WO2020114388A1 - 取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途 - Google Patents

取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途 Download PDF

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WO2020114388A1
WO2020114388A1 PCT/CN2019/122674 CN2019122674W WO2020114388A1 WO 2020114388 A1 WO2020114388 A1 WO 2020114388A1 CN 2019122674 W CN2019122674 W CN 2019122674W WO 2020114388 A1 WO2020114388 A1 WO 2020114388A1
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Prior art keywords
ret
deuterium
hydrogen
pharmaceutically acceptable
cancer
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PCT/CN2019/122674
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English (en)
French (fr)
Inventor
王义汉
任兴业
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深圳市塔吉瑞生物医药有限公司
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Priority to US17/299,999 priority Critical patent/US20220017539A1/en
Priority to JP2021532190A priority patent/JP7347853B2/ja
Priority to EP19892345.0A priority patent/EP3878852A4/en
Publication of WO2020114388A1 publication Critical patent/WO2020114388A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 present invention belongs to the technical field of medicine, and in particular relates to a substituted pyrazolo[1,5-a]pyridine compound, a composition containing the compound, and uses thereof. More specifically, the present invention relates to certain deuterium-substituted pyrazolo[1,5-a]pyridine compounds. These deuterium-substituted compounds and their compositions can be used to treat diseases or disorders mediated by RET kinase, and these Deuterium substituted compounds have better pharmacokinetic properties.
  • RET Rearranged during transfection
  • RET belongs to the family of receptor tyrosine kinase proteins and is a cell surface molecule that transmits signals to cell growth and differentiation.
  • the extracellular portion of RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and the periplasmic cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the receptor’s cytoplasm Part includes two tyrosine kinase subdomains.
  • RET protein belongs to glial cell-derived neurotrophic factor (GDNF) family, including GDNF, Neuroturin (NTRN, nerve growth factor), artemin (ARTN, artem factor) and persephin (PSPN, Pace factor).
  • GDNF glial cell-derived neurotrophic factor
  • NTRN Neuroturin
  • ARTN artemin
  • PSPN persephin
  • tyrosine kinase is phosphorylated in the intracellular domain, which in turn induces RET dimerization, autophosphorylation, and substrate phosphorylation, thereby activating multiple downstream signaling pathways in the cell, including Ras-MAPK And the PI3K-Akt/mTOR pathway, or lead to the recruitment of the CBL family of ubiquitin ligases that play a role in RET-mediated RET minor.
  • RET gene mutations or RET gene fusions have been identified as drivers of certain cancers.
  • the incidence of RET gene fusion in non-small cell lung cancer is about 2%, and the incidence in papillary thyroid carcinomas (Papillary Thyroid Cancers, PTCs) is 10% to 20%.
  • the most common fusion partners include KIF5B, TRIM33, CCDC6 and NCOA4.
  • the incidence of RET gene mutations in Medullary Thyroid Cancers (MTCs) is about 60%, and the most common mutation site is M918T.
  • RET inhibitor resistance mutations include but are not limited to amino acid position 804 (V804M, V804L, V804E), amino acid position 805 (E805K), amino acid position 806 (Y806C, Y806E).
  • WO 2017/011776 A1 and WO 2018/071447 A1 disclose a series of substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors, which can be used to treat and prevent RET kinase-mediated Disease or condition.
  • ADME absorption, distribution, metabolism, and/or excretion
  • the present invention discloses a novel deuterium-substituted pyrazolo[1,5-a]pyridine compound, a composition containing the same and its use, which has the ability to inhibit RET and RET in cells or patients
  • the activity of gene mutation and RET gene fusion, together with lower side effects and better pharmacokinetic properties, can be used to treat related diseases or conditions mediated by RET kinase.
  • the term "compounds of the invention” refers to compounds represented by formula (I) and formula (II) (including a subset thereof, such as formula (II-A), formula (II-B-a)).
  • the term also includes its tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.
  • Y is selected from CH or N, which is optionally substituted by deuterium, halogen or trifluoromethyl;
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen or deuterium;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • Z is selected from:
  • the additional condition is that the above compound contains at least one deuterium atom
  • the invention provides a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable excipient.
  • the compound of the present invention is provided in the pharmaceutical composition in an effective amount.
  • the compound of the invention is provided in a therapeutically effective amount.
  • the compounds of the present invention are provided in a prophylactically effective amount.
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the additional therapeutic agent is selected from cytotoxic chemotherapeutic agents, kinase-targeted therapeutic agents, apoptosis regulators, or signal transduction inhibitors.
  • the additional therapeutic agent is selected from one or more kinase targeted therapeutic agents.
  • the present invention provides a method for preparing a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention also relates to the preparation of compounds of the invention or their tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or the aforementioned drugs Use of the composition for the treatment of RET-related cancer.
  • the RET-related cancer is a cancer whose expression or activity or level of RET gene, RET kinase protein, or any of them is dysregulated.
  • the dysregulation of the expression or activity or level of the RET gene, RET kinase protein, or any of them is one or more point mutations in the RET gene.
  • one or more point mutations in the RET gene result in translation of the RET protein with one or more of the following amino acid substitutions: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q ,T338I,R360W,F393L,A510V,E511K,C515S,C531R,G533C,G533S,G550E,V591I,G593E,I602V,R600Q,K603Q,K603E,Y606C,C609Y,C609S,C609G,C609R,C609F,C609W,C611R ,C611G,C611Y,C611F,C611W,C618S,C618Y,C618R,C618Y,C618G,C618F,C618W,F619F
  • the RET gene, RET kinase protein, or any one of which is deregulated in expression or activity or level is a RET gene fusion.
  • the RET gene fusion is selected from: BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, ELKS-RET, RET-ELKS , FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PCM1, RET-PPKAR1A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13 -RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, PPKAR1A
  • the RET-related cancer is selected from the group consisting of lung cancer, papillary adenocarcinoma, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B multiple Endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion cell tumor or cervical cancer.
  • the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In specific embodiments, the compound is administered chronically.
  • deuterated means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration may be mono-substituted, di-substituted, poly-substituted, or fully substituted.
  • deuteration may be mono-substituted, di-substituted, poly-substituted, or fully substituted.
  • deuterated and “one or more deuterated” are used interchangeably.
  • non-deuterated compounds refer to compounds containing a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).
  • pharmaceutically acceptable salts refers to, within the scope of reliable medical judgment, suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/hazards The proportion of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts described in detail by Berge et al. in J. Pharmaceuticals (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 compounds of the present invention may be in amorphous or crystalline form.
  • the compounds of the present invention may exist in one or more crystalline forms. Therefore, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to the different arrangement of chemical drug molecules, which generally manifests as the existence of drug raw materials in a solid state.
  • a drug can exist in multiple crystalline substance states. Different crystalline forms of the same drug may dissolve and absorb in the body, which will affect the dissolution and release of the preparation.
  • the term "subject” includes, but is not limited to: humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, Young adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses , Sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effects that occur when a subject has a specific disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the disease, disorder Or the development of a disorder ("therapeutic treatment”), and also includes effects that occur before the subject begins to have a specific disease, disorder, or disease (“preventive treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present invention may vary according to factors such as: biological goals, pharmacokinetics of the compound, the disease 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 used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder or condition, or one or more associated with the disease, disorder or condition Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the number of therapeutic agents used alone or in combination with other therapies, which provides therapeutic benefits in the treatment of diseases, disorders or conditions.
  • the term "therapeutically effective amount” may include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
  • the "prophylactically effective amount" of a compound used herein is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with the disease, disorder or condition, or prevent a disease , The number of relapses of the disorder or condition.
  • a prophylactically effective amount of a compound refers to the number of therapeutic agents used alone or in combination with other agents, which provides prophylactic benefits during the prevention of diseases, disorders or conditions.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean that the therapeutic agents of the present invention are administered simultaneously or sequentially.
  • the compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously administered with another therapeutic agent in a single unit dosage form.
  • the present invention relates to compounds of formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • Y is selected from CH or N, which is optionally substituted by deuterium, halogen or trifluoromethyl;
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen or deuterium;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • Z is selected from:
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, more preferably greater than 99%.
  • the present invention contains at least one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably five deuterium atoms Atoms, better contain six deuterium atoms, better contain seven deuterium atoms, better contain eight deuterium atoms, better contain nine deuterium atoms, better contain ten deuterium atoms, better contain ten deuterium atoms, better Contains eleven deuterium atoms, better contains twelve deuterium atoms, better contains thirteen deuterium atoms, better contains fourteen deuterium atoms, better contains fifteen deuterium atoms, better contains fifteen deuterium atoms, better Contains sixteen deuterium atoms, more preferably seventeen deuterium atoms, more preferably eighteen deuterium atoms, more preferably nineteen deuterium atoms, more preferably twenty deuterium atoms.
  • Y is selected from CH or N, which is optionally substituted with deuterium, halogen, or trifluoromethyl; in other embodiments, Y is selected from CH, N, CD, CF, or CF 3 ; in another In some embodiments, Y is selected from CH; in other embodiments, Y is selected from N.
  • Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl; in other embodiments Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, F or trifluoromethyl; in other embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen; in other embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from deuterium.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9, and R 10 are each independently selected from hydrogen or deuterium; in other embodiments , R 1 is selected from hydrogen; in other embodiments, R 1 is selected from deuterium; in other embodiments, R 2 is selected from hydrogen; in other embodiments, R 2 is selected from deuterium; in other embodiments In the scheme, R 3 is selected from hydrogen; in other embodiments, R 3 is selected from deuterium; in other embodiments, R 4 is selected from hydrogen; in other embodiments, R 4 is selected from deuterium; in another In some embodiments, R 5 is selected from hydrogen; in other embodiments, R 5 is selected from deuterium; in other embodiments, R 6 is selected from hydrogen; in other embodiments, R 6 is selected from deuterium; In other embodiments, R 7 is selected from hydrogen; in other embodiments, R 7 is selected from deuterium; in other embodiments, R 8 is selected from hydrogen; in other embodiments, R
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D; in other embodiments, X is selected from CH 3 ; in other embodiments, X is selected from CD 3 ; in another In some embodiments, X is selected from CHD 2 ; in other embodiments, X is selected from CH 2 D.
  • Z is selected from It is optionally substituted with 1, 2, 3, 4 or 5 deuterium; in some embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from
  • Z is selected from It is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 deuterium; in other embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from In other embodiments, Z is selected from Z is selected from
  • Z is selected from It is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 deuteriums; in other embodiments, Z is selected from In other embodiments, Z is selected from, In other embodiments, Z is selected from In other embodiments, Z is selected from
  • the present invention also relates to compounds of formula (II), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • Y is selected from CH or N;
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen or deuterium;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • Z is selected from:
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (I-A), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen or deuterium;
  • Y 1 ′, Y 2 ′, Y 3 ′, Y 4 ′, Y 5 ′, Y 6 ′, Y 7 ′, Y 8 ′, Y 9 ′, Y 10 ′ and Y 11 ′ are each independently selected from hydrogen, Deuterium, halogen or trifluoromethyl;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, more preferably greater than 99%.
  • R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9 and R 10 are each independently selected from hydrogen or deuterium” includes R 1 is selected Hydrogen or deuterium, R 2 is selected from hydrogen or deuterium, R 3 is selected from hydrogen or deuterium, and so on until R 10 is selected from hydrogen or deuterium. More specifically, including R 1 is hydrogen or R 1 is deuterium, R 2 is hydrogen or R 2 is deuterium, R 3 is hydrogen or R 3 is deuterium, and so on until R 10 is hydrogen or R 10 is deuterium Technical solutions.
  • Y 1 ', Y 2 ', Y 3 ', Y 4', Y 5 ', Y 6', Y 7 ', Y 8', Y 9 ', Y 10' and Y 11 ' are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 1' is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 2 ' is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 3 ′ is selected from hydrogen, deuterium, halogen, or trifluoromethyl
  • Y 11 ′ is selected from hydrogen, deuterium, halogen, or trifluoromethyl.
  • Y 1 ′ is hydrogen, Y 1 ′ is deuterium, Y 1 ′ is halogen (F, Cl, Br or I) or Y 1 ′ is trifluoromethyl
  • Y 2 ′ is hydrogen, Y 2 ′ Is deuterium, Y 2 ′ is halogen (F, Cl, Br or I) or Y 2 ′ is trifluoromethyl
  • Y 3 ′ is hydrogen, Y 3 ′ is deuterium and Y 3 ′ is halogen (F, Cl, Br Or I) or Y 3 ′ is trifluoromethyl, and so on until Y 11 ′ is hydrogen, Y 11 ′ is deuterium, Y 11 ′ is halogen (F, Cl, Br or I) or Y 11 ′ is three Fluoromethyl technical solutions.
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D
  • X 1 selected from CH 3 , CD 3 , CHD 2 or CH 2 D
  • X 2 is selected from the technical solutions of CH 3 , CD 3 , CHD 2 or 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, X 2 is CH 3 , X 2 is CD 3 , X 2 is CHD 2 or X 2 It is the technical solution of CH 2 D.
