor developed by Japan Astellas Pharmaceutical Co., Ltd., which can effectively inhibit ITD and TKD, for the treatment of adult patients with recurrent or refractory AML with positive FLT3 mutation, can also inhibit kinases such as AXL.
  • ADME ulcerative co-oxidative desorption, distribution, metabolism, and/or excretion
  • Many of the drugs currently on the market also limit their range of applications due to poor ADME properties.
  • the rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body.
  • Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs.
  • rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
  • the present invention discloses a novel hydrazine-substituted aminoheterocyclic carboxamide compound, and compositions and uses thereof, which have better FLT3 and AXL kinase inhibitory activity, lower side effects, and higher selection. Sexuality and better pharmacodynamics/pharmacokinetic properties can be used to treat related cancers such as AML.
  • compound of the invention refers to compounds of formula ( ⁇ ), (I) and (II).
  • the term also encompasses pharmaceutically acceptable salts, prodrugs, hydrates or solvate compounds, polymorphs, stereoisomers or isotopic variations of the compounds of formula ( ⁇ ), (I) and (II).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are each independently selected from hydrogen or hydrazine;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 ;
  • Y 1 , Y 2 and Y 3 are each independently selected from hydrogen or hydrazine
  • the above compound has at least one ruthenium 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.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention also relates to a method of treating a disease mediated by FLT3 kinase in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the cancer is mediated by FLT3.
  • the patient is diagnosed or identified as having a FLT3-related cancer.
  • the FLT3 mediated disease is AML.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment of a disease mediated by FLT3 kinase.
  • Such use comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the disease is mediated by FLT3.
  • the patient is diagnosed or identified as having a FLT3-related cancer.
  • the FLT3 mediated disease is AML.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • the invention also relates to a method of treating a disease associated with AXL kinase in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the disease is mediated by AXL.
  • the patient is diagnosed or identified as having an AXL-related cancer.
  • the disease is a cancer that is highly expressed by AXL.
  • the disease is a cancer that is resistant to anti-cancer drug therapy by AXL activation.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • the invention also relates to the use of a compound of the invention for the manufacture of a medicament for AXL kinase-associated diseases.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the disease is mediated by AXL.
  • the patient is diagnosed or identified as having an AXL-related cancer.
  • the disease is a cancer that is highly expressed by AXL.
  • the disease is a cancer that is resistant to anti-cancer drug therapy by AXL activation.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon 14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may be in amorphous or crystalline form. Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state. A drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduction This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, the hydroxy, thiol and amino functional acetate/amide, formate/amide and benzoate/amide derivatives of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • crystalline form refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • the term "subject” includes, but is not limited to, a human (ie, a male or female of any age group, eg, a pediatric subject (eg, an infant, a 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 (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a “therapeutically effective amount” of a compound, as used herein, is a quantity sufficient to provide a therapeutic benefit, or one or more associated with a disease, disorder, or condition, in the course of treating a disease, disorder, or condition, unless otherwise stated. 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” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the present invention provides a compound of formula ( ⁇ ), or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, crystal form, stereoisomer or isotopic variation thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are each independently selected from hydrogen or hydrazine;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 ;
  • Y 1 , Y 2 and Y 3 are each independently selected from hydrogen or hydrazine
  • the above compound has at least one ruthenium atom.
  • the compound of the formula ( ⁇ ) contains at least one halogen atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms, more preferably five germanium atoms.
  • An atom more preferably six helium atoms, more preferably seven helium atoms, more preferably eight helium atoms, more preferably nine helium atoms, more preferably ten helium atoms, more preferably eleven helium atoms More preferably twelve helium atoms, more preferably thirteen helium atoms, more preferably fourteen helium atoms, more preferably fifteen helium atoms, more preferably sixteen helium atoms, more preferably ten Seven helium atoms, more preferably eighteen helium atoms, more preferably nineteen helium atoms, more preferably twenty helium atoms, more preferably twenty one helium atoms, more preferably twenty-two helium atoms An atom, more preferably twenty-three helium atoms, more preferably twenty-four helium atoms, more preferably twenty-five helium atoms, more preferably twenty-six helium atoms,
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • each The strontium isotope content in the generation location is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, and even more preferably greater than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70 More preferably, it is more than
  • the compound of formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, Twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-first, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight A cesium atom.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are each independently selected from hydrogen or hydrazine.
  • the technical solution includes that R 1 is selected from hydrogen or hydrazine.
  • R 2 is selected from hydrogen or hydrazine
  • R 3 is selected from hydrogen or hydrazine, and so on, until R 24 is selected from the group consisting of hydrogen or hydrazine; more specifically, R 1 is hydrogen or R 1 is hydrazine, R 2 Is hydrogen or R 2 is deuterium, R 3 is hydrogen or R 3 is deuterium, and so on until R 24 is hydrogen or R 24 is deuterium.
  • the technical scheme that "X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D" includes that X 1 is selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D, and X 1 are selected from the technical schemes of CH 3 , CD 3 , CHD 2 and CH 2 D; more specifically, X 1 is CH 3 , X 1 is CD 3 , X 1 is CHD 2 or X 1 is CH 2 D, and X 2 are CH 3 , X 2 is CD 3 , X 2 is CHD 2 or X 2 is CH 2 D.
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 ” technical solutions include X 3 is CH 2 CH 3 , X 3 is CH 2 CH 2 D, X 3 is CH 2 CHD 2 , X 3 is CH 2 CD 3 , X 3 is CHDCH 3 , X 3 is CHDCH 2 D, X 3 is CHDCHD 2 , X 3 is CHDCD 3 , X 3 is CD 2 CH 3 , X 3 is CD 2 CH 2 D, and X 3 is CD 2 CHD 2 or X 3 is a technical solution for CD 2 CD 3 .
  • the technical scheme that "Y 1 , Y 2 and Y 3 are each independently selected from hydrogen or hydrazine" includes Y 1 being selected from hydrogen or hydrazine, Y 2 being selected from hydrogen or hydrazine, and Y 3 being selected A technical scheme from hydrogen or helium; more specifically, a technical scheme comprising Y 1 being hydrogen or Y 1 being deuterium, Y 2 being hydrogen or Y 2 being deuterium, Y 3 being hydrogen or Y 3 being deuterium.
  • the invention relates to a compound of formula (I):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are each independently selected from hydrogen or hydrazine;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 ;
  • the above compound has at least one ruthenium atom
  • the compound of the formula (I) contains at least one halogen atom, more preferably one germanium atom, more preferably two germanium atoms, more preferably three germanium atoms, more preferably four germanium atoms.
  • the earth is eleven atoms, more preferably twelve helium atoms, more preferably thirteen helium atoms, more preferably fourteen helium atoms, more preferably fifteen helium atoms, more preferably sixteen Helium atom, more preferably seventeen helium atoms, more preferably eighteen helium atoms, more preferably nineteen helium atoms, more preferably twenty helium atoms, more preferably twenty one helium atoms, more Preferably twenty-two helium atoms, more preferably twenty-three helium atoms, more preferably twenty-four helium atoms, more preferably twenty-five helium atoms, more preferably twenty-six helium
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the compound of the formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, Twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-first, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight A cesium atom.
  • X 1 and X 2 are each independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D. In another preferred embodiment, X 1 and X 2 are each independently selected from CH 3 and CD 3 . In another preferred embodiment, X 1 is CH 3 . In another preferred embodiment, X 1 is CD 3 . In another preferred embodiment, X 2 is CH 3 . In another preferred embodiment, X 2 is CD 3 . In another preferred embodiment, X 1 and X 2 are the same. In another embodiment, X 1 and X 2 are different.
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • X 3 is selected from the group consisting of CH 2 CH 3 and CD 2 CD 3 .
  • X 3 is CH 2 CH 3 .
  • X 3 is CD 2 CD 3 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen or hydrazine.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are both deuterium.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or hydrazine.
  • R 9 , R 10 , R 11 and R 12 are the same, and R 13 , R 14 , R 15 and R 16 are the same.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are all hydrogen.
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are both deuterium.
  • R 9 , R 10 , R 11 and R 12 are both deuterium, and R 13 , R 14 , R 15 and R 16 are all hydrogen. In another preferred embodiment, R 9 , R 10 , R 11 and R 12 are all hydrogen, and R 13 , R 14 , R 15 and R 16 are both deuterium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, wherein R 9 - R 12 is hydrogen, R 1 - R 8 are each independently selected from hydrogen or hydrazine, and R 13 - R 24 are each independently selected from hydrogen or hydrazine, and X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D, X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 And CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 , with the proviso that the above compound has at least one ruthenium atom.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 1 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 24 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or deuterium
  • R 13 -R 24 are each independently selected from hydrogen or deuterium
  • X 3 is selected from CH. 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 to R 24 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or deuterium
  • R 13 -R 24 are each independently selected from hydrogen or deuterium
  • X 1 and X 2 Each is independently selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • X 2 is CD 3
  • R 1 - R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine.
  • X 1 is selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine.
  • X 2 is selected from the group consisting of CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 are hydrogen
  • R 13 -R 24 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , and R 1 - R 24 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , R 9 -R 12 are hydrogen, R 1 -R 8 are each independently selected from hydrogen or hydrazine, and R 13 -R 24 are each independently selected from Hydrogen or helium.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , R 1 - R 8 are hydrogen, and R 9 - R 24 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , R 1 - R 12 are hydrogen, and R 13 - R 24 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from hydrogen or hydrazine;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D;
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 ;
  • the above compound has at least one ruthenium atom
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, wherein R 9- R 12 is hydrogen, R 1 -R 8 are each independently selected from hydrogen or hydrazine, and X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D, and X 3 is selected from CH 2 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof
  • R 1 -R 12 are hydrogen
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 , with the proviso that the above compound has at least one hydrazine atom.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof
  • X 2 is CD 3
  • R 1 -R 12 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 9 -R 12 is hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • R 1 -R 12 is hydrogen
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 12 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • R 1 -R 12 are hydrogen
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 12 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from the group consisting of CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 9 -R 12 are hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 and X 2 are CD 3
  • R 1 -R 12 are hydrogen
  • X 3 is selected from CH 2 CH 3 , CH 2 CH 2 D, CH 2 CHD 2 , CH 2 CD 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3 , CD 2 CH 3 , CD 2 CH 2 D, CD 2 CHD 2 and CD 2 CD 3 .
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 to R 12 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 is hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 are hydrogen
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 3 is selected from CD 2 CD 3
  • X 2 is CD 3
  • R 1 - R 12 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 is hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 2 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 is hydrogen
  • X 1 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 9 -R 12 is hydrogen
  • R 1 -R 8 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 8 are hydrogen
  • R 9 -R 12 are each independently selected from hydrogen or hydrazine
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof,
  • X 1 is CD 3
  • X 3 is selected from CD 2 CD 3
  • R 1 -R 12 is hydrogen
  • X 2 is selected from CH 3 , CD 3 , CHD 2 and CH 2 D.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , and R 1 - R 12 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , R 9 - R 12 is hydrogen, and R 1 - R 8 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , R 1 - R 8 are hydrogen, and R 9 - R 12 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, crystalline form, stereoisomer or isotopic variation thereof, X 1 and X 2 are CD 3 , X 3 is selected from CD 2 CD 3 , and R 1 - R 12 are hydrogen.
  • the compound is selected from the group consisting of:
  • the compound does not include a non-deuterated compound.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), a buffer substance (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embe
  • compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules. , powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the invention or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, ocular Internal, intramuscular, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or phosphoric acid Calcium; silica; cross-linked hydroxymethylcellulose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, hydroxymethyl cellulose, cross-linked poly Vinyl pyrrolidone and the like.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compounds of the invention may be administered by any route and method of administration, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of the invention is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compounds of the invention is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration may be intermittent, for example, wherein the patient receives a daily dose of a compound of the invention over a period of several days, followed by a patient's daily dose of the compound of the invention for a period of several days or more. .
  • the compounds of the invention exhibit FLT3 protein tyrosine kinase inhibition and are useful in the treatment of FLT3 mediated diseases.
  • the invention provides a method of treating a disease mediated by FLT3 kinase in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • the cancer is mediated by FLT3.
  • the patient is diagnosed or identified as having a FLT3-related cancer.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly.
  • the compound is administered chronically.
  • the FLT3 mediated disease is AML.
  • the invention provides methods of cancer associated with AXL.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
  • AXL is a receptor-type tyrosine kinase, and is a protein having a cell transmembrane region at the center, a tyrosine kinase domain at its carboxy terminal side, and an extracellular region at the amino terminus.
  • Cancer associated with AXL refers to cancer of AXL, one of the causes of cancer.
  • AXL a highly expressed cancer of AXL, AML, astrocytoma, breast cancer, colon cancer, digestive tract stromal tumor, gastric cancer, hepatocellular carcinoma, Kaposi's sarcoma, lung cancer, melanoma, ovarian cancer, osteosarcoma, Pancreatic ductal adenocarcinoma, renal cell carcinoma, prostate cancer, thyroid cancer, endometrial cancer, AXL overexpressing cancer compared with normal tissue.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art. Advantages of the present invention include: First, the use of the compounds and compositions of the present invention provides a more advantageous therapeutic tool for the treatment of AML, particularly FLT3- and AXL-related AML. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Example 6 6-(Ethyl-d 5 )--3-((3-(methoxy-d 3 )-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)-5-((tetrahydro) Preparation of -2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Compound T-6).
  • Enzyme AXL Invitrogen-A31516, substrate ULight-poly GT peptide (PerkinElmer-TRF0100-M),
  • Antibody Eu-labeled anti-phos (PT66) (PerkinElmer-AD0069), ATP (Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650), 96-well plate (Corning, Cat. No. 3365), 384-well plate (Greiner, catalog number 784076).
  • the inhibitory activity of the test substance on AXL was measured using the LANCE Ultra TR-FRET method.
  • test compound was dissolved in DMSO, it was diluted by a 3-fold concentration gradient and diluted ten times.
  • the AXL kinase was transferred to a 384-well assay plate with different concentrations of compound prepared in advance dilution for 10 minutes at each concentration.
  • the substrate and ATP were added to initiate the reaction and incubated for 90 minutes at room temperature.
  • the final reaction concentrations in the system were: 3 nM AXL, 4.75 uM ATP, 50 nM peptide, 50 mM Hepes pH 7.5, 1 mM EGTA, 10 mM MgCl2, 0.01% Brij-35, 2 mM DTT.
  • the highest concentration of the test compound was 300 nM.
  • the compound of the present invention was tested in the above kinase inhibition assay, and it was found that the compound of the present invention has potent activity against AXL and has a better inhibitory effect than Giltiterinib.
  • the results for the representative example compounds are summarized in Table 1 below.
  • Cell MV-4-11 ATCC, catalog number CRL-9591), cell MOLM-13COBIOER, catalog number CBP60678), RPMI-1640 (GIBCO, catalog number A10491-01), penicillin-streptomycin (GIBCO, catalog number 15140 -122), fetal bovine serum (GIBCO, catalog number 10099-141), phosphate buffer solution PBS (GIBCO, catalog number 10010-031), DMSO (Sigma, catalog number D8418-1L), CelltiterGlo assay kit (CTG) (Promega, catalog number G7573), 96-well clear flat black panel (PerkinElmer, catalog number 6005680-50), plate vibrating screen (QILINBEIER, catalog number B-9002), centrifuge (Eppendorf, catalog number 5804R), CO2 Incubator (Thermo Scientific, catalog number 371), microscope (OLYMPUS catalog number CKX41), multi-plate reader (PerkinElmer catalog number EnVision).
  • MV-4-11 cell culture medium is IMDM + 10% FBS + 1% PS, cell density does not exceed 1X106 / ml.
  • the MOLM-13 cell culture medium is RPMI1640+20%FBS+1%PS, and the cell density does not exceed 1X106/ml.
  • the cell suspension was added to a 96-well plate at 100 ⁇ l per well, ie MV-4-11 cells 5000/well; MOLM-13 cells 5000/well.
  • the cell plates were placed in a 37 ° C, overnight culture in a 5% CO 2 incubator.
  • MV-4-11 cells Compounds were diluted from 10 mM to 60 uM with DMSO and then diluted three times in DMSO from 60 uM.
  • MOLM-13 cells Compounds were diluted from 10 mM to 200 uM with DMSO and then diluted three times at a concentration of 200 uM in DMSO.
  • MV-4-11 cells 300, 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, 0.046, 0 [nM].
  • MOLM-13 cells 1000, 333.3, 111.1, 37.04, 12.35, 4.1, 1.37, 0.46, 0.15, 0 [nM].
  • IC 50 was calculated using GraphPad Prism 6software.
  • the IC50 (half inhibitory concentration) of the compound was obtained by the following nonlinear fitting formula.
  • cell line Ba/F3parental suspension, 3000 cells/well, medium RPMI-1640 + 10% FBS + 8 ng/ml IL-3
  • cell line Ba/F3FLT3-ITD suspension, 3000/well, medium RPMI-1640+10% FBS
  • fetal bovine serum FBS GBICO, Cat#10099-141
  • Luminescent Cell Viability Assay Promega, Cat# G7572
  • 96-well transparent flat black panel Cat #3603
  • control compound AC220 Selleck, Cat #S1526
  • Instruments SpectraMax multi-label microplate reader, MD, 2104-0010A; CO 2 incubator, Thermo Scientific, Model 3100 Series; biosafety cabinet, Thermo Scientific, Model 1300 Series A2; inverted microscope, Olympus, CKX41SF; refrigerator, SIEMENS, KK25E76TI.
  • the cells in the 96-well plates were incubated overnight at 37 ° C, 5% CO 2 , 95% humidity.
  • the cells in the treated 96-well plates were further cultured at 37 ° C, 5% CO 2 , 95% humidity for 72 hours, followed by CTG analysis.
  • the compounds of the invention were tested in the above test experiments.
  • the results indicate that the compounds of the present invention have potent activity against Ba/F3FLT3-ITD and superior selectivity to cellular Ba/F3parental compared to gilteritinib.
  • the results of the inhibition of the in vitro proliferation of cells by representative examples are summarized in Table 3 below.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the undeuterated compound Gilteritinib was used as a control.
  • the compounds of the invention can significantly improve metabolic stability by comparison with the undeuterated compound Giltiterinib.