  • Y 1 ′, Y 2 ′, Y 3 ′, Y 4 ′, Y 5 ′, Y 6 ′, Y 7 ′, Y 8 ′, Y 9 ′, Y 10 ′ and Y 11 ' is independently selected from hydrogen or deuterium.
  • X 1 and X 2 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 1 -R 10 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3, CD 3, CHD 2 or CH 2 D, The additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 8 are deuterium, R 1, R 2, R 9 and R 10 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from From CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 9 and R 10 is deuterium, R 1 -R 8 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3, CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3, CD 3 , CHD 2 or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3 or CD 3 With the additional condition that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, X 1 is CD 3, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 2 are each independently selected from CH 3 Or CD 3 .
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, X 2 is CD 3, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 1 is independently selected from CH 3 Or CD 3 .
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, R 1 is deuterium, R 2 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IA), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof wherein, Y 1 '-Y 11' is hydrogen, R 3 -R 10 are hydrogen, R 1 and R 2 is deuterium, X 1 and X 2 are each independently selected from CH 3 or CD 3.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof :
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen or deuterium;
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 8 is deuterium, R 1 , R 2 , R 9 and R 10 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 9 and R 10 are deuterium
  • R 1 -R 8 are each independently selected from hydrogen or deuterium
  • X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 are hydrogen, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D, The additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 are hydrogen, R 1 and R 2 are each independently selected from hydrogen or deuterium, X 1 and X 2 are each independently selected from CH 3 or CD 3 , with the additional condition that the above compound is at least Contains a deuterium atom.
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 3 -R 10 is hydrogen
  • X 1 is CD 3
  • R 1 and R 2 are each independently selected from hydrogen or deuterium
  • X 2 is each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 3 -R 10 is hydrogen
  • X 2 is CD 3
  • R 1 and R 2 are each independently selected from hydrogen or deuterium
  • X 1 is independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 3 -R 10 is hydrogen
  • R 1 is deuterium
  • R 2 is each independently selected from hydrogen or deuterium
  • X 1 and X 2 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-A), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 3 -R 10 is hydrogen
  • R 1 and R 2 are deuterium
  • X 1 and X 2 are each independently selected from CH 3 or CD 3 .
  • R 1 is deuterium; in a preferred embodiment, R 1 is hydrogen.
  • R 2 is deuterium; in a preferred embodiment, R 2 is hydrogen.
  • R 1 and R 2 are deuterium; in a preferred embodiment, R 1 and R 2 are hydrogen.
  • R 3 and R 4 are deuterium; in a preferred embodiment, R 3 and R 4 are hydrogen.
  • R 5 -R 8 is deuterium; in a preferred embodiment, R 5 -R 8 is hydrogen.
  • R 9 and R 10 are deuterium; in a preferred embodiment, R 9 and R 10 are hydrogen.
  • X 1 is CH 3 ; in a preferred embodiment, X 1 is CD 3 .
  • X 2 is CH 3 ; in a preferred embodiment, X 2 is CD 3 .
  • the present invention relates to compounds of formula (I-B), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • W is selected from CR 9 R 10 ;
  • 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 and R 19 are each independently selected from hydrogen or deuterium;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, more preferably greater than 99%.
  • R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18 and R 19 are each independently selected from hydrogen or deuterium
  • R 1 is selected hydrogen or deuterium
  • R 2 is selected from hydrogen or deuterium
  • R 3 is selected from hydrogen or deuterium
  • R 19 is selected from hydrogen or deuterium. More specifically, including R 1 is hydrogen or R 1 is deuterium, R 2 is hydrogen or R 2 is deuterium, R 3 is hydrogen or R 3 is deuterium, and so on until R 19 is hydrogen or R 19 is deuterium Technical solutions.
  • Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 . 8 and Y are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y comprises 1 is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 2 is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 3 is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 8 Technical solutions selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 1 is hydrogen, Y 1 is deuterium, Y 1 is halogen (F, Cl, Br, or I) or Y 1 is trifluoromethyl
  • Y 2 is hydrogen, Y 2 is deuterium, and Y 2 is Halogen (F, Cl, Br or I) or Y 2 is trifluoromethyl
  • Y 3 is hydrogen, Y 3 is deuterium, Y 3 is halogen (
  • X is selected from CH 3, CD 3, CHD 2 or CH 2 D
  • X is selected from CH 3, CD 3, CHD 2 or CH 2 D aspect. More specifically, it includes technical solutions where X is CH 3 , X is CD 3 , X is CHD 2 or X is CH 2 D.
  • the invention relates to compounds of formula (IBa) or formula (IBb), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates thereof Or solvate:
  • W is selected from CR 9 R 10 ;
  • 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 and R 19 are each independently selected from hydrogen or deuterium;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from Hydrogen or deuterium.
  • X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 1 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, additional Provided that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is deuterium, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is deuterium, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is deuterium, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is deuterium, R 1 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is hydrogen, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is hydrogen, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 , with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is hydrogen, X is selected from CD 3 , and R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen Or deuterium.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is hydrogen, R 1 and R 2 are selected from deuterium, R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 3 -R 10 is hydrogen, R 11 and R 12 are selected from deuterium, R 1 , R 2 and R 13 -R 19 are each independently It is selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is hydrogen, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is hydrogen, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 ,
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is hydrogen, X is selected from CD 3 , and R 1 -R 12 are each independently selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is hydrogen, R 1 and R 2 are selected from deuterium, and R 3 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IB), (IBa) and (IBb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate, wherein Y 1 -Y 8 is hydrogen, R 13 -R 19 is hydrogen, R 11 and R 12 are selected from deuterium, and R 1 -R 10 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof :
  • W is selected from CR 9 R 10 ;
  • 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 and R 19 are each independently selected from hydrogen or deuterium;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-Ba) or formula (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable Salt, hydrate or solvate:
  • W is selected from CR 9 R 10 ;
  • 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 and R 19 are each independently selected from hydrogen or deuterium;
  • X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba) and (II-Bb), or tautomers, stereoisomers, prodrugs, crystals Type, pharmaceutically acceptable salts, hydrates or solvates, wherein R 1 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, additional conditions Yes, the above compounds contain at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , A pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 is deuterium, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , A pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 is deuterium, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 Or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 13 -R 19 are deuterium, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 Or CH 2 D.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof A pharmaceutically acceptable salt, hydrate or solvate, wherein R 13 -R 19 are deuterium, R 1 -R 12 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , A pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 is hydrogen, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 or CH 2 D, with the additional condition that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, Crystal form, pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 are hydrogen, R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 , with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , A pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 is hydrogen, X is selected from CD 3 , R 1 , R 2 and R 11 -R 19 are each independently selected from hydrogen or deuterium .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 3 -R 10 is hydrogen, R 1 and R 2 are selected from deuterium, R 11 -R 19 are each independently selected from hydrogen or deuterium, X is selected Since CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 3 -R 10 is hydrogen, R 11 and R 12 are selected from deuterium, R 1 , R 2 and R 13 -R 19 are each independently selected from Hydrogen or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 13 -R 19 are hydrogen, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 , CD 3 , CHD 2 Or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 13 -R 19 are hydrogen, R 1 -R 12 are each independently selected from hydrogen or deuterium, X is selected from CH 3 or CD 3 , additional conditions Yes, the above compounds contain at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 13 -R 19 are hydrogen, X is selected from CD 3 , and R 1 -R 12 are each independently selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 13- R 19 are hydrogen, R 1 and R 2 are selected from deuterium, R 3 -R 12 are each independently selected from hydrogen or deuterium, X is selected Since CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 13- R 19 are hydrogen, R 11 and R 12 are selected from deuterium, R 1 -R 10 are each independently selected from hydrogen or deuterium, X is selected Since CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 3 -R 10 and R 13 -R 19 are hydrogen, and R 1 , R 2 , R 11 and R 12 are each independently selected from hydrogen or deuterium X is selected from CH 3 or CD 3 with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 3 -R 10 and R 13 -R 19 are hydrogen, X is selected from CD 3 , R 1 , R 2 , R 11 and R 12 are each independent Ground is selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , Pharmaceutically acceptable salts, hydrates or solvates, wherein R 3 -R 10 and R 13 -R 19 are hydrogen, X is selected from CD 3 , R 1 and R 2 are deuterium, R 11 and R 12 Each is independently selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof , A pharmaceutically acceptable salt, hydrate or solvate, wherein R 3 -R 10 and R 13 -R 19 are hydrogen, X is selected from CD 3 , R 11 and R 12 are deuterium, R 1 and R 2 Each is independently selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 3 -R 10 and R 13 -R 19 are hydrogen, R 1 and R 2 are deuterium, and R 11 and R 12 are each independently selected from hydrogen Or deuterium, X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate, or solvent compound wherein R 3 -R 10 and R 13 -R 19 are hydrogen, R 1 and R 2 are deuterium, R 11 and R 12 are selected from deuterium, and X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-B), (II-Ba), and (II-Bb), or tautomers, stereoisomers, prodrugs, crystalline forms thereof ,
  • a pharmaceutically acceptable salt, hydrate or solvate wherein R 3 -R 10 and R 13 -R 19 are hydrogen, R 11 and R 12 are deuterium, and R 1 and R 2 are each independently selected from hydrogen Or deuterium, X is selected from CH 3 or CD 3 .
  • R 1 and R 2 are deuterium; in a preferred embodiment, R 1 and R 2 are hydrogen.
  • R 3 and R 4 are deuterium; in a preferred embodiment, R 3 and R 4 are hydrogen.
  • R 5 -R 8 is deuterium; in a preferred embodiment, R 5 -R 8 is hydrogen.
  • R 9 and R 10 are deuterium; in a preferred embodiment, R 9 and R 10 are hydrogen.
  • R 11 and R 12 are deuterium; in a preferred embodiment, R 11 and R 12 are hydrogen.
  • R 13 is deuterium; in a preferred embodiment, R 13 is hydrogen.
  • R 14 -R 19 is deuterium; in a preferred embodiment, R 14 -R 19 is hydrogen.
  • X is CH 3 ; in a preferred embodiment, X is CD 3 .
  • the present invention relates to compounds of formula (I-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 20 and R 21 are each independently selected from hydrogen or deuterium;
  • Y 1 ”, Y 2 ”, Y 3 ”, Y 4 ”, Y 5 ”, Y 6 ”, Y 7 ”, Y 8 ”and Y 9 ” are each independently selected from hydrogen, deuterium, halogen or trifluoromethyl ;
  • X, X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, more preferably greater than 99%.
  • R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 20 and R 21 are each independently selected from hydrogen or deuterium "Includes R 1 selected from hydrogen or deuterium, R 2 selected from hydrogen or deuterium, R 3 selected from hydrogen or deuterium, and so on until R 10 is selected from hydrogen or deuterium, and R 20 is selected from hydrogen or deuterium, R 21 Technical solution selected from hydrogen or deuterium.
  • R 1 is hydrogen or R 1 is deuterium
  • R 2 is hydrogen or R 2 is deuterium
  • R 3 is hydrogen or R 3 is deuterium
  • R 10 is hydrogen or R 10 is deuterium
  • R 20 is hydrogen or R 20 is deuterium
  • R 21 is hydrogen or R 21 is deuterium.
  • Y 1", Y 2 ", Y 3", Y 4 ", Y 5", Y 6 “, Y 7", Y 8 “ and Y 9" are each independently selected from hydrogen , deuterium, halogen or trifluoromethyl
  • Y 1 is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 2 is selected from hydrogen, deuterium, halogen or trifluoromethyl
  • Y 3 is selected from hydrogen, Deuterium, halogen or trifluoromethyl
  • Y 9 ′′ is selected from hydrogen, deuterium, halogen or trifluoromethyl technical solutions.
  • Y 1 ′′ is hydrogen, Y 1 ′′ is deuterium, Y 1 ”is halogen (F, Cl, Br or I) or Y 1 ” is trifluoromethyl, Y 2 ”is hydrogen, Y 2 ” is deuterium, Y 2 ”is halogen (F, Cl, Br or I) Or Y 2 ”is trifluoromethyl, Y 3 ” is hydrogen, Y 3 ”is deuterium, Y 3 ” is halogen (F, Cl, Br or I)
  • Y 3 is trifluoromethyl, and so on until Y 9 ” is hydrogen, Y 9 ”is deuterium, Y 9 ” is halogen (F, Cl, Br or I) or Y 9 ”is trifluoromethyl Technical solutions.
  • X, X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D
  • X 3 is selected from CH 3 , CD 3 , CHD 2 or CH 2 D
  • X 4 is selected from the technical solutions of CH 3 , CD 3 , CHD 2 or CH 2 D.
  • X is CH 3 , X is CD 3 , X is CHD 2 or X is CH 2 D, X 3 is CH 3 , X 3 is CD 3 , X 3 is CHD 2 or X 3 is CH 2 D , X 4 is CH 3 , X 4 is CD 3 , X 4 is CHD 2 or X 4 is CH 2 D.