  • Representative Examples Human liver microsome experiment results are summarized in Table 4 below.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

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Abstract

一种如式(Φ)所示的取代的氨基杂环甲酰胺化合物、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及其药物组合物和作为FLT3/AXL激酶的抑制剂用于治疗急性髓细胞白血病用途。 (ϕ)

Description

取代的二氨基杂环甲酰胺化合物及包含该化合物的组合物及其用途 技术领域
本发明属于医药技术领域，尤其涉及一种取代的二氨基杂环甲酰胺化合物及包含该化合物的组合物及其用途。更具体而言，本发明涉及某些氘取代的6-乙基-3-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺，这些氘取代的化合物显示为AXL和FLT3蛋白酪氨酸激酶抑制剂，且可用于治疗AXL和/或FLT3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和药效学性质。
背景技术
急性髓细胞白血病(Acute Myeloid(Myelocytic)Leukemia，AML)是一种由骨髓造血祖细胞恶性增殖造成的疾病。由于低分化的祖细胞失去了正常功能，扰乱了正常的造血过程，从而导致感染、出血和多器官的机能障碍。AML的总体发病率为3.4/10万，患者年龄的中位数为67岁，而超过半数的患者在65岁前发病。AML患者的预后普遍较差，尤其是老年和身体素质差的患者。
FMS样酪氨酸激酶3(fms-like tyrosine kinase 3,FLT3)是一种III型受体酪氨酸激酶，在造血细胞和淋巴细胞的增殖、分化、凋亡过程中发挥关键作用。FLT3的异常激活与AML的发生发展密切相关。研究表明超过1/3的AML患者伴随有FLT3的异常激活。
FLT3的结构包括由5个免疫球蛋白样组成的细胞膜外结构域、跨膜结构域和细胞膜内酪氨酸激酶结构域。FLT3主要在正常的造血肝细胞和造血祖细胞的细胞表面表达，其配体主要在骨髓基质细胞中表达。当配体与FLT3细胞膜外结构域结合后，促使FLT3受体二聚化，同时细胞膜内酪氨酸激酶域发生自身磷酸化，激活一系列下游信号传导途径，如Ras/MAPK、PI3K/Akt/mTOR和STAT5从而调控细胞的增殖和分化。FLT3突变通常会导致其异常活化，在不与配体结合的情况下，发生自身磷酸化激活下游信号通路，导致造血细胞和淋巴细胞的异常增殖，引发多种恶性血液疾病。
FLT3的激活突变主要有两种类型：近膜结构域的内部串联重复(Internal Tandem Duplication，ITD)突变；激酶结构域(tyrosine kinase domain，TKD)中活化环的点突变。
ITD突变是指在FLT3的近膜结构域插入重复串联的氨基酸序列，大约17％～34％的AML患者伴随有此突变，同时在骨髓增生异常综合征(Myelodysplastic syndrome，MDS)中也检测到该突变的发生。通常情况下，近膜结构域对FLT3具有自身抑制功能，能够对激酶结构域的磷酸化产生抑 制作用。但是ITD突变会破坏近膜结构域的自身抑制活性，致使该自抑制作用丧失，FLT3因此处于持续激活构象。具有ITD突变的AML患者，往往伴随有白细胞数目增多，原始骨髓细胞与血细胞百分比增加等临床表现。由于ITD突变后患者AML复发率高且不良反应多，所以与普通A ML患者相比，ITD突变患者的不良预后更差。
FLT3的点突变主要发生在TKD的活化环(activation loop)上。FLT3基因第20位外显子发生插入或者删除，可使FLT3中TKD的C端835位天冬氨酸残基发生突变。大约7％的AML患者中存在该突变。最常见的突变为Asp835Tyr，同时还有其它突变如Asp835Val，Asp835Glu和Asp835Asn。这些点突变能够将活化稳定于结合ATP时的构象，从而使FLT3持续活化。
鉴于FLT3在AML发病过程中起关键作用，FLT3靶向治疗已成为抗AML药物研究重点。
AXL为受体型酪氨酸激酶，并且是在中心具有细胞跨膜区、在其羧基末端侧具有酪氨酸激酶结构域、在氨基末端侧具有胞外区的蛋白质。到目前为止，报道了在急性白血病、星状细胞瘤、乳腺癌、大肠癌、食道癌、消化道间质瘤、胃癌、肝细胞癌、卡波西肉瘤、肺癌、黑色素瘤、卵巢癌、骨肉瘤、胰管腺癌、肾细胞癌、前列腺癌、甲状腺癌、子宫内膜癌中AXL的过度表达。
另外，已经报道了AXL和对化疗的抗药性有关的各种癌。在AML临床样本中，对于化疗获得了抗药性的细胞中也显示出AXL的过度表达，并且AXL稳定表达的AML细胞株也显示出化疗抗药性，因此据认为AXL为治疗抗药性的原因。
Gilteritinib(化学名称为6-乙基-3-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺，其具有以下结构式)是日本安斯泰来制药公司研发的FLT3抑制剂，能有效抑制ITD和TKD，用于FLT3突变阳性的复发或难治性AML成人患者治疗，同时还可抑制AXL等激酶.临床实验表明Gilteritinib能够有效抑制FLT3的突变以及活性，同时能够使患者的寿命获得显著的延长。2017年7月，FDA颁发了孤儿药资格；2017年10月，FDA授予快速通道认定；2018年11月，FDA批准上市。
Figure PCTCN2019080011-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Gilteritinib能有效治疗AML，但是FLT3突变阳性AML患者治疗存在严重的临床未满足需求，而且发现具有治疗AML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FLT3激酶介导疾病具有选择性抑制活性或更好地药效学/药代动力学的化合物，本发明提供了这样的化合物。
发明概述
针对以上技术问题，本发明公开了一种新的氘取代的氨基杂环甲酰胺化合物及其组合物和用途，其具有更好地FLT3和AXL激酶抑制活性、更低的副作用、更高的选择性和更好地药效学/药代动力学性能，可用于治疗AML等相关癌症。
如本文所用，术语“本发明化合物”指式(Φ)、(I)和(II)所示的化合物。该术语还包括及式(Φ)、(I)和(II)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(Φ)化合物：
Figure PCTCN2019080011-appb-000002
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24各自独立地选自氢或氘；
X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
Y 1、Y 2和Y 3各自独立地选自氢或氘；
附加条件是，上述化合物至少具有一个氘原子；
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由FLT3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。在具体实施方案中，所述癌症通过FLT3介导。在具体实施方案中，患者诊断或鉴定为患有FLT3-相关的癌症。在具体的实施方案中，FLT3介导的疾病为AML。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。
在另一方面，本发明还涉及提供一种本发明化合物在制备治疗由FLT3激酶介导的疾病的药物中的用途。该用途包括向该受试者给药治疗有效量的本发明化合物。在具体实施方案中，所述疾病通过FLT3介导。在具体实施方案中，患者诊断或鉴定为患有FLT3-相关的癌症。在具体的实施方案中，FLT3介导的疾病为AML。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。
在另一方面，本发明还涉及提供一种在受试者中治疗由AXL激酶相关的疾病的方法。该方法包括向该受试者给药治疗有效量的本发明化合物。在具体实施方案中，所述疾病通过AXL介导。在具体实施方案中，患者诊断或鉴定为患有AXL-相关的癌症。在具体实施方案中，所述疾病为AXL高度表达的癌症。在具体实施方案中，所述疾病为因AXL活化而获得对抗癌药物治疗的抗药性的癌症。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。
在另一方面，本发明还涉及提供一种本发明化合物在制备AXL激酶相关的疾病的药物中的用途。该方法包括向该受试者给药治疗有效量的本发明化合物。在具体实施方案中，所述疾病通过AXL介导。在具体实施方案中，患者诊断或鉴定为患有AXL-相关的癌症。在具体实施方案中，所述疾病为AXL高度表达的癌症。在具体实施方案中，所述疾病为因AXL活化而获得对抗癌药物治疗的抗药性的癌症。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。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H， 3H， 13C， 14C， 15N， 17O， 18O， 31P， 32P， 35S， 18F以及 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳14，即 14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
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“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”指本发明化合物与水进行配位形成的配合物。
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。
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(Φ)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 PCTCN2019080011-appb-000003
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24各自独立地选自氢或氘；
X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
Y 1、Y 2和Y 3各自独立地选自氢或氘；
附加条件是，上述化合物至少具有一个氘原子。
作为本发明的具体实施方案，式(Φ)中化合物至少含有一个氘原子，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，更佳地二十一个氘原子，更佳地二十二个氘原子，更佳地二十三个氘原子，更佳地二十四个氘原子，更佳地二十五个氘原子，更佳地二十六个氘原子，更佳地二十七个氘原子，更佳地二十八个氘原子，更佳地二十九个氘原子，更佳地三十个氘原子，更佳地三十一个氘原子，更佳地三十二个氘原子，更佳地三十三个氘原子，更佳地三十四个氘原子，更佳地三十五个氘原子，更佳地三十六个氘原子，更佳地三十七个氘原子，更佳地三十八个氘原子。
作为本发明的优选实施方案，氘在氘代位置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R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、Y 1、Y 2、Y 3、X 1、X 2和X 3，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％。
在另一具体实施方案中，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、Y 1、Y 2、Y 3、X 1、X 2和X 3，至少其中一个含氘，更佳地两个含氘，更佳地三个含氘，更佳地四个含氘，更佳地五个含氘，更佳地六个含氘，更佳地七个含氘，更佳地八个含氘，更佳地九个含氘，更佳地十个含氘，更佳地十一个含氘，更佳地十二个含氘，更佳地十三个含氘，更佳地十四个含氘，更佳地十五个含氘，更佳地十六个含氘，更佳地十七个含氘，更佳地十八个含氘，更佳地十九个含氘，更佳地二十个含氘，更佳地二十一个氘原子，更佳地二十二个氘原子，更佳地二十三个氘原子，更佳地二十四个氘原子，更佳地二十五个氘原子，更佳地二十六个氘原子，更佳地二十七个氘原子，更佳地二十八个氘原子，更佳地二十九个氘原子，更佳地三十个氘原子，更佳地三十一个氘原子，更佳地三十二个氘原子，更佳地三十三个氘原子，更佳地三十四个氘原子，更佳地三十五个氘原子，更佳地三十六个氘原子，更佳地三十七个氘原子，更佳地三十八个氘原子。具体而言，式(I)中化合物至少含有一个、两个、 三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、十六个、十七个、十八个、十九个、二十、二十一、二十二、二十三、二十四、二十五、二十六、二十七、二十八、二十九、三十、三十一、三十二、三十三、三十四、三十五、三十六、三十七、三十八个氘原子。
在另一个具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24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 24选自氢或氘的技术方案；更具体地，包括R 1是氢或R 1是氘，R 2是氢或R 2是氘，R 3是氢或R 3是氘，以此类推，直至R 24是氢或R 24是氘的技术方案。
在另一个具体实施方案中，“X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D”的技术方案包括X 1选自CH 3、CD 3、CHD 2和CH 2D，和X 1选自CH 3、CD 3、CHD 2和CH 2D的技术方案；更具体地，包括X 1是CH 3、X 1是CD 3、X 1是CHD 2或X 1是CH 2D，和X 2是CH 3、X 2是CD 3、X 2是CHD 2或X 2是CH 2D的技术方案。
在另一个具体实施方案中，“X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3”的技术方案包括X 3是CH 2CH 3、X 3是CH 2CH 2D、X 3是CH 2CHD 2、X 3是CH 2CD 3、X 3是CHDCH 3、X 3是CHDCH 2D、X 3是CHDCHD 2、X 3是CHDCD 3、X 3是CD 2CH 3、X 3是CD 2CH 2D、X 3是CD 2CHD 2或X 3是CD 2CD 3的技术方案。
在另一个具体实施方案中，“Y 1、Y 2和Y 3各自独立地选自氢或氘”的技术方案包括Y 1选自氢或氘，Y 2选自氢或氘，和Y 3选自氢或氘的技术方案；更具体地，包括Y 1是氢或Y 1是氘，Y 2是氢或Y 2是氘，Y 3是氢或Y 3是氘的技术方案。
在另一实施方案中，本发明涉及式(I)化合物：
Figure PCTCN2019080011-appb-000004
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24各自独立地选自氢或氘；
X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
附加条件是，上述化合物至少具有一个氘原子；
或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。
作为本发明的具体实施方案，式(I)中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，更佳地二十一个氘原子，更佳地二十二个氘原子，更佳地二十三个氘原子，更佳地二十四个氘原子，更佳地二十五个氘原子，更佳地二十六个氘原子，更佳地二十七个氘原子，更佳地二十八个氘原子，更佳地二十九个氘原子，更佳地三十个氘原子，更佳地三十一个氘原子，更佳地三十二个氘原子，更佳地三十三个氘原子，更佳地三十四个氘原子，更佳地三十五个氘原子。
作为本发明的优选实施方案，氘在氘代位置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R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、X 1、X 2和X 3，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％。
在另一具体实施方案中，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、X 1、X 2和X 3，至少其中一个含氘，更佳地两个含氘，更佳地三个含氘，更佳地四个含氘，更佳地五个含氘，更佳地六个含氘，更佳地七个含氘，更佳地八个含氘，更佳地九个含氘，更佳地十个含氘，更佳地十一个含氘，更佳地十二个含氘，更佳地十三个含氘，更佳地十四个含氘，更佳地十五个含氘，更佳地十六个含氘，更佳地十七个含氘，更佳地十八个含氘，更佳地十九个含氘，更佳地二十个含氘。具体而言，式(I)中化合物至少含有一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、十六个、十七个、十八个、十九个、二十、二十一、二十二、二十三、二十四、二十五、二十六、二十七、二十八、二十九、三十、三十一、三十二、三十三、三十四、三十五、三十六、三十七、三十八个氘原子。
作为本发明的具体实施方案，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。在另一优选实施方案中，X 1和X 2各自独立地选自CH 3和CD 3。在另一优选实施方案中，X 1是CH 3。在另一优选实施方案中，X 1是CD 3。在另一优选实施方案中，X 2是CH 3。在另一优选实施方案中，X 2是CD 3。在另一优选实施方案中，X 1和X 2是相同的。在另一实施方案中，X 1和X 2是不同的。
作为本发明的具体实施方案，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。在另一优选实施方案中，X 3选自CH 2CH 3和CD 2CD 3。在另一优选实施方案中，X 3是CH 2CH 3。在另一优选实施方案中，X 3是CD 2CD 3。
作为本发明的具体实施方案，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8各自独立地选自氢或氘。在另一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8是相同的。另一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8均为氢。另一优选实施方案中，，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8均为氘。
作为本发明的具体实施方案，R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或氘。另一优选实施方案中，R 9、R 10、R 11和R 12是相同的，且R 13、R 14、R 15和R 16是相同的。另一优选实施方案中，R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16均为氢。另一优选实施方案中，R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16均为氘。另一优选实施方案中，R 9、R 10、R 11和R 12均为氘，且R 13、R 14、R 15和R 16均为氢。另一优选实施方案中，R 9、R 10、R 11和R 12均为氢，且R 13、R 14、R 15和R 16均为氘。
在一个具体实施方案中，本发明涉及式(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 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(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 8是氢，R 9-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(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 12是氢，R 13-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，R 1-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、 CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，R 1-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，R 1-R 24各自独立地选自 氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(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 3选自CD 2CD 3，R 1-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 3选自CD 2CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 3选自CD 2CD 3，X 2是CD 3，R 1-R 24各自 独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 2是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，X 3选自CD 2CD 3，R 1-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 1是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 24各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，R 13-R 24各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 24各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢，R 13-R 24各自独立地选自氢或氘。
在另一实施方案中，本发明涉及式(II)化合物：
Figure PCTCN2019080011-appb-000005
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘；
X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
附加条件是，上述化合物至少具有一个氘原子；
或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。
在一个具体实施方案中，本发明涉及式(II)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 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、 CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(II)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 8是氢，R 9-R 12各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(II)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 12是氢，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3，附加条件是，上述化合物至少具有一个氘原子。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，R 1-R 12各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，R 1-R 12是氢，X 1选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，R 1-R 12各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，R 1-R 12是氢，X 2选自CH 3、CD 3、CHD 2和CH 2D，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，R 1-R 12各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，R 1-R 12是氢，X 3选自 CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3。
在另一个具体实施方案中，本发明涉及式(II)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 3选自CD 2CD 3，R 1-R 12各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 3选自CD 2CD 3，R 1-R 12是氢，X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 3选自CD 2CD 3，X 2是CD 3，R 1-R 12各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 2是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢，X 1选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，X 3选自CD 2CD 3，R 1-R 12各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 1是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢，X 2选自CH 3、CD 3、CHD 2和CH 2D。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 12各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，X 3选自CD 2CD 3，R 9-R 12是氢，R 1-R 8各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 8是氢，R 9-R 12各自独立地选自氢或氘。
在另一个具体实施方案中，本发明涉及式(II)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 1和X 2是CD 3，X 3选自CD 2CD 3，R 1-R 12是氢。
作为本发明的优选实施方案中，所述化合物选自下组化合物：
Figure PCTCN2019080011-appb-000006
Figure PCTCN2019080011-appb-000007
作为本发明的优选实施方案中，所述化合物不包括非氘代化合物。
药物组合物和施用方法
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。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.5-2000mg本发明化合物/剂，更佳地，含有1-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、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体、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。
本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的赋形剂组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明的化合物或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、抚摸内、肌内、皮下、静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的赋形剂混合来配置该药物组合物。这些赋形剂能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羟甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羟甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明化合物可以通过任何使用途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。本发明化合物的治疗有效量为从约0.0001到20mg/kg体重/天，例如从0.001到10mg/kg体重/天。
本发明化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受本发明化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式本发明化合物的每日剂量。
本发明化合物的治疗适应症
本发明化合物展现FLT3蛋白酪氨酸激酶抑制作用，且该化合物可用于治疗FLT3介导的疾病。
在一些实施方案中，本发明提供一种在受试者中治疗由FLT3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。在具体实施方案中，所述癌症通过FLT3介导。在具体实施方案中，患者诊断或鉴定为患有FLT3-相关的癌症。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。在具体的实施方案中，FLT3介导的疾病为AML。
在一些实施方案中，本发明提供与AXL相关的癌症的方法。该方法包括向该受试者给药治疗有效量的本发明化合物。AXL为受体型酪氨酸激酶，并且是在中心具有细胞跨膜区、在其羧基末端侧具有酪氨酸激酶结构域、在氨基末端具有胞外区的蛋白质。与AXL相关癌症是指癌的原因之一为AXL的癌。作为AXL高度表达的癌，可以列举AML、星状细胞瘤、乳腺癌、大肠癌、消化道间质瘤、胃癌、肝细胞癌、卡波西肉瘤、肺癌、黑色素瘤、卵巢癌、骨肉瘤、胰管腺癌、肾细胞癌、前列腺癌、甲状腺癌、子宫内膜癌当中与正常组织相比AXL过度表达的癌。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的优点包括：第一，采用本发明技术方案的化合物和组合物为AML，特别是FLT3-和AXL相关的AML的治疗提供了更有利的治疗工具。第二，改进了化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。第三，提高了化合物在动物体内的药物浓度，提高了药物疗效。第四，抑制了某些代谢产物，提高化合物的安全性。
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。
实施例1 6-乙基-3-((3-(甲氧基-d 3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H- 吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-1)的制备。
Figure PCTCN2019080011-appb-000008
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000009
步骤1 化合物2的合成
依次往配有磁力搅拌的100mL单口烧瓶中加入乙腈(30mL)和5-氟-2-硝基苯酚(化合物1)(2.0g，12.7mmol)，搅拌溶清，再加入无水碳酸钾(3.5g，25.4mmol)和对甲苯磺酸氘代甲酯(3.12g，16.5mmol)，氮气氛下升温到60℃并保温搅拌反应2小时。冷却到室温，减压蒸除溶剂，加入水(20mL)，乙酸乙酯萃取(30mLx3)，合并有机层，无水硫酸钠干燥，过滤，滤液浓缩得白色固体2.0g，收率90％。LC-MS(APCI):m/z＝175.2(M+1) +.
步骤2 化合物4的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入乙腈(20mL)和化合物2(1.74g，10mmol)，搅拌溶清，搅拌下加入化合物3(2.2g，12mmol)和碳酸钾(2.1g，15mmol)，氮气氛下升温到 60℃并保温搅拌反应2小时，冷却到室温，减压蒸除溶剂，加入水(60mL)，析出大量黄色固体，过滤，水洗(20mL)，烘干得该黄色固体2.6g，收率77.1％。LC-MS(APCI):m/z＝338.2(M+1) +.
步骤3 化合物5的合成
向配有磁力搅拌50mL单口瓶中加入化合物4(1.34g，4.0mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(0.12g，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体1.18g，收率98.2％。LC-MS(APCI):m/z＝308.2(M+1) +.
步骤4 化合物7的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中化合物5(0.62g，2.0mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.50g，2.28mmol)和DIPEA(N,N-二异丙基乙胺，0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.82g，收率83.7％。LC-MS(APCI):m/z＝491.3(M+1) +. 1H NMR(500MHz,CDCl 3)δ(ppm):10.75(s,1H),7.72(s,1H),7.35(d,J＝2.0Hz,1H),7.13(dd,J＝9.5Hz,J＝2.0Hz,1H),6.88(d,J＝9.5Hz,1H),5.55(s,1H),3.53(d,J＝11.5Hz,2H),2.99-2.75(m,10H),2.57(t,J＝11.5Hz,2H),2.49(s,3H),2.05-1.95(m,2H),1.90-1.82(m,2H),1.27(t,J＝7.0Hz,3H).
步骤5 化合物T-1的合成
向10mL微波管中加入化合物7(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝556.3(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.57-3.51(m,4H),3.15-2.75(m,8H),2.62-2.49(m,7H),2.10-1.98(m,4H),1.88-1.85(m,2H),1.62-1.60(m,2H),1.34-1.29(m,3H).