  • Y 1 ", Y 2 “, Y 3 “, Y 4 “, Y 5 “, Y 6 “, Y 7 “, Y 8 “, and Y 9 " are each Independently selected from hydrogen or deuterium.
  • X, X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • Y 1 ”-Y 9 is hydrogen
  • R 1 -R 10 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 are each independently selected from CH 3 and CD 3 , CHD 2 or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is deuterium
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 are each independent Ground is selected from CH 3 , CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is deuterium
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 are each independent Groundly selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 are each independently
  • CH 3 , CD 3 , CHD 2 or CH 2 D the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 are each independently
  • CH 3 or CD 3 the additional condition is that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • X is selected from CD 3
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X 3 and X 4 is independently CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • X 3 is selected from CD 3
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X and X 4 is independently CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • X 4 is selected from CD 3
  • R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X and X 3 is independently CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • Y 1 ”-Y 9 is hydrogen
  • R 3 -R 10 is hydrogen
  • R 1 and R 2 are selected from deuterium
  • R 20 and R 21 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 Each independently CH 3 or CD 3 .
  • the present invention relates to compounds of formula (IC), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof ,
  • IC formula
  • R 3 -R 10 is hydrogen
  • R 20 and R 21 are selected from deuterium
  • R 1 and R 2 are each independently selected from hydrogen or deuterium
  • X, X 3 and X 4 Each independently CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvent compounds thereof:
  • W is selected from CR 9 R 10 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 20 and R 21 are each independently selected from hydrogen or deuterium;
  • X, X 3 and X 4 are each independently selected from CH 3 , CD 3 , CHD 2 or CH 2 D;
  • the additional condition is that the above compound contains at least one deuterium atom.
  • X, X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is deuterium, R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, and X, X 3 and X 4 are each independently selected from CH 3 and CD 3 , CHD 2 or CH 2 D.
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is deuterium, R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, X, X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is hydrogen, R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, and X, X 3 and X 4 are each independently selected from CH 3 and CD 3 , CHD 2 or CH 2 D, with the proviso that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 are hydrogen, R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, X, X 3 and X 4 are each independently selected from CH 3 or CD 3 With the additional condition that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is hydrogen, X is selected from CD 3 , R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is hydrogen, X 3 is selected from CD 3 , R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, X and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is hydrogen, X 4 is selected from CD 3 , R 1 , R 2 , R 20 and R 21 are each independently selected from hydrogen or deuterium, X and X 3 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 is hydrogen, R 1 and R 2 are selected from deuterium, R 20 and R 21 are each independently selected from hydrogen or deuterium, and X, X 3 and X 4 are each independently selected from CH 3 Or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 are hydrogen, R 20 and R 21 are selected from deuterium, R 1 and R 2 are each independently selected from hydrogen or deuterium, X, X 3 and X 4 are each independently selected from CH 3 Or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 , R 20 and R 21 are hydrogen, R 1 and R 2 are each independently selected from hydrogen or deuterium, and X, X 3 and X 4 are each independently selected from CH 3 or CD 3 With the additional condition that the above compound contains at least one deuterium atom.
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 , R 20 and R 21 are hydrogen, X is selected from CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, and X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 , R 20 and R 21 are hydrogen, X and X 3 are CD 3 , R 1 and R 2 are deuterium, X 4 is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 , R 20 and R 21 are hydrogen, X and X 4 are selected from CD 3 , R 1 and R 2 are deuterium, and X 3 is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, X and X 3 are selected from CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, X 4 is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof
  • R 3 -R 10 and R 20 and R 21 are hydrogen
  • X, X 3 and X 4 are selected from CD 3
  • R 1 and R 2 are each independently selected from hydrogen or deuterium.
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compound, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, X and X 4 are selected from CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, X 3 is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, R 1 and R 2 are deuterium, and X, X 3 and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds wherein R 3 -R 10 and R 20 and R 21 are hydrogen, R 1 and R 2 are deuterium, X 3 is CD 3 , and X and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, R 1 and R 2 are deuterium, X 4 is CD 3 , and X and X 3 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, X 3 is CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, X and X 4 are each independently selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, X 3 and X 4 are CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, and X is selected from CH 3 or CD 3 .
  • the present invention relates to compounds of formula (II-C), or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates, or solvents thereof Compounds, wherein R 3 -R 10 and R 20 and R 21 are hydrogen, X 4 is CD 3 , R 1 and R 2 are each independently selected from hydrogen or deuterium, X and X 3 are each independently selected from CH 3 or CD 3 . In a preferred embodiment, R 1 and R 2 are deuterium; in a preferred embodiment, R 1 and R 2 are hydrogen.
  • R 3 and R 4 are deuterium; in a preferred embodiment, R 3 and R 4 are hydrogen.
  • R 5 -R 8 is deuterium; in a preferred embodiment, R 5 -R 8 is hydrogen.
  • R 20 and R 21 are deuterium; in a preferred embodiment, R 20 and R 21 are hydrogen.
  • X is CH 3 ; in a preferred embodiment, X is CD 3 .
  • X 3 is CH 3 ; in a preferred embodiment, X 3 is CD 3 .
  • X 4 is CH 3 ; in a preferred embodiment, X 4 is CD 3 .
  • the compound has any of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures:
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomers and/or diastereomers.
  • the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (eg cis and trans isomers), or may be in the form of mixtures of stereoisomers, This includes racemic mixtures and mixtures rich in one or more stereoisomers.
  • Isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high-pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • HPLC high-pressure liquid chromatography
  • organic compounds can form a complex with a solvent in which they react or precipitate or crystallize from the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called “hydrate”. The present invention covers all solvates of the compounds of the present invention.
  • solvate refers to the form of a compound or salt thereof that is generally formed by a solvolysis reaction and is combined with a solvent. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in a solution state and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of the compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of the compound can be represented by, for example, the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than 0.
  • R is the compound
  • x is a number greater than 0.
  • a given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5 H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • the compound of the present invention may be in an amorphous or crystalline form (polymorph).
  • the compounds of the present invention may exist in one or more crystalline forms. Therefore, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to the crystalline form (or its salt, hydrate or solvate) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause a crystalline form to dominate.
  • Various polymorphs of the compound can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds which are equivalent to those described in the compounds of the present invention, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number common in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Tritium, ie 3 H and carbon-14, ie 14 C isotopes are particularly preferred because they are easy to prepare and detect.
  • Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in such a way that, when performing the processes disclosed in the following schemes and/or examples and preparation examples, the isotope-labeled reagents are used instead of non-isotopic reagents. Labeled reagents.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form having a medical effect by hydrolysis in the body, for example, in the blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of AC Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra “Improved oral delivery: delivery: limits of overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each introduced This article is for reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body.
  • Prodrugs are usually prepared by modifying functional groups in such a way that the modification can be produced by conventional operations or by cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, compounds of the present invention in which a hydroxyl group, amino group, or sulfhydryl group is bonded to any group, which, when administered to a patient, can be cleaved to form a hydroxyl group, amino group, or thiol group.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, mercapto, and amino functional groups of compounds of formula (I).
  • esters such as methyl ester, ethyl ester, and the like can be used.
  • the ester itself may be active and/or may be hydrolyzed under human body conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or its salt.
  • the compounds of the present invention can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be carried out in a suitable solvent, and those skilled in the art of organic synthesis can easily select the solvent.
  • a suitable solvent may be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out (eg, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent).
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • the skilled person can select the solvent for the specific reaction step according to the specific reaction step.
  • the preparation of the compounds of the present invention may involve the protection and deprotection of different chemical groups. Those skilled in the art can easily determine whether protection and deprotection are required and the selection of appropriate protecting groups.
  • the chemical properties of protecting groups can be found in, for example, Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the compound of the present invention can be prepared into a single stereo by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers and recovering the optically pure enantiomer isomer.
  • the diastereomeric derivatives of the compounds of the present invention can be used for enantiomeric resolution, preferentially dissociable complexes (eg, crystalline diastereomeric salts).
  • Diastereomers have significantly different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.), and can be easily separated by taking advantage of these dissimilarities.
  • Diastereomers can be separated by chromatography, preferably by separation/resolution techniques based on differences in solubility. Then by any practical means that does not racemize, the optically pure enantiomer is recovered together with the resolution reagent.
  • a more detailed description of techniques applicable to the resolution of stereoisomers of compounds starting from racemic mixtures can be found in Jean Jacques, Andre Collet, Samue1 H. Wilen, "Enantiomers, Racemates and Resolution” (“Enantiomers , Racemates and Resolutions”), John Wiley AndSons, Inc., 1981.
  • the reaction can be monitored according to any suitable method known in the art.
  • spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (eg 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (eg UV-visible light), mass spectrometry (MS)
  • chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) are used to monitor product formation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of active ingredient.
  • the pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do 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 (such as human serum albumin ), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Segment polymers
  • kits eg, pharmaceutical packaging.
  • the provided kit may include the compound of the present invention and other therapeutic agents, as well as the first and second containers containing the compound of the present invention and other therapeutic agents (eg, vials, ampoules, bottles, syringes, and/or dispersible packaging or other Suitable container).
  • the provided kit may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and/or other therapeutic agents.
  • the compound of the present invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the doctor .
  • the compounds provided herein are administered to subjects who are at risk of developing the disorder, typically based on physician advice and administered under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular disorder generally include subjects with a family history of the disorder, or those subjects who have been determined to be particularly sensitive to the development of the disorder by genetic testing or screening.
  • the pharmaceutical compositions provided herein can also be administered chronically ("long-term administration").
  • Long-term administration refers to administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or continuous administration indefinitely, For example, the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • the pharmaceutical composition may be administered by bolus injection, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active component.
  • the intramuscular or subcutaneous bolus dose allows the active component to be slowly released, while the bolus injection delivered directly to the vein (for example, by IV intravenous drip) can be more The rapid delivery allows the concentration of the active component in the blood to rapidly increase to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV IV infusion, thereby providing a steady state concentration of the active component in the body of the subject.
  • the bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, to facilitate precise dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining portion is each useful for forming a desired administration form
  • a minor component about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight
  • a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, and the preferred doses each provide about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is usually selected in a quantity of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given.
  • the maximum total dose cannot exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example, microcrystalline cellulose, tragacanth or gelatin; excipients, for example, starch or lactose, disintegrating agents, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.
  • binders for example, microcrystalline cellulose, tragacanth or gelatin
  • excipients for example, starch or lactose
  • disintegrating agents For example, alginic acid, Primogel or corn starch
  • lubricants
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • the transdermal composition is typically formulated as a topical ointment or cream containing the active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other components used to enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.
  • transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are only representative.
  • Other materials and processing techniques are described in Remington's Pharmaceuticals, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Section 8, which is incorporated by reference in this article.
  • the compounds of the present invention can also be administered in sustained release form or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceuticals.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation contains water.
  • the formulation contains a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrins consisting of 6, 7, and 8 ⁇ -1,4-linked glucose units, which optionally include a Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is sulfoalkyl ether ⁇ -cyclodextrin, for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the present invention are inhibitors of RET kinase and can be used to treat diseases and disorders treated with RET kinase inhibitors, such as RET-related diseases and disorders, such as proliferative disorders (such as cancer, including blood cancers and solid tumors), and Gastrointestinal disease (IBS).
  • RET-related diseases and disorders such as proliferative disorders (such as cancer, including blood cancers and solid tumors), and Gastrointestinal disease (IBS).
  • RET-related disease or disorder refers to the expression or activity of the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them (eg, one or more) Or a disorder or condition associated with a level disorder (eg, RET gene, RET kinase, RET kinase domain or any type of expression or level disorder described herein).
  • RET-related diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).
  • RET-related cancer refers to a cancer that is dysregulated with the expression or activity or level of RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them. This article describes non-limiting examples of RET-related cancers.
  • RET gene RET kinase
  • a genetic mutation eg, a translocation of the RET gene that results in the expression of the fusion protein, resulting in a deletion that contains at least one amino acid compared to the wild-type RET protein Deletion in the RET gene expressed by the RET protein, or a mutation in the RET gene that results in the expression of the RET protein with one or more point mutations, or a RET protein that causes the deletion of at least one amino acid in the RET protein compared to the wild-type RET protein Alternative splicing form of RET mRNA), or RET gene amplification, which results in overexpression of RET protein or autocrine activity caused by overexpression of RET gene in the cell, resulting in activity of the kinase domain of RET protein in the cell Increased pathogenicity (eg, constitutive activation of the kinase domain of the RET protein).
  • the dysregulation of the expression or activity or level of any of the RET gene, RET kinase, or any of them may be a mutation in the RET gene encoding the RET protein, which is in contrast to the protein encoded by the RET gene that does not contain the mutation Ratio, having constitutive activity or having increased activity.
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them can be the result of a translocation of a gene or chromosome, which results in the expression of a fusion protein that contains the first functional kinase domain-containing domain
  • the RET part and the second part of the chaperone protein ie not RET).
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them may be the result of gene translation of one RET gene and another RET gene.