实施例2 6-乙基-3-((3-甲氧基-4-(4-(4-(甲基-d 3)哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H- 吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物 T-2)的制备。
Figure PCTCN2019080011-appb-000010
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000011
步骤1 化合物10的合成
搅拌下，氢氧化钠固体(11.2g，0.28mol)缓慢加入到水(100mL)中，搅拌全溶，冰水浴冷却到10℃以下，加入化合物9(50g，0.27mol)，缓慢滴加入对甲苯磺酸甲酯-d 3(53.32g，0.28mol)的丙酮(250mL)溶液，室温下搅拌反应过夜。反应液中加入二碳酸二叔丁酯(3.42g，0.013 mol)，继续搅拌反应1h，室温下减压蒸除丙酮，残留物用乙酸乙酯(150mLx3)萃取，合并有机相，依次水(50mLx3)、饱和碳酸钠(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩到约250mL，冰水浴冷却，缓慢滴加入氯化氢异丙醇溶液(5M)，控制温度低于10℃，调pH到4，生成大量白色固体，氮气氛下保温搅拌半小时，加入过滤，乙酸乙酯(50mL)洗涤滤饼，滤饼真空干燥得该白色固体38g，收率61.6％。 1H NMR(400MHz,DMSO-d6)δ(ppm):11.45(br s,1H),3.97-3.95(m,2H),3.33-3.29(m,4H),2.95-2.93(m,2H),1.41(s,9H).
步骤2 化合物11的合成
冰水浴搅拌下，向化合物10(50g，0.21mol)中加入氯化氢异丙醇溶液(210mL，5M)，氮气氛下搅拌反应4小时。加入乙酸乙酯(400mL)，搅拌半小时，过滤，乙酸乙酯(50mL)洗涤，滤饼氮气氛下装入烧瓶中，减压蒸出乙酸乙酯，得到产物30g，收率82.2％。
步骤3 化合物14的合成
向配有磁力搅拌和冷凝管的100mL单口烧瓶中加入化合物12(5.0g，29.2mmol)加入到乙腈(40mL)中，搅拌溶清，依次加入一水合4-哌啶酮盐酸盐(化合物13)(5.38g，35.1mmol)和DIPEA(11.3g，87.7mol)，反应混合物氮气氛下升温到80℃，并保温搅拌反应过夜。冷却到室温，减压蒸除乙腈，残留物倒入搅拌的冷水(200mL)中，析出大量黄色固体，搅拌半小时，过滤，滤饼水(100mL)洗涤，真空干燥所得固体加入到正己烷(50mL)中，搅拌下升温回流1h，冷却到室温，过滤、烘干得黄色固体6.20g，收率84.8％。LC-MS(APCI):m/z＝251.2(M+1) +.
步骤4 化合物15的合成
向配有磁力搅拌和冷凝管的100mL单口烧瓶中加入化合物14(1.81g，7.2mmol)和二氯甲烷(18mL)，搅拌溶清，依次加入化合物11(1.66g，9.4mol)和DIPEA(2.43g，18.8mol)，搅拌10分钟，溶清，加入粉末型
Figure PCTCN2019080011-appb-000012
分子筛(1.44g)，搅拌10分钟，一次性加入三乙酰氧基硼氢化钠(3.05g，14.4mol)，氮气保护下搅拌反应过夜。加入水(40mL)，搅拌20分钟，通过硅藻土滤掉分子筛，滤液分出水层，二氯甲烷层水萃取(10mLx3)，合并水层，滴加入氨水(28％-30％)，调pH到10，二氯甲烷反萃(60mLx3)，合并二氯甲烷层，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干得黄色固体2.1g，收率86.5％。LC-MS(APCI):m/z＝338.2(M+1) +.
步骤5 化合物16的合成
向配有磁力搅拌50mL单口瓶中加入化合物15(1.34g，4.0mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(0.12g，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体1.18g，收率98.2％。 LC-MS(APCI):m/z＝308.2(M+1) +.
步骤6 化合物17的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中化合物16(0.62g，2.0mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.50g，2.28mmol)和DIPEA(0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.82g，收率83.7％。LC-MS(APCI):m/z＝491.3(M+1)+. 1H NMR(500MHz,CDCl 3)δ(ppm):10.69(s,1H),7.72(s,1H),7.35(d,J＝2.0Hz,1H),7.13(dd,J＝9.5Hz,J＝2.0Hz,1H),6.88(d,J＝9.5Hz,1H),5.55(s,1H),3.89(s,3H),3.53(d,J＝11.5Hz,2H),3.12-2.88(m,7H),2.85(q,J＝7.0Hz,2H),2.57(t,J＝11.5Hz,2H),2.05-1.95(m,2H),1.90-1.82(m,2H),1.27(t,J＝7.0Hz,3H).
步骤7 化合物T-2的合成
向10mL微波管中加入化合物17(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝556.3(M+1) +. 1H NMR(300MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.87(s,3H),3.57-3.51(m,4H),3.15-2.75(m,8H),2.62-2.49(m,7H),2.10-1.98(m,4H),1.88-1.85(m,2H),1.62-1.60(m,2H),1.34-1.29(m,3H).
实施例3 6-乙基-3-((3-(甲氧基-d 3)-4-(4-(4-(甲基-d 3)哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢 -2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-3)的制备。
Figure PCTCN2019080011-appb-000013
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000014
步骤1 化合物19的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入乙腈(20mL)和化合物2(1.74g，10mmol)，搅拌溶清，搅拌下加入化合物18(3.2g，12mmol)和碳酸钾(2.1g，15mmol)，氮气氛下升温到60℃并保温搅拌反应2小时，冷却到室温，减压蒸除溶剂，加入水(60mL)，析出大量黄色固体，过滤，水洗(20mL)，烘干得该黄色固体2.8g，收率66.2％。LC-MS(APCI):m/z＝424.2(M+1) +.
步骤2 化合物20的合成
向配有磁力搅拌的50mL单口瓶中加入化合物19(2.8g，6.6mmol)和二氯甲烷(30mL)，搅拌溶清，搅拌下滴加入三氟乙酸(10mL)，氮气氛下室温搅拌反应2小时。减压蒸除溶剂至干，加入二氯甲烷(30mL)，搅拌下滴加入氨甲醇溶液(7M)，调pH～10，搅拌10分钟，滤除生成的氯化铵固体，减压浓缩得黄色固体2.0g，收率93.9％。LC-MS(APCI):m/z＝324.2(M+1) +.
步骤3 化合物21的合成
向配有磁力搅拌的50mL单口瓶中加入化合物20(1.0g，3.13mmol)和MeOD(10mL)，搅拌溶清，滴加入氘代甲醛重水溶液(0.56g，3.76mmol，20％w/w)和三滴CH 3COOD，氮气氛下搅拌10分钟，加入氘代氰基硼氢化钠(0.31g，4.70mmol)，继续搅拌反应1小时。加入饱和碳酸氢钠水液(20mL)淬灭反应，二氯甲烷萃取(30mLx3)，合并有机相，饱和食盐水洗涤(20mL)， 无水硫酸钠干燥，过滤，浓缩过硅胶柱得黄色固体0.85g，收率80.6％。LC-MS(APCI):m/z＝341.2(M+1) +.
步骤4 化合物22的合成
向配有磁力搅拌50mL单口瓶中加入化合物21(0.68g，2.0mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(70mg，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体0.6g，收率98.2％。LC-MS(APCI):m/z＝311.2(M+1) +.
步骤5 化合物23的合成
向配有磁力搅拌和冷凝管的50mL单口瓶加入化合物22(0.6g，2.0mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.50g，2.28mmol)和DIPEA(0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.82g，收率83.7％。LC-MS(APCI):m/z＝494.3(M+1) +. 1H NMR(500MHz,CDCl 3)δ(ppm):10.75(s,1H),7.72(s,1H),7.35(d,J＝2.0Hz,1H),7.13(dd,J＝9.5Hz,J＝2.0Hz,1H),6.88(d,J＝9.5Hz,1H),5.55(s,1H),3.53(d,J＝11.5Hz,2H),2.99-2.75(m,10H),2.57(t,J＝11.5Hz,2H),2.05-1.95(m,2H),1.90-1.82(m,2H),1.27(t,J＝7.0Hz,3H).
步骤6 化合物T-3的合成
向10mL微波管中加入化合物23(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝559.3(M+1) +.1H NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.57-3.51(m,4H),3.15-2.75(m,8H),2.62-2.49(m,5H),2.10-1.98(m,4H),1.88-1.85(m,2H),1.62-1.60(m,2H),1.34-1.29(m,3H).
实施例4 6-(乙基-d 5)-3-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢-2H-吡 喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-4)的制备。
Figure PCTCN2019080011-appb-000015
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000016
步骤1 化合物25的合成
向配有磁力搅拌50mL单口瓶中加入化合物24(1.72g，10mmol)和DMF(20mL)，搅拌溶清，冰水浴下滴加入化合物8(1.0g，10mmol)和DIPEA(1.93g，15mmol)，滴毕，拆去冰浴，氮气氛下室温搅拌反应2小时。加入水(100mL)淬灭反应，乙酸乙酯(80mLx2)萃取，水洗(100mLx3)，饱和食盐水洗(50mL)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色固体1.8g，收率75.6％。LC-MS(APCI):m/z＝239.2(M+1) +. 1H NMR(500MHz,CDCl3)δ/ppm:7.78(s,1H),5.27(br s,1H),4.13-4.10(m,1H),4.04-4.00(m,2H),3.57-3.52(m,2H),2.05-2.01(m,2H),1.63-1.54(m,2H).
步骤2 化合物26的合成
向配有磁力搅拌50mL单口瓶中加入化合物25(1.5g，6.3mmol)和DMF(10mL)，搅拌溶清，加入NBS(N-溴代琥珀酰亚胺，1.57g，8.8mmol)，氮气氛下升温到80℃并保温搅拌反应2小时。减压蒸除溶剂，残留物过硅胶柱得白色固体1.7g，收率81.5％。LC-MS(APCI):m/z＝317.1(M+1) +. 1H NMR(300MHz,CDCl3)δ(ppm):5.80(d,J＝6.6Hz,1H),4.24-4.16(m,1H),4.07-4.02(m,2H),3.61-3.52(m,2H),2.07-2.02(m,2H),1.71-1.62(m,2H).