  • Non-limiting examples of fusion proteins and non-limiting examples of RET kinase protein point mutation/insertion are described herein.
  • Other examples of RET kinase protein point mutations are RET inhibitor resistance mutations.
  • Non-limiting examples of RET inhibitor resistance mutations are described herein.
  • wild type describes a nucleic acid (eg RET gene or RET mRNA) or protein (eg RET protein) that does not have an increase in the development of RET-related diseases such as RET-related cancers (and optionally also RET-related diseases) Risk and/or not suspected of having a RET-related disease), or from an increased risk of developing a RET-related disease and/or from a RET-related disease such as RET-related cancer (and optionally also without a RET-related disease) Not found in cells or tissues of subjects suspected of having RET-related diseases).
  • RET-related diseases such as RET-related cancers (and optionally also RET-related diseases)
  • RET-related cancers and optionally also RET-related diseases
  • the hematological cancer (e.g., a hematological cancer associated with RET) is selected from leukemia, lymphatic non-Hodgkin lymphoma, Hodgkin lymphoma, and myeloma.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • APL acute promyelocytic leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • CML chronic neutrophilic leukemia
  • AUL acute undifferentiated leukemia
  • AUL anaplastic large cell lymphoma
  • ALCL juvenile lymphocytic leukemia
  • PML juvenile monocytic leukemia
  • JMML juvenile monocytic leukemia
  • MCL triple-type myelodysplastic AML
  • MDS myelodysplastic syndrome
  • MDS myeloproliferative disease
  • MMD myeloproliferative disease
  • MM multiple myeloma
  • blood cancers include myeloma proliferative diseases (MPD), such as polycythemia vera (PV), primary thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF/IPF/PMF) .
  • MPD myeloma proliferative diseases
  • PV polycythemia vera
  • ET primary thrombocytopenia
  • IMF/IPF/PMF idiopathic primary myelofibrosis
  • the hematological cancer eg, as a hematological cancer associated with RET
  • AML or CML is AML or CML.
  • the cancer is a solid tumor.
  • solid tumors eg, solid tumors as cancers associated with RET
  • the cancer is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B multiple endocrine tumors (respectively MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion cell tumor and cervical cancer.
  • lung cancer papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B multiple endocrine tumors (respectively MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion cell tumor and cervical cancer.
  • the compounds of the present invention and their pharmaceutically acceptable salts and solvates, or pharmaceutical compositions containing the compounds of the present invention and their pharmaceutically acceptable salts and solvates can also be used to treat RET-related cancers.
  • RET-related cancer eg, any exemplary RET-related cancer disclosed herein
  • the method comprising using to the patient a therapeutically effective amount as described herein A defined compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.
  • disorders in the expression or activity or level of RET kinase, RET gene, or any of them may contribute to tumorigenesis.
  • dysregulation of the expression or activity or level of RET kinase, RET gene, or any of them may be translocation, overexpression, activation, amplification, or mutation of RET kinase, RET gene, or RET kinase domain.
  • the translocation may include a translocation involving the RET kinase domain
  • the mutation may include a mutation involving the RET ligand binding site
  • the amplification may be the RET gene.
  • Other disorders may include RET mRNA splicing variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.
  • dysregulation of the expression or activity or level of the RET gene, RET kinase protein, or any of them includes one or more chromosomal translocations or inversions that lead to fusion of the RET gene.
  • the RET gene, RET kinase protein, or any of the same in which the expression or activity or level is deregulated is the result of a genetic translocation, wherein the expressed protein is a fusion protein containing residues from a non-RET chaperone protein, and Include the least functional RET kinase domain.
  • non-limiting examples of RET fusion proteins are BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, ELKS-RET, RET-ELKS , FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PCM1, RET-PPKAR1A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13 -RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, PPKAR1A-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET , MYH13-RET, PI
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes one or more deletions (eg, deletion of amino acid at position 4), insertions, or point mutations in the RET kinase.
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes the deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes at least one point mutation in the RET gene, which results in one or more amino acid substitutions compared to the wild-type RET kinase The generation of RET kinase.
  • exemplary RET point mutations include but are not limited to: S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E511K, C515S, C531R, G533C, G533S, G550E, V591I, G593E, I602V, R600Q, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, C618S, C618Y, C618Y, C618Y, C618G, C618F, C618W, F619F, C620S, C620W, C620R,
  • dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them includes at least one point mutation in the RET gene, which results in the production of RET kinase, which has the same activity as wild-type RET
  • the mutation of the RET inhibitor resistance may result in one of increased Vmax, decreased Km, and decreased KD RET kinase of one or more (compared to wild-type RET kinase or RET kinase that does not have the same mutation in the presence of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof).
  • RET inhibitor resistance mutations may include, for example, point mutations, insertions or deletions in and near the ATP binding site in the RET kinase tertiary structure, including but not limited to gatekeeper residues, P-loop residues, Or residues in or near the DFG motif, and ATP crack left solvent front (ATP) left amino acid residues.
  • Other examples of these types of mutations include changes in residues that may affect enzyme activity and/or drug binding, including but not limited to residues in the activation loop, residues near the activation loop, or residues that interact with the activation loop , Residues that contribute to active or inactive enzyme conformation include mutations, deletions, and insertions in the C-helix loop and in the C-helix.
  • RET inhibitor resistance mutations include, but are not limited to, based on human wild-type RET protein sequence (eg, SEQ ID NO: 1).
  • RET inhibitor resistance mutations include but are not limited to amino acid position 804 (V804M, V804L, V804E), amino acid position 804/805 (V804M/E805K), amino acid position 806 (Y806C, Y806E). Changes to these residues may include single or multiple amino acid changes, insertions within or flanking the sequence, and deletions inside or flanking the sequence.
  • the compounds of the present invention can be used to treat RET inhibitor resistance mutations (which result in solvation of compounds or pharmaceutically acceptable salts or solvates that are not of the present invention Increased resistance of the substance, such as substitution at amino acid position 804, such as V804M, V804L, or V804E), in patients with cancer who are treated by co-administration or as an existing drug (eg, not a compound of the present invention or its pharmacy) Subsequent treatment of other RET kinase inhibitors of pharmaceutically acceptable salts or solvates).
  • RET inhibitor resistance mutations which result in solvation of compounds or pharmaceutically acceptable salts or solvates that are not of the present invention Increased resistance of the substance, such as substitution at amino acid position 804, such as V804M, V804L, or V804E
  • RET kinase inhibitors are described herein (eg, other RET kinase inhibitors that are not compounds of the present invention or pharmaceutically acceptable salts or solvates thereof).
  • the RET kinase inhibitor may be selected from the group consisting of carbotinib, vandetanib, alatinib, sorafenib, lovastinib, punatinib, dovitinib, and sunitinib , Foratinib, BLU667 and BLU6864.
  • the compounds of the present invention and pharmaceutically acceptable salts and solvates thereof can be used to treat mutations that have been identified as having resistance to one or more RET inhibitors (which results in The resistance of a RET inhibitor of a pharmaceutically acceptable salt or solvate is increased, such as a substitution at amino acid position 804, such as V804M, V804L, or V804E).
  • RET-related cancer eg, RET-related cancer that includes one or more RET inhibitor resistance mutations
  • a method comprising administering to a patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • This article also provides for the treatment of patients identified or diagnosed as having RET-related cancer (eg, patients who have been identified or diagnosed as having RET-related cancer by using a regulatory agency approved test or assay such as FDA approval, said test Or assays used to identify dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them in a patient or a biopsy sample of a patient) (e.g., any RET-related cancer described herein or known in the art) ( For example, a method of RET-related cancer comprising one or more RET inhibitor resistant mutations), comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical combination thereof Thing.
  • RET-related cancer e.g, patients who have been identified or diagnosed as having RET-related cancer by using a regulatory agency approved test or assay such as FDA approval, said test Or assays used to identify dysregulation of the expression or activity or level of the
  • RET-related cancers such as RET-related cancers having one or more RET inhibitor resistance mutations
  • the patient is a patient in need or a patient identified or diagnosed with RET-related cancer (eg, by using a regulatory agency approved, such as a FDA approved kit to identify or diagnose a patient with RET-related cancer, The kit is used to identify dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them in a patient or a patient's biopsy sample (eg, any RET-related cancer described herein or known in the art) .
  • a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of cancer in a patient (eg, RET-related cancer, eg, having one or more RET inhibition Agent-resistant mutant RET-related cancer), the patient is identified or diagnosed as a patient with RET-related cancer (eg, by using a regulatory agency approved, such as an FDA-approved kit to identify or diagnose a patient with RET-related cancer , The kit is used to identify dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them in a patient or patient's biopsy sample (eg, any RET-related described herein or known in the art) cancer)
  • This article also provides methods for treating subjects.
  • the method includes assaying a sample obtained from a subject to determine whether the subject has a disorder in the expression or level of the RET gene, RET protein, or any of them (eg, one or more RET inhibitor resistance mutations).
  • the method also includes administering a therapeutically effective amount of the general formula (I) to a subject determined to have a disorder in the expression or activity or level of the RET gene, RET protein, or any of them (eg, one or more RET inhibitor resistance mutations) ) Compound or a pharmaceutically acceptable salt or solvate thereof.
  • the RET fusion may be selected from KIF5B-RET fusion and CCDC6-RET fusion.
  • a dysregulation of the expression or activity of the RET gene, RET kinase protein, or it is a gene or chromosome translocation that results in the expression of a RET fusion protein (eg, any RET fusion protein described herein).
  • dysregulation of the expression or activity or level of the RET gene, RET kinase protein, or any of them is one or more point mutations in the RET gene (eg, one or more RET points described herein Any of the mutations).
  • One or more point mutations in the RET gene can result in, for example, translation of RET proteins with one or more of the following amino acid substitutions: M918T, M918V, C634W, V804L, and V804M.
  • the expression or activity or level of any of the RET gene, RET kinase protein, or one of the disorders is one or more RET inhibitor resistance mutations (eg, one or more RET described herein) Any combination of inhibitor resistance mutations).
  • Some embodiments of these methods further include administering to the subject another anticancer agent (eg, another RET inhibitor, such as a RET inhibitor that is not a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof , Or another RET inhibitor of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof).
  • another anticancer agent eg, another RET inhibitor, such as a RET inhibitor that is not a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof , Or another RET inhibitor of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • oncology In the field of oncology medicine, it is common to use a combination of different forms of treatment to treat each patient with cancer.
  • other components of such combination therapy or therapy may be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors, and/or monoclonal Antibody.
  • chemotherapeutic agents such as kinase inhibitors, signal transduction inhibitors, and/or monoclonal Antibody.
  • the compounds of the invention can therefore also be used as an adjunct to cancer treatment, ie they can be used in combination with one or more other therapies or therapeutic agents, for example chemotherapeutic agents acting through the same or different mechanisms.
  • the compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent, the at least one other The therapeutic agent is selected from one or more other therapeutic or therapeutic (eg, chemotherapeutic) agents.
  • Non-limiting examples of other therapeutic agents include: other RET targeted therapeutic agents (ie other RET kinase inhibitors; RET inhibitors that are not compounds of the invention or pharmaceutically acceptable salts or solvates thereof), receptor tyramine Acid kinase-targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway regulators (eg Obataclax); cytotoxic chemotherapeutic agents, angiogenesis-targeted therapeutic agents, immune-targeted agents and radiotherapy .
  • RET targeted therapeutic agents ie other RET kinase inhibitors; RET inhibitors that are not compounds of the invention or pharmaceutically acceptable salts or solvates thereof
  • receptor tyramine Acid kinase-targeted therapeutic agents eg., signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway regulators (eg Obataclax); cytotoxic chemotherapeutic agents, angiogenesis-targeted therapeutic agents, immune-target
  • the other RET targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.
  • other RET targeted therapeutic inhibitors are selective for RET kinase.
  • Exemplary RET targeted therapeutic agents can exhibit inhibitory activity against RET kinase (IC50) of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM or less than about 1 nM .
  • Non-limiting examples of RET-targeted therapeutic agents include alatinib, apatinib, carbotinib (XL-184), dovitinib, lovastinib, motesanib, nidanib, puna Tinib, Regrafenib, Sitravatinib, Sunitinib, Sorafenib, Vataranib, Vandetanib, AUY-922 (5-(2,4-Dihydroxy- 5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, NVP-AST487(1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino) Pyrimidin-4-yl]oxyphenyl]ure
  • a method of treating cancer comprising administering to a patient in need a combination of drugs for treating cancer, which includes (a) a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, (b) other treatments Agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in the treatment of cancer, wherein the amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and The amounts of other therapeutic agents are jointly effective in treating cancer.
  • other therapeutic agents include any of the therapies or therapeutic agents listed above, the therapy or therapeutic agent having an expression or activity or level of RET gene, RET protein, or any of them Standards of care for dysregulated cancer.
  • These other therapeutic agents can be administered together with one or more doses of the compound of general formula (I) or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof as part of the same or separate dosage form, by the same Or different routes of administration, and/or in the same or different administration regimens according to standard pharmaceutical practices known to those skilled in the art.