步骤3 化合物27的合成
向配有磁力搅拌100mL双口瓶中加入化合物26(1.5g，4.74mmol)、CuI(8.9mg，0.095mmol)和双三苯基膦二氯化钯(66mg，0.095mmol)，抽真空并氮气置换三次，氮气氛下通过注射器依次加入无水THF(30mL)、三乙胺(0.96g，9.5mmol)和三甲基硅基乙炔(0.55g，5.69mmol)，加毕，氮气氛下室温继续搅拌反应2小时。加入二氯甲烷(50mL)，滤除不溶性固体，减压蒸除溶剂，残留物过硅胶柱得灰色固体1.0g，收率80.5％。LC-MS(APCI):m/z＝261.1(M-1) -. 1H NMR(300MHz,CDCl 3)δ(ppm):5.80(d,J＝6.4Hz,1H),4.23-4.20(m,1H),4.05-4.01(m,2H),3.68(s,1H),3.60-3.54(m,2H),2.06-2.02(m,2H),1.67-1.59(m,2H).
步骤4 化合物29的合成
向配有磁力搅拌100mL单口瓶中加入化合物27(1.0g，3.82mmol)和MeOD(30mL)，氮气氛下室温搅拌3小时。加入Pd/C(100mg，10％)，抽真空并氘气置换三次，氘气球氛下室温搅拌反应2小时。加入二氯甲烷(50mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩并过硅胶柱得白色固体0.8g，收率79.5％。LC-MS(APCI):m/z＝270.2(M-1) -. 1H NMR(500MHz,CDCl 3)δ(ppm):5.00(d,J＝7.0Hz,1H),4.25-4.22(m,1H),4.05-4.01(m,2H),3.60-3.54(m,2H),2.06-2.02(m,2H),1.60-1.55(m,2H).
步骤5 化合物30的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中加入乙腈(20mL)和化合物9(1.74g，10mmol)，搅拌溶清，搅拌下加入化合物3(2.2g，12mmol)和碳酸钾(2.1g，15mmol)，氮气氛下升温到60℃并保温搅拌反应2小时，冷却到室温，减压蒸除溶剂，加入水(60mL)，析出大量黄色固体，过滤，水洗(20mL)，烘干得该黄色固体2.6g，收率77.1％。LC-MS(APCI):m/z＝335.2(M+1) +.
步骤6 化合物31的合成
向配有磁力搅拌50mL单口瓶中加入化合物30(1.34g，4.0mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(0.14g，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体1.18g，收率98.2％。LC-MS(APCI):m/z＝305.2(M+1) +.
步骤7 化合物32的合成
向配有磁力搅拌50mL双口瓶中加入化合物29(100mg，0.37mmol)、化合物31(347mg，1.11mmol)、Pd(OAc) 2(醋酸钯，25mg，0.11mmol)、BINAP(2,2'-双-(二苯膦基)-1,1'-联萘，69mg，0.11mmol)和碳酸铯(481mg，1.48mmol)，抽真空并氮气置换三次，注射器加入无水1,4-二氧六环(10mL)，升温到120℃并保温搅拌反应4小时。冷却到室温，加入二氯甲烷(40mL)，滤除不溶性固体，滤液浓缩并过硅胶柱得白色粉末120mg，收率60.3％。LC-MS(APCI):m/z＝540.4(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):7.21(dd,J＝8.4Hz,J＝2.0Hz,1H),6.87-6.84(m,2H),6.69(s,1H),4.75(d,J＝7.2Hz,1H),4.1-4.08(m,1H),4.02-3.99(m,2H),3.88(s,3H),3.56-3.45(m,4H),2.90-2.47(m,11H),2.41(s,3H),2.05-1.95(m,4H),1.87-1.79(m,2H),1.60-1.51(m,2H).
步骤8 化合物T-4的合成
向配有磁力搅拌50mL双口瓶中加入化合物32(120mg，0.22mmol)和MeOD(8mL)，搅拌下加入无水DMSO(2mL)，搅拌溶清，缓慢滴加入双氧水(1mL，33％)，滴毕，氮气氛下室温搅拌反应半小时。加入乙腈(8mL)，搅拌5分钟，加入水(40mL)和乙酸乙酯(40mL)，静置分层，分出有机层，水相乙酸乙酯萃取(40mLx2)，合并有机相，水洗(60mLx2)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色固体100mg，收率81.6％。LC-MS(APCI):m/z＝558.4(M+1) +. 1H NMR(500MHz,CDCl 3)δ(ppm):10.73(s,1H),7.51(br s,1H),7.46(dd,J＝9.0Hz,J＝2.5Hz,1H),6.91(d,J＝2.5Hz,1H),6.84(d,J＝9.0Hz,1H),5.21(br s,1H),4.62(d,J＝7.0Hz,1H),4.22-4.19(m,1H),4.04-4.01(m,2H),3.87(s,3H),3.57-3.51(m,4H),2.82-2.48(m,11H),2.39(s,3H),2.10-2.07(m,2H),1.96-1.94(m,2H),1.87-1.80(m,2H),1.61-1.53(m,2H).
实施例5 6-(乙基-d 5)-3-((3-甲氧基-4-(4-(4-(甲基-d 3)哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢 -2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-5)的制备。
Figure PCTCN2019080011-appb-000017
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000018
步骤1 化合物33的合成
向配有磁力搅拌50mL双口瓶中加入化合物29(100mg，0.37mmol)、化合物16(347mg，1.11mmol)、Pd(OAc) 2(25mg，0.11mmol)、BINAP(69mg，0.11mmol)和碳酸铯(481mg，1.48mmol)，抽真空并氮气置换三次，注射器加入无水1,4-二氧六环(10mL)，升温到120℃并保温搅拌反应4小时。冷却到室温，加入二氯甲烷(40mL)，滤除不溶性固体，滤液浓缩并过硅胶柱得白色粉末120m g，收率60.3％。LC-MS(APCI):m/z＝543.4(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):7.21(dd,J＝8.4Hz,J＝2.0Hz,1H),6.87-6.84(m,2H),6.69(s,1H),4.75(d,J＝7.2Hz,1H),4.1-4.08(m,1H),4.02-3.99(m,2H),3.88(s,3H),3.56-3.45(m,4H),2.90-2.47(m,11H),2.05-1.95(m,4H),1.87-1.79(m,2H),1.60-1.51(m,2H).
步骤8 化合物T-5的合成
向配有磁力搅拌50mL双口瓶中加入化合物33(120mg，0.22mmol)和MeOD(8mL)，搅 拌下加入无水DMSO(2mL)，搅拌溶清，缓慢滴加入双氧水(1mL，33％)，滴毕，氮气氛下室温搅拌反应半小时。加入乙腈(8mL)，搅拌5分钟，加入水(40mL)和乙酸乙酯(40mL)，静置分层，分出有机层，水相乙酸乙酯萃取(40mLx2)，合并有机相，水洗(60mLx2)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色固体100mg，收率81.6％。LC-MS(APCI):m/z＝561.4(M+1) +. 1H NMR(400MHz,CDCl3)δ(ppm):10.73(s,1H),7.51(br s,1H),7.46(dd,J＝8.8Hz,J＝2.5Hz,1H),6.91(d,J＝2.4Hz,1H),6.84(d,J＝8.8Hz,1H),5.21(br s,1H),4.62(d,J＝7.2Hz,1H),4.22-4.19(m,1H),4.04-4.01(m,2H),3.87(s,3H),3.57-3.51(m,4H),2.82-2.48(m,11H),2.10-2.07(m,2H),1.96-1.94(m,2H),1.87-1.80(m,2H),1.61-1.53(m,2H).
实施例6 6-(乙基-d 5)--3-((3-(甲氧基-d 3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-((四氢 -2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-6)的制备。
Figure PCTCN2019080011-appb-000019
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000020
步骤1 化合物34的合成
向配有磁力搅拌50mL双口瓶中加入化合物29(100mg，0.37mmol)、化合物5(347mg，1.11mmol)、Pd(OAc) 2(25mg，0.11mmol)、BINAP(69mg，0.11mmol)和碳酸铯(481mg，1.48mmol)， 抽真空并氮气置换三次，注射器加入无水1,4-二氧六环(10mL)，升温到120℃并保温搅拌反应4小时。冷却到室温，加入二氯甲烷(40mL)，滤除不溶性固体，滤液浓缩并过硅胶柱得白色粉末120mg，收率60.3％。LC-MS(APCI):m/z＝543.4(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):7.21(dd,J＝8.4Hz,J＝2.0Hz,1H),6.87-6.84(m,2H),6.69(s,1H),4.75(d,J＝7.2Hz,1H),4.1-4.08(m,1H),4.02-3.99(m,2H),3.56-3.45(m,4H),2.90-2.47(m,11H),2.41(s,3H),2.05-1.95(m,4H),1.87-1.79(m,2H),1.60-1.51(m,2H).
步骤8 化合物T-6的合成
向配有磁力搅拌50mL双口瓶中加入化合物34(120mg，0.22mmol)和MeOD(8mL)，搅拌下加入无水DMSO(2mL)，搅拌溶清，缓慢滴加入双氧水(1mL，33％)，滴毕，氮气氛下室温搅拌反应半小时。加入乙腈(8mL)，搅拌5分钟，加入水(40mL)和乙酸乙酯(40mL)，静置分层，分出有机层，水相乙酸乙酯萃取(40mLx2)，合并有机相，水洗(60mLx2)，饱和食盐水洗(30mL)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得黄色固体100mg，收率81.6％。LC-MS(APCI):m/z＝561.4(M+1) +. 1H NMR(400MHz,CDCl3)δ(ppm):10.73(s,1H),7.51(br s,1H),7.46(dd,J＝8.8Hz,J＝2.5Hz,1H),6.91(d,J＝2.4Hz,1H),6.84(d,J＝8.8Hz,1H),5.21(br s,1H),4.62(d,J＝7.2Hz,1H),4.22-4.19(m,1H),4.04-4.01(m,2H),3.57-3.51(m,4H),2.82-2.48(m,11H),2.39(s,3H),2.10-2.07(m,2H),1.96-1.94(m,2H),1.87-1.80(m,2H),1.61-1.53(m,2H).