  • a pharmaceutical combination for treating cancer in a patient in need (eg, RET-related cancer (eg, RET-related cancer having one or more RET inhibitor resistance mutations)), which comprises ( a) a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, (b) at least one other therapeutic agent (such as any exemplary other therapeutic agent described herein or known in the art), and ( c) optionally at least one pharmaceutically acceptable carrier is used to treat cancer simultaneously, separately or sequentially, wherein the amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof is together with the amount of other therapeutic agents Effective treatment of cancer; (ii) a pharmaceutical composition containing this combination; (iii) the use of this combination in the preparation of a medicament for treating cancer; and (iv) a commercial package or product, which contains this combination as a , Separate or sequential combination preparations; and relates to a method of treating cancer in patients in need.
  • RET-related cancer eg, RET-related cancer having one
  • the term "pharmaceutical combination” refers to a drug therapy that results from a mixture or combination of more than one active ingredient and includes fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” refers to a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and at least one other therapeutic agent (eg, a chemotherapeutic agent), which are administered to a patient simultaneously in a single composition or dose.
  • non-fixed combination means that the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent (eg, chemotherapeutic agent) are formulated as separate compositions or dosages so that they can differ in The intervention time limits the simultaneous, parallel or sequential administration to patients in need, where the administration provides effective levels of two or more compounds in the patient. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • therapeutic agent eg, chemotherapeutic agent
  • RET-related cancer eg, RET-related cancer having one or more RET inhibitor resistance mutations
  • the method comprising administering a drug combination to a patient in need
  • the pharmaceutical combination includes (a) a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, (b) another therapeutic agent, and (c) optionally at least one pharmaceutically acceptable A carrier for simultaneous, separate, or sequential use to treat cancer, wherein the other therapeutic agent and the amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof are effective to treat cancer.
  • the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and other therapeutic agents are administered simultaneously as separate doses. In one embodiment, the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and other therapeutic agents are administered as separate doses in any order, in a combined therapeutically effective amount (eg, daily or intermittent doses). In one embodiment, the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and other therapeutic agents are administered simultaneously as a combined dose.
  • RET disease or disorder mediated by RET in a patient in need of treatment
  • the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate or pharmaceutical composition thereof.
  • the disease is cancer (eg, RET-related cancer).
  • the cancer is any cancer described herein or a RET-related cancer.
  • Step 6 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazole-4- ) Pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 4 3-cyano-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate
  • N-phenylbis(trifluoromethanesulfonimide) (4.71g) was added to 4-hydroxy-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile (2.87 g, 11.21 mmol) and DIPEA (4.17 mL) in DMA (25 mL), the reaction was stirred at room temperature for 2 hrs. The reaction was quenched by adding to water (300 mL), the solid was filtered and washed with water (50 mL x 3).
  • Step 6 3-(5-(3-cyano-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl )Pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester
  • Step 7 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-(methyl-d 3 )-1H- Synthesis of pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 4 6-((6-methoxypyridin-3-yl)methyl-d 2 )-3-(5-(4,4,5,5-tetramethyl-1,3,2-diox Synthesis of heteroborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane
  • Step 2 6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2- Synthesis of dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane
  • Step 2 6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3-(5-(4,4,5,5-tetramethyl-1,3 Of 2,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane
  • Step 2 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane
  • Example 1 4-(6-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -base) Pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 3 4-(6-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]heptane (Alkan-3-yl) Pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 4 4-(6-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -base) Pyridin-3-yl)-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 6 4-(6-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]hept (Alkan-3-yl) Pyridin-3-yl)-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 7 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine -3-yl)-6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 8 4-(5-(6-((6-methoxypyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]heptane-3-yl ) Pyridine Oxazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 2 4-(5-(6-((6-methoxypyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]heptan-3-yl) Synthesis of pyrazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 9 4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -base) Pyrazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 (2R)-2-(((3-cyano-4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3,6- Diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazole[1,5-a]pyridin-6-yl)oxy)methyl)morpholine-4-carboxy Synthesis of tert-butyl acid
  • Step 2 4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3- Of Pyrazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Example 10 4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]hept Alkane-3- Yl)pyrazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 1 (2R)-2-(((3-cyano-4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3 ,6-diazabicyclo[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazole[1,5-a]pyridin-6-yl)oxy)methyl)morpholine- Synthesis of 4-carboxylic acid tert-butyl ester
  • Step 2 4-(5-(6-((6-(methoxy-d 3 )pyridin-3-yl)methyl-d 2 )-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyrazin-2-yl)-6-(((R)-morpholin-2-yl)methoxy))pyrazolo[1,5-a]pyridine-3-carbonitrile synthesis
  • HMM Human liver microsomes
  • RLM rat liver microsomes
  • MLM mouse liver microsomes
  • Coenzyme NADPH/NADH
  • Magnesium chloride 5mM, 100mM phosphate buffer (pH 7.4).
  • Stock solution preparation A certain amount of powders of the example compound and the reference compound are accurately weighed and dissolved in DMSO to 5 mM.
  • phosphate buffer solution 100 mM, pH 7.4.
  • the pH value of the solution was 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 solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride), and place on wet ice before use.
  • Preparation of 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 respectively, mix well to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of SD rat liver microsomes respectively, mix well to obtain a liver microsome dilution of 0.625 mg/mL protein concentration.
  • Determination of metabolic stability Add 300 ⁇ L of pre-chilled stop solution to each well of 96-well deep-well plate and place on ice as a stop plate. Place the 96-well incubation plate and NADPH regeneration system in a 37°C water bath, shake at 100 rpm, and pre-incubate for 5 min. Take 80 ⁇ L of incubation solution from each well of the incubation plate and add it to the stop plate, mix well, and add 20 ⁇ L of NADPH regeneration system solution as a 0 min sample. Then add 80 ⁇ L of NADPH regeneration system solution to each well of the incubation plate to start the reaction and start timing.
  • the reaction concentration of the corresponding compound was 1 ⁇ M, and the protein concentration was 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was added to the stop plate, and vortexed for 3 min to stop the reaction. Centrifuge the stop plate at 5000 ⁇ g for 10 min at 4°C. Take 100 ⁇ L of supernatant to a 96-well plate with 100 ⁇ L of distilled water added in advance, mix well, and use LC-MS/MS for sample analysis.
  • the compound of the present invention was tested in the above in vitro stability experiment, and it was found that the compound of the present invention has excellent metabolic stability.
  • the results of liver microsome experiments in representative examples are summarized in Table 3 below.
  • Rats were fed on standard feed and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit. The time points for blood collection were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours.
  • the rats were briefly anesthetized, and 300 ⁇ L blood samples were collected in the test tubes. There is 30 ⁇ L of 1% heparin salt solution in the test tube. Before use, the test tube was dried at 60°C overnight. After the blood samples were collected at the last time point, the rats were sacrificed after ether anesthesia.
  • the blood sample was centrifuged at 5000 rpm for 5 minutes at 4°C to separate the plasma from the red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the compound name and time point. Plasma was stored at -80°C until analysis. The concentration of the compound of the present invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.
  • Reagents and consumables Ret wt (Carna, catalog number 08-159-10ug), RET (V804M), Active (Signalchem, catalog number R02-12GG), HTRF KinEASE-TK kit (Cisbio, catalog number 62TK0PEC), CEP- 32496 (MCE, catalog number HY-15200), ATP (Sigma, catalog number A7699), DMSO (Sigma, catalog number D8418-1L), DTT (Sigma, catalog number D0632), MgCl 2 (Sigma, catalog number M1028), 384-well plate (Labcyte, catalog number P-05525-BC).
  • Compound preparation Dissolve the test compound in DMSO to make a 10 mM stock solution. Then, dilute three times in a DMSO medium gradient and dilute ten times. When adding drugs, dilute with buffer 10 times.
  • Ret wt and RET V804M kinase detection In 5x kinase buffer A, Ret wt or RET V804M kinase was mixed with pre-diluted compounds of different concentrations for 10 minutes, and each concentration was doubled. Add the corresponding substrate and ATP, and react at room temperature for 20 minutes (in which a negative positive control is set: a negative is a blank control, and a positive is CEP-32496). After the reaction, the detection reagent (the reagent in the HTRF KinEASE-TK kit) was added.
  • the enzyme activity in the presence of each concentration of the compound of the present invention was measured by the Envision microplate reader, and the compounds of different concentrations were calculated
  • the inhibitory activity of enzyme activity according to Graphpad 5.0 software, the inhibitory activity of enzyme activity under different concentrations of compounds was fitted to calculate the IC 50 value.
  • the compound of the present invention was tested in the above kinase inhibition experiment, and it was found that the compound of the present invention has strong activity against Retwt and RETV804M.
  • the results of the representative example compounds are summarized in Table 4 below.
  • fetal bovine serum FBS Gibco, catalog number 10099141
  • Luminescent Cell Viability Assay Promega, Cat#G7572
  • 96-well transparent flat bottom black wall plate Cat#3603
  • the cells in the 96-well plate added with drugs were placed under 37° C., 5% CO 2 , and 95% humidity conditions to continue culturing for 72 hours, and then CTG analysis was performed.
  • GraphPad Prism 5.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated therefrom.
  • Cell survival rate (%) (Lum test drug-Lum culture liquid control)/(Lum cell control-Lum culture liquid control) ⁇ 100%.
  • the compounds of the present invention were tested in the above-mentioned cytotoxicity experiments, and it was found that the compounds of the present invention have potent activity on the cell lines Ba/F 3 KIF5B-RET and Ba/F 3 KIF5B-RET V804M and are superior to Ba/F 3 parental Selective.
  • the results of the inhibitory effect of the compounds of the representative examples on the proliferation of cancer cells in vitro are summarized in Table 5 below.