实施例7 6-乙基-3-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基-3,3,5,5-d 4)苯基)氨基)-5-((四氢 -2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-7)的制备。
Figure PCTCN2019080011-appb-000021
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000022
步骤1 化合物35的合成
向配有磁力搅拌250mL单口瓶中加入化合物14(1.0g，4mmol)和氘代氯仿(80mL)，搅拌溶清，搅拌下加入1,5,7-三叠氮双环(4.4.0)癸-5-烯(75mg，0.55mmol)，N 2氛下室温搅拌反应过夜。混合物依次水洗(20mL)、0.5M HCl洗(10mL)，有机相无水硫酸钠干燥，过滤，浓缩至干得黄色固体0.98g，收率98％。LC-MS(APCI):m/z＝255.2(M+1) +。
步骤2 化合物36的合成
向配有磁力搅拌100mL单口瓶中加入甲醇(20mL)，冷却到0℃，加入化合物35(0.98g，4mmol)，搅拌溶清，缓慢加入硼氢化钠(168mg，4mmol)，氮气氛下搅拌反应5分钟。加入水(5mL)淬灭反应，并常温搅拌30min，依次加入水(60mL)和乙酸乙酯(60mL)，分出有机层，水层乙酸乙酯萃取(30mLx2)，浓缩，残留物再次溶于乙酸乙酯(50mL)，饱和食盐水洗涤(20mLx1)，有机相无水硫酸钠干燥，过滤，浓缩得黄色固体0.99g，收率99％。LC-MS(APCI):m/z＝257.2(M+1) +.
步骤3 化合物37的合成
向配有磁力搅拌50mL单口瓶中加入化合物36(0.99g，4.0mmol)和二氯甲烷(20mL)，搅拌溶清，加入三乙胺(0.6g，6.0mmol)，缓慢滴加入甲基磺酰氯(0.57g，5.0mmol)，室温氮气氛下搅拌反应1h。加入水(30mL)，震荡分出有机层，水层二氯甲烷萃取(20mLx2)，合并有机层， 依次用0.5M HCl水液(20mLx1)、饱和碳酸氢钠水液(15mLx1)、饱和食盐水(15mLx1)，无水硫酸钠干燥，过滤，浓缩得黄色固体1.2g，收率89.8％，直接用于下一步。
步骤4 化合物38的合成
向配有磁力搅拌50mL单口瓶中加入化合物37(1.2g，3.6mmol)和DMF(3mL)，搅拌溶清，加入DIPEA(2.33g，18mmol)和1-甲基哌嗪(3.6g，36mmol)，氮气氛下升温到120℃并保温反应过夜。冷却到室温，减压蒸除溶剂，残留物过硅胶柱得黄色固体0.6g，收率49.3％。LC-MS(APCI):m/z＝339.2(M+1) +.
步骤5 化合物39的合成
向配有磁力搅拌50mL单口瓶中加入化合物38(0.6g，1.78mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(60mg，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体0.52g，收率95.4％。LC-MS(APCI):m/z＝309.2(M+1) +.
步骤6 化合物40的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中化合物39(0.52g，1.69mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.44g，2.0mmol)和DIPEA(0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.6g，收率72.3％。LC-MS(APCI):m/z＝492.3(M+1) +.
步骤7 化合物T-7的合成
向10mL微波管中加入化合物40(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝557.3(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.57-3.51(m,4H),3.15-2.75(m,8H),2.62-2.49(m,7H),2.10-1.98(m,2H),1.62-1.60(m,2H),1.34-1.29(m,3H).
实施例8 6-乙基-3-((3-甲氧基-4-(4-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)哌啶-1-基)苯基)氨 基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-8)的制备。
Figure PCTCN2019080011-appb-000023
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000024
步骤1 化合物41的合成
向配有磁力搅拌的50mL单口烧瓶中加入化合物14(1.81g，7.2mmol)和二氯甲烷(18mL)，搅拌溶清，依次加入N-Boc-哌嗪-2,2,3,3,5,5,6,6-d 8(1.8g，9.4mol)和DIPEA(0.47g，3.6mol)，搅拌10分钟，溶清，加入粉末型
Figure PCTCN2019080011-appb-000025
分子筛(1.44g)，搅拌10分钟，一次性加入三乙酰氧基硼氢化钠(3.05g，14.4mol)，氮气保护下室温搅拌反应过夜。加入水(40mL)，搅拌20分钟，通过硅藻土滤掉分子筛，滤液分出水层，二氯甲烷萃取(30mLx3)，合并有机相，无水硫酸钠干燥，过 滤，浓缩并过硅胶柱得黄色固体2.2g，收率71.4％。LC-MS(APCI):m/z＝429.2(M+1) +.
步骤2 化合物42的合成
向配有磁力搅拌的50mL单口烧瓶中加入化合物41(2.2g，5.14mmol)和二氯甲烷(20mL)，搅拌溶清，加入三氟醋酸(10mL)，氮气氛下室温搅拌2小时。减压蒸除溶剂，加入二氯甲烷(30mL)，搅拌下滴加入氨甲醇溶液(7M)，调pH～10，搅拌10分钟，滤除生成的氯化铵固体，减压浓缩得黄色固体1.6g，收率94.9％。LC-MS(APCI):m/z＝329.2(M+1) +.
步骤3 化合物43的合成
向配有磁力搅拌的50mL单口瓶中加入化合物42(1.0g，3.13mmol)和MeOH(10mL)，搅拌溶清，滴加入甲醛水溶液(0.56g，3.76mmol，20％w/w)和三滴冰醋酸，氮气氛下搅拌10分钟，加入氰基硼氢化钠(0.31g，4.70mmol)，继续搅拌反应1小时。加入饱和碳酸氢钠水液(20mL)淬灭反应，二氯甲烷萃取(30mLx3)，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，浓缩过硅胶柱得黄色固体0.85g，收率80.6％。LC-MS(APCI):m/z＝343.2(M+1) +.
步骤4 化合物44的合成
向配有磁力搅拌50mL单口瓶中加入化合物43(0.68g，2.0mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(70mg，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体0.6g，收率98.2％。LC-MS(APCI):m/z＝313.2(M+1) +.
步骤5 化合物45的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中化合物44(0.6g，2.0mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.50g，2.28mmol)和DIPEA(0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.82g，收率83.7％。LC-MS(APCI):m/z＝496.3(M+1) +.
步骤6 化合物T-8的合成
向10mL微波管中加入化合物45(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝559.3(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.87(s,3H),3.57-3.51(m,4H),2.62-2.49(m,5H),2.41(s,3H),2.10-1.98(m,4H),1.88-1.85(m,2H), 1.62-1.60(m,2H),1.34-1.29(m,3H).
实施例9 6-乙基-3-((3-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基-2,2,3,3,5,5,6,6-d8)哌啶-1-基)苯基)氨 基)-5-((四氢-2H-吡喃-4-基)氨基)吡嗪-2-甲酰胺(化合物T-9)的制备。
Figure PCTCN2019080011-appb-000026
采用以下路线进行合成：
Figure PCTCN2019080011-appb-000027
步骤1 化合物46的合成
向配有磁力搅拌的50mL单口瓶中加入化合物42(1.0g，3.13mmol)和MeOD(10mL)，搅拌溶清，滴加入氘代甲醛重水溶液(0.56g，3.76mmol，20％w/w)和三滴CH 3COOD，氮气氛下搅拌10分钟，加入氘代氰基硼氢化钠(0.31g，4.70mmol)，继续搅拌反应1小时。加入饱和碳酸氢钠水液(20mL)淬灭反应，二氯甲烷萃取(30mLx3)，合并有机相，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，浓缩过硅胶柱得黄色固体0.85g，收率80.6％。LC-MS(APCI):m/z＝346.2(M+1) +.
步骤2 化合物47的合成
向配有磁力搅拌50mL单口瓶中加入化合物46(0.68g，2.0mmol)和甲醇(10mL)，搅拌溶清，加入Pd/C(70mg，10％)，抽真空并氢气置换三次，氢气球氛下室温搅拌反应过夜。加入二氯甲烷(30mL)，滤除催化剂，二氯甲烷(5mL)洗涤，减压浓缩得微棕色固体0.6g，收率98.2％。LC-MS(APCI):m/z＝316.2(M+1) +.
步骤3 化合物48的合成
向配有磁力搅拌和冷凝管的50mL单口瓶中化合物47(0.6g，2.0mmol)和1,4-二氧六环(10mL)，搅拌溶清，加入化合物6(0.50g，2.28mmol)和DIPEA(0.8mL，5.0mmol)，氮气氛下升温到110℃并保温搅拌反应过夜。减压浓缩蒸除溶剂，残留物过硅胶柱得黄色固体0.82g，收率83.7％。LC-MS(APCI):m/z＝499.3(M+1) +.
步骤4 化合物T-9的合成
向10mL微波管中加入化合物48(0.20g，0.41mmol)和DMF(5mL)，搅拌溶清，加入化合物8(0.41g，4.1mmol)和碳酸钾(0.18g，1.21mmol)，微波反应器中升温到150℃并保温反应2小时。减压蒸除溶剂，残留物过硅胶柱得黄色固体0.16g，收率70.3％。LC-MS(APCI):m/z＝564.3(M+1) +. 1H NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),7.53-7.46(m,2H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8.8Hz,1H),5.17(br s,1H),4.62(d,J＝7.2Hz,1H),4.29-4.15(m,1H),4.14-4.01(m,2H),3.87(s,3H),3.57-3.51(m,4H),2.62-2.49(m,5H),2.10-1.98(m,4H),1.88-1.85(m,2H),1.62-1.60(m,2H),1.34-1.29(m,3H).
生物活性测试。
(1)激酶活性评价
试剂和耗材：
酶AXL：Invitrogen-A31516，底物ULight-poly GT peptide(PerkinElmer-TRF0100-M)，
抗体Eu-labeled anti-phos(PT66)(PerkinElmer-AD0069)，ATP(Sigma,目录号A7699-1G)，DMSO(Sigma,目录号D2650)，96孔板(Corning,目录号3365)，384孔板(Greiner,目录号784076)。
具体实验方法：
使用LANCE Ultra TR-FRET方法，测定待测物对AXL的抑制活性。
将受试化合物溶于DMSO后，3倍浓度梯度稀释，稀释十次。将AXL激酶与预先稀释配制的不同浓度的化合物转移到384孔测试板混合10分钟，每个浓度双复孔。加入底物及ATP启动反应，室温下孵育90分钟。体系中最终反应浓度为：3nM AXL,4.75uM ATP,50nM peptide,50mM Hepes pH7.5,1mM EGTA,10mM MgCl 2,0.01％Brij-35,2mM DTT。待测化合物最高浓度为300nM。反应完毕后，加入含2nM抗体及10mM EDTA的检测试剂，室温孵育60分钟。最后通过Envision酶标仪，测定在各浓度的本发明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，发现本发明化合物对AXL具有强效的活性，且比Gilteritinib具有更好的抑制效果。代表性实施例化合物的结果归纳于如下表1中。
表1：
实施例化合物 AXL IC 50(nM)
Gilteritinib 7.46
T-1 7.35
T-2 7.01
T-3 6.62
T-4 5.87
T-5 5.33
T-6 5.15
T-7 6.24
T-8 7.10
T-9 6.50
(2)细胞MV-4-11和细胞MOLM-13的抑制作用材料与仪器：
细胞MV-4-11(ATCC,目录号CRL-9591)，细胞MOLM-13COBIOER,目录号CBP60678)， RPMI-1640(GIBCO,目录号A10491-01)，青霉素-链霉素(GIBCO,目录号15140-122)，胎牛血清(GIBCO,目录号10099-141)，磷酸盐缓冲溶液PBS(GIBCO,目录号10010-031)，DMSO(Sigma,目录号D8418-1L)，CelltiterGlo检测试剂盒(CTG)(Promega,目录号G7573)，96孔透明平底黑壁板(PerkinElmer,目录号6005680-50)，板振动筛(QILINBEIER,目录号B-9002)，离心分离机(Eppendorf,目录号5804R)，CO2培养箱(Thermo Scientific,目录号371)，显微镜(OLYMPUS目录号CKX41)，多板读卡器(PerkinElmer目录号EnVision)。
实验步骤：
(1)细胞培养：
MV-4-11细胞培养基是IMDM+10％FBS+1％PS，细胞密度不超过1X106/ml.
MOLM-13细胞培养基是RPMI1640+20％FBS+1％PS，细胞密度不超过1X106/ml.
(2)细胞悬液的制备
a)收集培养瓶中的培养基离心，1000rpm，5min。
b)弃去上清，用含10％胎牛血清的培养基重悬，计数制备细胞悬液(细胞活力大于90％)。
c)将细胞悬液加入96孔板，每孔100μl，即MV-4-11细胞5000/孔；MOLM-13细胞5000/孔。
d)将细胞板放置37℃,5％CO2培养箱中培养过夜。
(3)化合物的制备
化合物在DMSO中稀释：
a)MV-4-11细胞：化合物用DMSO从10mM稀释到60uM，然后在DMSO中从60uM开始三倍稀释9个浓度。
b)MOLM-13细胞：化合物用DMSO从10mM稀释到200uM，然后在DMSO中从200uM开始三倍稀释9个浓度。
c)化合物Taxol用DMSO从10mM稀释到200uM，然后在DMSO中从200uM开始三倍稀释9个浓度。
(4)化合物处理细胞(细胞板过夜后)
a)每孔补99μl含10％FBS的生长培养基，然后加1μl稀释好的化合物到孔中，DMSO的浓度为0.5％。
b)测试化合物浓度:
MV-4-11细胞：300,100,33.3,11.1,3.7,1.23,0.41,0.137,0.046,0[nM]。
MOLM-13细胞：1000,333.3,111.1,37.04,12.35,4.1,1.37,0.46,0.15,0[nM]。
c)对照化合物Taxol浓度:1000,333.3,111.1,37.04,12.35,4.12,1.37,0.46,0.15,0[nM]。
d)将细胞板放置培养箱72小时。
(5)CTG方法检测
a)将待测板放置室温平衡30分钟，弃掉60μl培养基。
b)加60μlCTG试剂(CelltiterGlo试剂盒)，放置快速振荡器振荡2min，再在室温放20min。
c)用Envision仪器读值。
(6)数据分析
用GraphPad Prism 6software计算IC 50。利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值
Y:抑制率(％inhibition)
％inhibition(抑制率)＝100*(High Control读值-测试化合物孔的读值)/(High Control读值-Low Control的读值)
在上述测试实验中测试了本发明化合物。结果表明：与gilteritinib相比，本发明化合物对细胞MV-4-11和细胞MOLM-13具有更强效的活性。代表性实施例对癌细胞的体外增殖的抑制作用的结果归纳于下表2中。
表2：
实施例化合物 MV-4-11 IC 50(nM) MOLM-1 IC 50(nM)
Gilteritinib 2.23 14.27
T-1 2.17 15.00
T-2 2.35 14.31
T-3 2.25 14.22
T-4 1.92 12.98
T-5 2.01 12.02
T-6 2.07 11.91
T-7 1.64 12.67
T-8 2.17 14.80
T-9 2.03 14.52
(3)Ba/F3FLT3-ITD细胞的抑制作用和选择性
细胞系置于37℃、5％CO 2、95％湿度条件下培养：细胞系Ba/F3parental(悬浮，3000个/孔，培养基RPMI-1640+10％FBS+8ng/ml IL-3)，细胞系Ba/F3FLT3-ITD(悬浮，3000个/孔，培养基RPMI-1640+10％FBS)
试剂和耗材：胎牛血清FBS(GBICO,Cat#10099-141)，
Figure PCTCN2019080011-appb-000028
Luminescent Cell Viability Assay(Promega,Cat#G7572)，96孔透明平底黑壁板(
Figure PCTCN2019080011-appb-000029
Cat#3603)，对照化合物AC220(Selleck，Cat#S1526)。
仪器：SpectraMax多标记微孔板检测仪，MD，2104-0010A；CO 2培养箱，Thermo Scientific，Model 3100Series；生物安全柜，Thermo Scientific，Model 1300Series A2；倒置显微镜，Olympus，CKX41SF；冰箱，SIEMENS，KK25E76TI。
实验步骤：
细胞培养和接种：
1.收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上；
2.调整细胞浓度；分别添加90μL细胞悬液至96孔板中；
3.将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。
药物稀释和加药：
1.配制10倍药物溶液，最高浓度为100μM，9个浓度，3.16倍稀释，在接种Ba/F3 parental细胞的96孔板中每孔加入10μL药物溶液；每个药物浓度设置三个复孔。
2.配制10倍药物溶液，最高浓度为10μM，9个浓度，3.16倍稀释，在接种Ba/F3 FLT3-ITD细胞的96孔板中每孔加入10μL药物溶液；每个药物浓度设置三个复孔。
3.将已加药的96孔板中的细胞置于37℃、5％CO2、95％湿度条件下继续培养72小时，之后进行CTG分析。
终点读板：
1.融化CTG试剂并平衡细胞板至室温30分钟；
2.每孔加入等体积的CTG溶液；
3.在定轨摇床上振动5分钟使细胞裂解；
4.将细胞板放置于室温20分钟以稳定冷光信号；
5.读取冷光值。
数据处理
使用GraphPad Prism 8.0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IC50值。
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。
在上述测试实验中测试了本发明化合物。结果表明：与gilteritinib相比，本发明化合物对Ba/F3FLT3-ITD具有更强效的活性以及优于细胞Ba/F3parental的优异选择性。代表性实施例对细胞的体外增殖的抑制作用的结果归纳于下表3中。
表3：
Figure PCTCN2019080011-appb-000030
(4)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；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。
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 PCTCN2019080011-appb-000031
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Gilteritinib作为对照品。在人和大鼠肝微粒体实验中，通过与未经氘代的化合物Gilteritinib对照，本发明化合物可以明显改善代谢稳定性。代表性实施例人肝微粒体实验结果归纳于下表4中。
表4：
Figure PCTCN2019080011-appb-000032
Figure PCTCN2019080011-appb-000033
(5)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(静脉10mg/kg，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理效果。代表性实施例化合物的大鼠药代动力学实验结果归纳于下表5中。
表5：
Figure PCTCN2019080011-appb-000034
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(Φ)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 PCTCN2019080011-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24各自独立地选自氢或氘；
    X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
    X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
    Y 1、Y 2和Y 3各自独立地选自氢或氘；
    附加条件是，上述化合物至少具有一个氘原子。
  2. 根据权利要求1所述的化合物，其为式(I)化合物：
    Figure PCTCN2019080011-appb-100002
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23和R 24各自独立地选自氢或氘；
    X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
    X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
    附加条件是，上述化合物至少具有一个氘原子；
    或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。
  3. 根据权利要求1或2所述的化合物，其为式(II)化合物：
    Figure PCTCN2019080011-appb-100003
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自氢或氘；
    X 1和X 2各自独立地选自CH 3、CD 3、CHD 2和CH 2D；
    X 3选自CH 2CH 3、CH 2CH 2D、CH 2CHD 2、CH 2CD 3、CHDCH 3、CHDCH 2D、CHDCHD 2、CHDCD 3、CD 2CH 3、CD 2CH 2D、CD 2CHD 2和CD 2CD 3；
    附加条件是，上述化合物至少具有一个氘原子；
    或其药学上可接受的盐、前药、水合物或溶剂化合物、晶型、立体异构体或同位素变体。
  4. 根据权利要求1-3中任一项所述的化合物，其中，R 9、R 10、R 11和R 12是氢。
  5. 根据权利要求1-4中任一项所述的化合物，其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8是氢。
  6. 根据权利要求1-5中任一项所述的化合物，其中，X 2是CD 3。
  7. 根据权利要求1-6中任一项所述的化合物，其中，X 1是CD 3。
  8. 根据权利要求1-7中任一项所述的化合物，其中，X 3是CD 2CD 3。
  9. 根据权利要求1-8中任一项所述的化合物，其中所述化合物选自下述化合物，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：
    Figure PCTCN2019080011-appb-100004
    Figure PCTCN2019080011-appb-100005
    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. 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1-9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。
  11. 一种在受试者中治疗由FLT3激酶介导的疾病的方法，包括给药有效量的权利要求1-9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10的药物组合物。
  12. 一种如权利要求1-9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10的药物组合物在制备治疗由FLT3激酶介导的疾病的药物中的用途。
  13. 一种在受试者中治疗由AXL激酶介导的疾病的方法，包括给药有效量的权利要求1-9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10的药物组合物。
  14. 一种如权利要求1-9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10的药物组合物在制备治疗由AXL激酶介导的疾病的药物中的用途。
  15. 根据权利要求11-14所述的方法，其中所述疾病为急性髓细胞白血病。
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