Abstract

本发明提供了一种取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途，所述的取代的吡唑并[1,5-a]吡啶化合物如式(I)所示化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。本发明化合物及其组合物可用于治疗RET激酶介导的疾病或病症且具有更优良的药代动力学性质。

Description

取代的吡唑并[1,5-a]吡啶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吡唑并[1,5-a]吡啶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吡唑并[1,5-a]吡啶的化合物，这些氘取代的化合物及其组合物可用于治疗RET激酶介导的疾病或病症，且这些氘取代的化合物具有更优良的药代动力学性质。
背景技术
RET(Rearranged during transfection，转染期重排)属于受体酪氨酸激酶蛋白家族，是细胞生长和分化传到信号的细胞表面分子。RET激酶的胞外部分含有涉及配体结合的四个钙依赖性钙粘着蛋白样重复序列和RET胞外结构域的正确折叠所必需的近膜半胱氨酸富集区，而受体的细胞质部分包括两个酪氨酸激酶亚结构域。
RET蛋白的主要配体属于神经胶质细胞源性神经营养因子(Glial cell line derived neurotrophic factor,GDNF)家族，包括GDNF、Neurturin(NTRN，神经生长因子)、artemin(ARTN，阿特姆因子)及persephin(PSPN，佩斯因子)。RET受体与其配体结合后，胞内区酪氨酸激酶磷酸化，继而诱导RET二聚化、自体磷酸化、底物磷酸化，从而激活细胞内多条下游信号传导通路，包括Ras-MAPK和PI3K-Akt/mTOR途径，或导致在RET介导功能的RET小调中起作用的泛素连接酶的CBL家族的招募。
RET基因突变或RET基因融合被鉴定为某些癌症的驱动因素。RET基因融合在非小细胞肺癌中的发生率约为2％，在甲状腺乳头状癌(Papillary Thyroid Cancers，PTCs)中的发生率为10％～20％，最常见的融合伴侣包括KIF5B、TRIM33、CCDC6和NCOA4。RET基因突变在甲状腺髓样癌(Medullary Thyroid Cancers，MTCs))中的发生率为60％左右，最常见的突变位点是M918T。RET抑制剂抗性突变包括但不限于氨基酸位置804(V804M，V804L，V804E)，氨基酸位置805(E805K)，氨基酸位置806(Y806C，Y806E)。
国际公布号WO 2017/011776 A1和WO 2018/071447 A1中公布了一系列作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡啶化合物，可用于治疗和预防RET激酶介导的疾 病或病症。
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。
至今仍然没有RET抑制剂批准上市，因此该领域仍存在严重的临床未满足需求。发现具有治疗RET相关疾病且具有很好的口服生物利用度且有成药性的新型化合物还是具有挑战性的工作。因此，本领域仍需开发对适用作RET抑制剂具有选择性抑制活性和/或更好地药效学/药代动力学的化合物，本发明提供了这样的化合物。
发明内容
针对以上技术问题，本发明公开了一种新型的氘取代的吡唑并[1,5-a]吡啶化合物及其包含该化合物的组合物及其用途，其具有抑制细胞或患者中RET、RET基因突变和RET基因融合的活性，同时具有更低的副作用、更好地药代动力学性能，可用于治疗RET激酶介导的相关疾病或病症。
如本文所用，术语“本发明化合物”指式(I)和式(II)(包括其子集，例如式(II-A)、式(II-B-a))所示的化合物。该术语还包括及其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
对此，本发明采用以下技术方案：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2019122674-appb-000001
其中，
Y选自CH或N，其任选被氘、卤素或三氟甲基取代；
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
X选自CH 3、CD 3、CHD 2或CH 2D；
Z选自：
Figure PCTCN2019122674-appb-000002
其任选被1、2、3、4、5、6、7、8或9个氘取代；
*表示与母核连接的键；
附加条件是，上述化合物至少含有一个氘原子；
或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。在具体实施方案中，药物组合物还包含另外的治疗剂。在具体实施方案中，另外的治疗剂选自细胞毒性化学治疗剂，激酶靶向治疗剂，细胞凋亡调节剂或信号转导抑制剂。在具体实施方案中，另外的治疗剂选自一种或多种激酶靶向治疗剂。
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，本发明还涉及制备本发明化合物化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或上述药物组合物用于治疗RET相关癌症的药物的用途。在具体实施方案中，RET相关癌症是RET基因、RET激酶蛋白或其任何一者的表达或活性或水平失调的癌症。在具体实施方案中，RET基 因、RET激酶蛋白或者其中任何一者的表达或活性或水平的失调是RET基因中的一个或多个点突变。在具体实施方案中，RET基因中的一个或多个点突变导致翻译具有一个或多个下述氨基酸取代的RET蛋白：S32L,D34S,L40P,P64L,R67H,R114H,V145G,V292M,G321R,R330Q,T338I,R360W,F393L,A510V,E511K,C515S,C531R,G533C,G533S,G550E,V591I,G593E,I602V,R600Q,K603Q,K603E,Y606C,C609Y,C609S,C609G,C609R,C609F,C609W,C611R,C611S,C611G,C611Y,C611F,C611W,C618S,C618Y,C618R,C618Y,C618G,C618F,C618W,F619F,C620S,C620W,C620R,C620G,C620L,C620Y,C620F,E623K,D624N,C630A,C630R,C630S,C630Y,C630F,D631N,D631Y,D631A,D631G,D631V,D631E,E632K,E632G,C634W,C634Y,C634S,C634R,C634F,C634G,C634L,C634A,C634T,R635G,T636P,T636M,A640G,A641S,A641T,V648I,S649L,A664D,H665Q,K666E,K666M,K666N,S686N,G691S,R694Q,M700L,V706M,V706A,E713K,G736R,G748C,A750P,S765P,P766S,P766M,E768Q,E768D,L769L,R770Q,D771N,N777S,V778I,Q781R,L790F,Y791F,V804L,V804M,V804E,E805K,Y806E,Y806F,Y806S,Y806G,Y806C,E818K,S819I,G823E,Y826M,R833C,P841L,P841P,E843D,R844W,R844Q,R844L,M848T,I852M,A866W,R873W,A876V,L881V,A883F,A883S,A883T,E884K,R886W,S891A,R897Q,D898V,E901K,S904F,S904C,K907E,K907M,R908K,G911D,R912P,R912Q,M918T,M918V,M918L,A919V,E921K,S922P,S922Y,T930M,F961L,R972G,R982C,M1009V,D1017N,V1041G或M1064T。在具体实施方案中，RET基因、RET激酶蛋白或者其中任何一者的表达或活性或水平的失调是RET基因融合体。在具体实施方案中，所述RET基因融合体选自：BCR-RET,CLIP1-RET,KIF5B-RET,CCDC6-RET,NCOA4-RET,TRIM33-RET,ERC1-RET,ELKS-RET,RET-ELKS,FGFR1OP-RET,RET-MBD1,RET-RAB61P2,RET-PCM1,RET-PPKAR1A,RET-TRIM24,RET-RFG9,RFP-RET,RET-GOLGA5,HOOK3-RET,KTN1-RET,TRIM27-RET,AKAP13-RET,FKBP15-RET,SPECC1L-RET,TBL1XR1/RET,CEP55-RET,CUX1-RET,KIAA1468-RET,PPKAR1A-RET,RFG8/RET,RET/RFG8,H4-RET,ACBD5-RET,PTCex9-RET,MYH13-RET,PIBF1-RET,KIAA1217-RET或MPRIP-RET。在具体实施方案中，所述RET相关癌症选自：肺癌、乳头状腺癌、甲状腺髓样癌，分化的甲状腺癌、复发性甲状腺癌、难治性分化型甲状腺癌、2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤、甲状 旁腺增生、乳腺癌、结直肠癌、乳头状肾细胞癌、胃肠粘膜神经节细胞瘤或宫颈癌。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。
具体实施方式
定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。
本发明化合物可以是无定形或结晶形式。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
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。
化合物
在一个实施方案中，本发明涉及式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000003
其中，
Y选自CH或N，其任选被氘、卤素或三氟甲基取代；
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
X选自CH 3、CD 3、CHD 2或CH 2D；
Z选自：
Figure PCTCN2019122674-appb-000004
其任选被1、2、3、4、5、6、7、8或9个氘取代；
*表示与母核相连的键；
附加条件是，上述化合物至少含有一个氘原子。
作为本发明的优选实施方案，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％。
作为本发明的优选实施方案，本发明至少含有一个氘原子，更佳地含有二个氘原子，更佳地含有三个氘原子，更佳地含有四个氘原子，更佳地含有五个氘原子，更佳地含有六个氘原子，更佳地含有七个氘原子，更佳地含有八个氘原子，更佳地含有九个氘原子，更佳地含有十个氘原子，更佳地含有十一个氘原子，更佳地含有十二个氘原子，更佳地含有十三个氘原子，更佳地含有十四个氘原子，更佳地含有十五个氘原子，更佳地含有十六个氘原子，更佳地含有十七个氘原子，更佳地含有十八个氘原子， 更佳地含有十九个氘原子，更佳地含有二十个氘原子。
在一些实施方案中，Y选自CH或N，其任选被氘、卤素或三氟甲基取代；在另一些实施方案中，Y选自CH、N、CD、CF或CF 3；在另一些实施方案中，Y选自CH；在另一些实施方案中，Y选自N。
在一些实施方案中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；在另一些实施方案中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、F或三氟甲基；在另一些实施方案中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢；在另一些实施方案中，Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氘。
在一些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；在另一些实施方案中，R 1选自氢；在另一些实施方案中，R 1选自氘；在另一些实施方案中，R 2选自氢；在另一些实施方案中，R 2选自氘；在另一些实施方案中，R 3选自氢；在另一些实施方案中，R 3选自氘；在另一些实施方案中，R 4选自氢；在另一些实施方案中，R 4选自氘；在另一些实施方案中，R 5选自氢；在另一些实施方案中，R 5选自氘；在另一些实施方案中，R 6选自氢；在另一些实施方案中，R 6选自氘；在另一些实施方案中，R 7选自氢；在另一些实施方案中，R 7选自氘；在另一些实施方案中，R 8选自氢；在另一些实施方案中，R 8选自氘；在另一些实施方案中，R 9选自氢；在另一些实施方案中，R 9选自氘；在另一些实施方案中，R 10选自氢；在另一些实施方案中，R 10选自氘。
在一些实施方案中，X选自CH 3、CD 3、CHD 2或CH 2D；在另一些实施方案中，X选自CH 3；在另一些实施方案中，X选自CD 3；在另一些实施方案中，X选自CHD 2；在另一些实施方案中，X选自CH 2D。
在一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000005
其任选被1、2、3、4或5个氘取代；在一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000006
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000007
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000008
在一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000009
其任选被1、2、3、4、5、6、7、8或9个氘取代；在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000010
Figure PCTCN2019122674-appb-000011
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000012
Figure PCTCN2019122674-appb-000013
Figure PCTCN2019122674-appb-000014
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000015
Figure PCTCN2019122674-appb-000016
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000017
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000018
另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000019
在一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000020
其任选被1、2、3、4、5、6、7或8个氘取代；在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000021
Figure PCTCN2019122674-appb-000022
在另一些实施方案中，Z选自、
Figure PCTCN2019122674-appb-000023
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000024
在另一些实施方案中，Z选自
Figure PCTCN2019122674-appb-000025
在另一个实施方案中，本发明还涉及式(II)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000026
其中，
Y选自CH或N；
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；
X选自CH 3、CD 3、CHD 2或CH 2D；
Z选自：
Figure PCTCN2019122674-appb-000027
其任选被1、2、3、4、5、6、7、8或9个氘取代；
*表示与母核相连的键；
附加条件是，上述化合物至少含有一个氘原子。
在另一个实施方案中，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000028
其中，
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；
Y 1’、Y 2’、Y 3’、Y 4’、Y 5’、Y 6’、Y 7’、Y 8’、Y 9’、Y 10’和Y 11’各自独立地选自氢、氘、卤素或三氟甲基；
X 1和X 2各自独立地选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
作为本发明的优选实施方案，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％。
在具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘”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 10选自氢或氘的技术方案。更具体地，包括R 1为氢或R 1为氘，R 2为氢或R 2为氘，R 3为氢或R 3为氘，以此类推，直至R 10为氢或R 10为氘的技术方案。
在另一具体实施方案中，“Y 1’、Y 2’、Y 3’、Y 4’、Y 5’、Y 6’、Y 7’、Y 8’、Y 9’、Y 10’和Y 11’各自独立地选自氢、氘、卤素或三氟甲基”包括Y 1’选自氢、氘、卤素或三氟甲基，Y 2’选自氢、氘、卤素或三氟甲基，Y 3’选自氢、氘、卤素或三氟甲基，以此类推，直至Y 11’选自氢、氘、卤素或三氟甲基的技术方案。更具体地，包括Y 1’为氢、Y 1’为氘、Y 1’为卤素(F、Cl、Br或I)或Y 1’为三氟甲基，Y 2’为氢、Y 2’为氘、Y 2’为卤素(F、Cl、Br或I)或Y 2’为三氟甲基，Y 3’为氢、Y 3’为氘、Y 3’为卤素(F、Cl、Br或I)或Y 3’为三氟甲基，以此类推，直至Y 11’为氢、Y 11’为氘、Y 11’为卤素(F、Cl、Br或I)或Y 11’为三氟甲基的技术方案。
在另一具体实施方案中，“X 1和X 2各自独立地选自CH 3、CD 3、CHD 2或CH 2D”包括X 1选自CH 3、CD 3、CHD 2或CH 2D，X 2选自CH 3、CD 3、CHD 2或CH 2D的技术方案。更具体地，包括X 1为CH 3、X 1为CD 3、X 1为CHD 2或X 1为CH 2D，X 2为CH 3、X 2为CD 3、X 2为CHD 2或X 2为CH 2D的技术方案。
在一些实施方案中，优选地，Y 1’、Y 2’、Y 3’、Y 4’、Y 5’、Y 6’、Y 7’、Y 8’、Y 9’、Y 10’和Y 11’各自独立地选自氢或氘。
在一些实施方案中，优选地，X 1和X 2各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体 异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 1-R 10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或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 8为氘，R 1、R 2、R 9和R 10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或CH 2D。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 9和R 10为氘，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或CH 2D。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 10为氢，R 1和R 2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或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 10为氢，R 1和R 2各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 10为氢，X 1为CD 3，R 1和R 2各自独立地选自氢或氘，X 2各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 10为氢，X 2为CD 3，R 1和R 2各自独立地选自氢或氘，X 1各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢， R 3-R 10为氢，R 1为氘，R 2各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1’-Y 11’为氢，R 3-R 10为氢，R 1和R 2为氘，X 1和X 2各自独立地选自CH 3或CD 3。
在另一个实施方案中，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000029
其中，
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10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或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 8为氘，R 1、R 2、R 9和R 10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或CH 2D。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 9和R 10为氘，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或CH 2D。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1和R 2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或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1和R 2各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X 1为CD 3，R 1和R 2各自独立地选自氢或氘，X 2各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X 2为CD 3，R 1和R 2各自独立地选自氢或氘，X 1各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1为氘，R 2各自独立地选自氢或氘，X 1和X 2各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-A)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1和R 2为氘，X 1和X 2各自独立地选自CH 3或CD 3。
在优选的实施方案中，R 1是氘；在优选的实施方案中，R 1是氢。
在优选的实施方案中，R 2是氘；在优选的实施方案中，R 2是氢。
在优选的实施方案中，R 1和R 2是氘；在优选的实施方案中，R 1和R 2是氢。
在优选的实施方案中，R 3和R 4是氘；在优选的实施方案中，R 3和R 4是氢。
在优选的实施方案中，R 5-R 8是氘；在优选的实施方案中，R 5-R 8是氢。
在优选的实施方案中，R 9和R 10是氘；在优选的实施方案中，R 9和R 10是氢。
在优选的实施方案中，X 1是CH 3；在优选的实施方案中，X 1是CD 3。
在优选的实施方案中，X 2是CH 3；在优选的实施方案中，X 2是CD 3。
在另一个实施方案中，本发明涉及式(I-B)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000030
其中，
W选自CR 9R 10；
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和R 19各自独立地选自氢或氘；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
X选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
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％。
在具体实施方案中，“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和R 19各自独立地选自氢或氘”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 19选自氢或氘的技术方案。更具体地，包括R 1为氢或R 1为氘，R 2为氢或R 2为氘，R 3为氢或R 3为氘，以此类推，直至R 19为氢或R 19为氘的技术方案。
在另一具体实施方案中，“Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基”包括Y 1选自氢、氘、卤素或三氟甲基，Y 2选自氢、氘、卤素或三氟甲基，Y 3选自氢、氘、卤素或三氟甲基，以此类推，直至Y 8选自氢、氘、卤素或三氟甲基的技术方案。更具体地，包括Y 1为氢、Y 1为氘、Y 1为卤素(F、Cl、Br或I)或Y 1为三氟甲基，Y 2为氢、Y 2为氘、Y 2为卤素(F、Cl、Br或I)或Y 2为三氟甲基，Y 3为氢、Y 3为氘、Y 3为卤素(F、Cl、Br或I)或Y 3为三氟甲基，以此类推，直至Y 8为氢、Y 8为氘、Y 8为卤素(F、Cl、Br或I)或Y 8为三氟甲基的技术方案。
在另一具体实施方案中，“X选自CH 3、CD 3、CHD 2或CH 2D”包括X选自CH 3、CD 3、CHD 2或CH 2D技术方案。更具体地，包括X为CH 3、X为CD 3、X为CHD 2或X为CH 2D的技术方案。
在另一具体实施方案中，本发明涉及式(I-B-a)或式(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000031
其中，
W选自CR 9R 10；
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和R 19各自独立地选自氢或氘；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
X选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
在通式(I-B)、(I-B-a)和(I-B-b)一些实施方案中，优选地，Y 1、Y 2、Y 3、Y 4、Y 5、 Y 6、Y 7和Y 8各自独立地选自氢或氘。
在通式(I-B)、(I-B-a)和(I-B-b)一些实施方案中，优选地，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 1-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氘，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氘，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氘，R 1-R 12各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氘，R 1-R 12各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氢，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氢，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氢，X选自CD 3，R 1、R 2和R 11-R 19各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氢，R 1和R 2选自氘，R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 3-R 10为氢，R 11和R 12选自氘，R 1、R 2和R 13-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氢，R 1-R 12各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氢，R 1-R 12各自独立地选自氢或氘，X选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氢，X选自CD 3，R 1-R 12各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1-Y 8为氢，R 13-R 19为氢，R 1和R 2选自氘，R 3-R 12各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-B)、(I-B-a)和(I-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中， Y 1-Y 8为氢，R 13-R 19为氢，R 11和R 12选自氘，R 1-R 10各自独立地选自氢或氘，X选自CH 3或CD 3。
在另一个实施方案中，本发明涉及式(II-B)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000032
其中，
W选自CR 9R 10；
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和R 19各自独立地选自氢或氘；
X选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
在另一具体实施方案中，本发明涉及式(II-B-a)或式(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000033
Figure PCTCN2019122674-appb-000034
其中，
W选自CR 9R 10；
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和R 19各自独立地选自氢或氘；
X选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
在通式(II-B)、(II-B-a)和(II-B-b)一些实施方案中，优选地，X选自CH 3或CD 3。
在)一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 1-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氘，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氘，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氘，R 1-R 12各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氘，R 1-R 12各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在通式一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1、R 2和R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X选自CD 3，R 1、R 2和R 11-R 19各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1和R 2选自氘，R 11-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 11和R 12选自氘，R 1、R 2和R 13-R 19各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氢，R 1-R 12各自独立地选自氢或氘，X选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氢，R 1-R 12各自独立地选自氢或氘，X选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氢，X选自CD 3，R 1-R 12各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氢，R 1和R 2选自氘，R 3-R 12各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 13-R 19为氢，R 11和R 12选自氘，R 1-R 10各自独立地选自氢或氘，X选自CH 3或CD 3。在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，R 1、R 2、R 11和R 12各自独立地选自氢或氘，X选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，X选自CD 3，R 1、R 2、R 11和R 12各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，X选自CD 3，R 1和R 2为氘，R 11和R 12各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，X选自CD 3，R 11和R 12为氘，R 1和R 2各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，R 1和R 2为氘，R 11和R 12各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 13-R 19为氢，R 1和R 2为氘，R 11和R 12选自氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-B)、(II-B-a)和(II-B-b)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 13-R 19为氢，R 11和R 12为氘，R 1和R 2各自独立地选自氢或氘，X选自CH 3或CD 3。
在优选的实施方案中，R 1和R 2是氘；在优选的实施方案中，R 1和R 2是氢。
在优选的实施方案中，R 3和R 4是氘；在优选的实施方案中，R 3和R 4是氢。
在优选的实施方案中，R 5-R 8是氘；在优选的实施方案中，R 5-R 8是氢。
在优选的实施方案中，R 9和R 10是氘；在优选的实施方案中，R 9和R 10是氢。
在优选的实施方案中，R 11和R 12是氘；在优选的实施方案中，R 11和R 12是氢。
在优选的实施方案中，R 13是氘；在优选的实施方案中，R 13是氢。
在优选的实施方案中，R 14-R 19是氘；在优选的实施方案中，R 14-R 19是氢。
在优选的实施方案中，X是CH 3；在优选的实施方案中，X是CD 3。
在另一个实施方案中，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2019122674-appb-000035
其中，
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 20和R 21各自独立地选自氢或氘；
Y 1”、Y 2”、Y 3”、Y 4”、Y 5”、Y 6”、Y 7”、Y 8”和Y 9”各自独立地选自氢、氘、卤素或三氟甲基；
X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
作为本发明的优选实施方案，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％。
在具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 20和R 21各自独立地选自氢或氘”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 10选自氢或氘，以及R 20选自氢或氘，R 21选自氢或氘的技术方案。更具体地，包括R 1为氢或R 1为氘，R 2为氢或R 2为氘，R 3为氢或R 3为氘，以此类推，直至R 10为氢或R 10为氘，以及R 20为氢或R 20为氘，R 21为氢或R 21为氘的技术方案。
在另一具体实施方案中，“Y 1”、Y 2”、Y 3”、Y 4”、Y 5”、Y 6”、Y 7”、Y 8”和Y 9”各自独立地选自氢、氘、卤素或三氟甲基”包括Y 1”选自氢、氘、卤素或三氟甲基，Y 2”选自氢、氘、卤素或三氟甲基，Y 3”选自氢、氘、卤素或三氟甲基，以此类推，直至Y 9”选自氢、氘、卤素或三氟甲基的技术方案。更具体地，包括Y 1”为氢、Y 1”为氘、Y 1”为卤素(F、Cl、Br或I)或Y 1”为三氟甲基，Y 2”为氢、Y 2”为氘、Y 2”为卤素(F、Cl、Br或I)或Y 2”为三氟甲基，Y 3”为氢、Y 3”为氘、Y 3”为卤素(F、Cl、Br或I)
或Y 3”为三氟甲基，以此类推，直至Y 9”为氢、Y 9”为氘、Y 9”为卤素(F、Cl、Br或I)或Y 9”为三氟甲基的技术方案。
在另一具体实施方案中，“X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D”包括X选自CH 3、CD 3、CHD 2或CH 2D，X 3选自CH 3、CD 3、CHD 2或CH 2D，和X 4选自CH 3、CD 3、CHD 2或CH 2D技术方案。更具体地，包括X为CH 3、X为CD 3、X为CHD 2或X为CH 2D，X 3为CH 3、X 3为CD 3、X 3为CHD 2或X 3为CH 2D，X 4为CH 3、X 4为CD 3、X 4为CHD 2或X 4为CH 2D的技术方案。
在通式(I-C)一些实施方案中，优选地，Y 1”、Y 2”、Y 3”、Y 4”、Y 5”、Y 6”、Y 7”、Y 8”和Y 9”各自独立地选自氢或氘。
在通式(I-C)一些实施方案中，优选地，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 1-R 10、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氘，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氘，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，X选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X 3和X 4各自独立地CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，X 3选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X和X 4各自独立地CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，X 4选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X和X 3各自独立地CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，R 1和R 2选自氘，R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(I-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，Y 1”-Y 9”为氢，R 3-R 10为氢，R 20和R 21选自氘，R 1和R 2各自独立地选自氢或氘，X、X 3和X 4各自独立地CH 3或CD 3。
在另一个实施方案中，本发明涉式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物：
Figure PCTCN2019122674-appb-000036
其中，
W选自CR 9R 10；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 20和R 21各自独立地选自氢或氘；
X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D；
附加条件是，上述化合物至少含有一个氘原子。
在通式(II-C)一些实施方案中，优选地，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氘， R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氘，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X 3选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，X 4选自CD 3，R 1、R 2、R 20和R 21各自独立地选自氢或氘，X和X 3各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 1和R 2选自氘，R 20和R 21各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10为氢，R 20和R 21选自氘，R 1和R 2各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10、R 20和R 21为氢，R 1和R 2各自独立地选自氢或氘，X、X 3和X 4各自独立地选自CH 3或CD 3，附加条件是，上述化合物至少含有一个氘原子。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10、R 20和R 21为氢，X选自CD 3，R 1和R 2各自独立地选自氢或氘，X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10、R 20和R 21为氢，X选自CD 3，R 1和R 2是氘，X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10、R 20和R 21为氢，X和X 3是CD 3，R 1和R 2是氘，X 4选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10、R 20和R 21为氢，X和X 4选自CD 3，R 1和R 2是氘，X 3选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 20和R 21为氢，X和X 3选自CD 3，R 1和R 2各自独立地选自氢或氘，X 4选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 20和R 21为氢，X、X 3和X 4选自CD 3，R 1和R 2各自独立地选自氢或氘。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 3-R 10和R 20和R 21为氢，X和X 4选自CD 3，R 1和R 2各自独立地选自氢或氘，X 3选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，R 1和R 2是氘，X、X 3和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，R 1和R 2是氘，X 3是CD 3，X和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，R 1和R 2是氘，X 4是CD 3，X和X 3各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，X 3是CD 3，R 1和R 2各自独立地选自氢或氘，X和X 4各自独立地选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，X 3和X 4是CD 3，R 1和R 2各自独立地选自氢或氘，X选自CH 3或CD 3。
在一些实施方案中，优选地，本发明涉及式(II-C)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，R 3-R 10和R 20和R 21为氢，X 4是CD 3，R 1和R 2各自独立地选自氢或氘，X和X 3各自独立地选自CH 3或CD 3。在优选的实施方案中，R 1和R 2是氘；在优选的实施方案中，R 1和R 2是氢。
在优选的实施方案中，R 3和R 4是氘；在优选的实施方案中，R 3和R 4是氢。
在优选的实施方案中，R 5-R 8是氘；在优选的实施方案中，R 5-R 8是氢。
在优选的实施方案中，R 20和R 21是氘；在优选的实施方案中，R 20和R 21是氢。
在优选的实施方案中，X是CH 3；在优选的实施方案中，X是CD 3。
在优选的实施方案中，X 3是CH 3；在优选的实施方案中，X 3是CD 3。
在优选的实施方案中，X 4是CH 3；在优选的实施方案中，X 4是CD 3。
作为本发明的优选实施方案，所述化合物为如下任一结构，或其药学上可接受的盐，但不限于下列结构：
Figure PCTCN2019122674-appb-000037
Figure PCTCN2019122674-appb-000038
Figure PCTCN2019122674-appb-000039
Figure PCTCN2019122674-appb-000040
Figure PCTCN2019122674-appb-000041
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、 THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5 H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2 H 2O)和六水合物(R·6 H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物，它们等同于本发明化合物所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实 施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
制备本发明化合物的方法
本发明化合物(包括其盐)可使用已知有机合成技术来制备，且可按照多种可能合成途径中的任一种(诸如下文方案中的那些)来合成。用于制备本发明化合物的反应可在合适的溶剂中进行，有机合成领域的技术人员可容易地选择溶剂。合适的溶剂可在进行反应的温度(例如，在溶剂结冻温度至溶剂沸点温度范围内的温度)下与起始物质(反应物)、中间体或产物实质上不反应。既定反应可在一种溶剂或一种以上溶剂的混合物中进行。技术人员可依据具体反应步骤来选择用于具体反应步骤的溶剂。
本发明化合物的制备可涉及不同化学基团的保护和去除保护。本领域技术人员可容易地判定是否需要保护和去除保护以及适当保护基的选择。保护基的化学性质可参 见例如Wuts和Greene，Protective Groups in Organic Synthesis，第4版，John Wiley&Sons：New Jersey，(2006)，其通过引用整体并入本文中。
本发明化合物可通过化合物的消旋混合物与光学活性的拆分剂反应形成一对非对映异构体化合物、分离非对映异构体并回收光学纯度的対映体，制备成其单个立体异构体。对映体拆分时可使用本发明化合物的非对映体衍生物进行，优先可解离的复合物(例如，结晶非对映体盐)。非对映体具有显著不同的物理性质(例如，熔点、沸点、溶解度、反应性等)，并可通过这些不相似性的优势容易地得到分离。非对映体可通过色谱，优选通过基于溶解度的差异的分离/拆分技术进行分离。然后通过不会消旋化的任何实际手段，回收光学纯对映体，连同拆分试剂。适用于从消旋混合物开始拆分得到化合物立体异构体的技术的更详细的描述可见于Jean Jacques，Andre Collet，Samue1 H.Wilen，“对映体、消旋体和拆分”(“Enantiomers，Racemates and Resolutions”)，John Wiley And Sons，Inc.,1981。
可按照本领域已知任何合适的方法来监测反应。例如，可通过光谱手段(诸如核磁共振(NMR)光谱法(例如 1H或 13C)、红外(IR)光谱法、分光光度法(例如，UV-可见光)、质谱(MS))或通过色谱方法(诸如高效液相色谱法(HPLC)或薄层色谱法(TLC))来监测产物形成。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度快速提高至有效水平。推注剂量取决于活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物 组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
适应症
本发明化合物是RET激酶的抑制剂，并且可用于治疗用RET激酶抑制剂治疗的疾病和病症，例如RET相关的疾病和病症，如增殖性病症(如癌症，包括血液癌症和实体瘤)，以及胃肠道疾病(IBS)。
如本文所用的术语“RET相关疾病或病症”是指与RET基因、RET激酶(在本文中也成称为RET激酶蛋白或RET激酶)或其中任何(例如一种或多种)的表达或活性或水平失调(例如，本文所述的RET基因、RET激酶、RET激酶结构域或其中任何一者的表达或水平失调的任何类型)相关的疾病或病症。RET相关疾病或病症的非限制性示例包括例如癌症和胃肠病症如肠易激综合征(IBS)。
本文使用的术语“RET相关癌症”是指与RET基因、RET激酶(在本文中也称为RET激酶蛋白或RET激酶)或其中任何一者的表达或活性或水平或具有失调的癌症。本文描述了RET相关癌症的非限制性示例。
短语“RET基因、RET激酶或其中任何一者的表达或活性或水平失调”是指基因突变(例如导致融合蛋白表达的RET基因易位，导致与野生型RET蛋白相比包含至少一个氨基酸缺失的RET蛋白表达的RET基因中的缺失，或导致具有一个或多个点突变的RET蛋白表达的RET基因中的突变，或导致与野生型RET蛋白相比RET蛋白中的至少一个氨基酸缺失的RET蛋白的RET mRNA的可变剪接形式)，或RET基因扩增，所述基因扩增导致RET蛋白过表达或由细胞RET基因过表达导致的自分泌活性，导致细胞中RET蛋白的激酶结构域的活性的致病性增加(例如，RET蛋白的激酶结构域的组成性激活)。作为另一个示例，RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是编码RET蛋白的RET基因中的突变，所述RET蛋白与不包含该突变的RET基因编码的蛋白质相比，具有组成型活性或具有增加的活性。例如，RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是基因或染色体易位的结果，其导致融合蛋白的表达，所述融合蛋白包含第一包含功能性激酶结构域的RET部分和伴侣蛋白的第二部分(即不是RET)。在一些示例中，RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是一个RET基因与另一个RET基因的基因翻译的结果。本文中描述了融合蛋白的非限制性示例和RET激酶蛋白点突变/插入的非限制性示例。RET激酶蛋白点突变的其他示例是RET抑制剂抗性突变。本文中描述了RET抑制剂抗性突变的非限制性示例。
术语“野生型”描述这样的核酸(例如RET基因或RET mRNA)或蛋白质(例如RET蛋白)，其在不具有RET相关疾病例如RET相关癌症(并且任选地也不具有发展RET相关疾病的增加的风险和/或不被怀疑具有RET相关疾病)的对象中发现，或者在来自不具有RET相关疾病例如RET相关癌症(并且任选地也不具有发展的RET相关疾病的增加的风险和/或不被怀疑具有RET相关疾病)的对象的细胞或组织中发现。
在一些实施方式中，血液学癌症(例如，与RET相关的癌症的血液学癌症)选自白血病，淋非霍奇金淋巴瘤，霍奇金淋巴瘤和骨髓瘤。例如，急性淋巴细胞白血病(ALL)，急性骨髓性白血病(AML)，急性早幼粒细胞白血病(APL)，慢性淋巴细胞白血病(CLL)，慢性粒细胞白血病(CML)，慢性髓单核细胞白血病(CMML)，慢性 嗜中性白血病(CNL)，急性未分化型白血病(AUL)，间变性大细胞淋巴瘤(ALCL)，幼淋巴细胞白血病(PML)，幼年型单核细胞白血病(JMML)，成人T细胞ALL，三联型骨髓发育不良的AML(AML/TMDS)，混合谱系白血病(MLL)，骨髓增生异常综合征(MDS)，骨髓增殖性疾病(MPD)和多发性骨髓瘤(MM)。血液癌症的其它实例包括骨髓瘤增殖性疾病(MPD)，如真性红细胞增多症(PV)，原发性血小板减少症(ET)和特发性原发性骨髓纤维化(IMF/IPF/PMF)。在一个实施方式中，血液学癌症(例如，作为与RET相关癌症的血液学癌症)是AML或CML。
在一些实施方式中，癌症(例如RET相关癌症)是实体瘤。实体瘤(例如，作为与RET相关癌症的实体瘤)的实例包括例如甲状腺癌(例如乳头状甲状腺癌，甲状腺髓样癌)，肺癌(例如肺腺癌，小细胞肺癌)，胰腺癌，胰腺导管癌，乳腺癌，结肠癌，结直肠癌，前列腺癌，肾细胞癌，头颈肿瘤，神经母细胞瘤和黑素瘤。参见，例如，Nature Reviews Cancer,2014,14,173-186。
在一些实施方式中，癌症选自肺癌，乳头状甲状腺癌，甲状腺髓样癌，分化的甲状腺癌，复发性甲状腺癌，难治性分化型甲状腺癌，2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤，甲状旁腺增生，乳腺癌，结直肠癌，乳头状肾细胞癌，胃肠粘膜神经节细胞瘤和宫颈癌。
本发明化合物及其药学上可接受的盐和溶剂合物，或包含本发明化合物及其药学上可接受的盐和溶剂合物药物组合物也可用于治疗RET相关的癌症。
因此，本文还提供了用于治疗诊断患有或鉴定为具有RET相关癌症(例如本文公开的任何示例性RET相关癌症)的患者的方法，所述方法包括向患者使用治疗有效量的如本文所限定的本发明化合物或其药学上可接受的盐或溶剂合物，或其药物组合物。
RET激酶、RET基因或其中任何(例如一种或多种)的表达或活性或水平的失调可能有助于肿瘤发生。例如，RET激酶、RET基因或其中任何一者的表达或活性或水平的失调可以是RET激酶、RET基因或RET激酶结构域的易位、过表达、激活、扩增或突变。易位可以包括涉及RET激酶结构域的易位，突变可以包括涉及RET配体结合位点的突变，并且扩增可以是RET基因。其他失调可包括RET mRNA剪接变体和RET自分泌/旁分泌信号传导，这也可能有助于肿瘤发生。
在一些实施方式中，RET基因、RET激酶蛋白或其中任何一者的表达或活性或水平的失调包括导致RET基因融合的一个或多个染色体易位或倒位。在一些实施方式中， RET基因、RET激酶蛋白质或其中任何相同的表达或活性或水平的失调是遗传易位的结果，其中表达的蛋白质是含有来自非RET伴侣蛋白的残基的融合蛋白，并且包括最少的功能性RET激酶结构域。
在一些实施方式中，RET融合蛋白的非限制性示例为BCR-RET,CLIP1-RET,KIF5B-RET,CCDC6-RET,NCOA4-RET,TRIM33-RET,ERC1-RET,ELKS-RET,RET-ELKS,FGFR1OP-RET,RET-MBD1,RET-RAB61P2,RET-PCM1,RET-PPKAR1A,RET-TRIM24,RET-RFG9,RFP-RET,RET-GOLGA5,HOOK3-RET,KTN1-RET,TRIM27-RET,AKAP13-RET,FKBP15-RET,SPECC1L-RET,TBL1XR1/RET,CEP55-RET,CUX1-RET,KIAA1468-RET,PPKAR1A-RET,RFG8/RET,RET/RFG8,H4-RET,ACBD5-RET,PTCex9-RET,MYH13-RET,PIBF1-RET,KIAA1217-RET或MPRIP-RET。
表1.示例性的RET融合伴侣和癌症 1
Figure PCTCN2019122674-appb-000042
Figure PCTCN2019122674-appb-000043
1国际公开号WO2017/011776A1.
在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶中的一个或多个缺失(例如4位氨基酸的缺失)、插入或点突变。在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶的一个或多个残基的缺失，导致RET激酶结构域的组成型活性。在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET基因中的至少一个点突变，其导致与野生型RET激酶相比具有一个或多个氨基酸取代 的RET激酶的产生。在一些实施方式中，示例性RET点突变包括但不限：S32L,D34S,L40P,P64L,R67H,R114H,V145G,V292M,G321R,R330Q,T338I,R360W,F393L,A510V,E511K,C515S,C531R,G533C,G533S,G550E,V591I,G593E,I602V,R600Q,K603Q,K603E,Y606C,C609Y,C609S,C609G,C609R,C609F,C609W,C611R,C611S,C611G,C611Y,C611F,C611W,C618S,C618Y,C618R,C618Y,C618G,C618F,C618W,F619F,C620S,C620W,C620R,C620G,C620L,C620Y,C620F,E623K,D624N,C630A,C630R,C630S,C630Y,C630F,D631N,D631Y,D631A,D631G,D631V,D631E,E632K,E632G,C634W,C634Y,C634S,C634R,C634F,C634G,C634L,C634A,C634T,R635G,T636P,T636M,A640G,A641S,A641T,V648I,S649L,A664D,H665Q,K666E,K666M,K666N,S686N,G691S,R694Q,M700L,V706M,V706A,E713K,G736R,G748C,A750P,S765P,P766S,P766M,E768Q,E768D,L769L,R770Q,D771N,N777S,V778I,Q781R,L790F,Y791F,V804L,V804M,V804E,E805K,Y806E,Y806F,Y806S,Y806G,Y806C,E818K,S819I,G823E,Y826M,R833C,P841L,P841P,E843D,R844W,R844Q,R844L,M848T,I852M,A866W,R873W,A876V,L881V,A883F,A883S,A883T,E884K,R886W,S891A,R897Q,D898V,E901K,S904F,S904C,K907E,K907M,R908K,G911D,R912P,R912Q,M918T,M918V,M918L,A919V,E921K,S922P,S922Y,T930M,F961L,R972G,R982C,M1009V,D1017N,V1041G或M1064T。
在一些实施方式中，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET基因中的至少一个点突变，其导致RET激酶的产生，所述RET激酶具有与野生型RET激酶相比的一个或多个氨基酸取代，并且与野生型RET激酶或不具有相同突变的RET激酶相比，其对本发明化合物或其药学上可接受的盐或溶剂合物具有增加的抗性。在这样的实施方式中，在本发明化合物或其药学上可接受的盐或溶剂合物的存在下，RET抑制剂抗性突变可导致具有增加的Vmax、减少的Km和减少的KD中的一者或多者的RET激酶(与在本发明化合物或其药学上可接受的盐或溶剂合物存在下的野生型RET激酶或不具有相同突变的RET激酶相比较)。
RET抑制剂抗性突变的示例可以例如包括RET激酶三级结构中ATP结合位点内和附近的点突变、插入或缺失，包括但不限于看门人(gatekeeper)残基，P-环残基，或DFG基序内或附近的残基，和ATP裂隙溶剂前沿(ATP cleft solvent front)氨基酸残基。这些类型的突变的其他示例包括可能影响酶活性和/或药物结合的残基中的变化，包括但不 限于活化环中的残基，活性环附近的残基或与活性环相互作用的残基，有助于活性或失活的酶构象的残基，包括进行C-螺旋的环中和C-螺旋中的突变、缺失和插入的变化。可以改变的特定残基或残基区域(并且是RET抑制剂抗性突变)包括但不限于基于人类野生型RET蛋白序列(例如，SEQ ID NO：1)。RET抑制剂抗性突变包括但不限于氨基酸位置804(V804M，V804L，V804E)，氨基酸位置804/805(V804M/E805K)，氨基酸位置806(Y806C，Y806E)。对这些残基的改变可以包括单个或多个氨基酸改变，序列内或侧翼的插入，以及序列内侧或侧翼的缺失。
在一些实施方式中，本发明化合物及其药学上可接受的盐和溶剂合物可用于治疗患有RET抑制剂抗性突变(其导致对不是本发明化合物或药学上可接受的盐或溶剂合物的抗性增加，例如在氨基酸位置804处的取代，例如V804M、V804L或V804E)的癌症的患者，所述治疗通过联合给药或作为现有药物治疗(例如，不是本发明化合物或其药学上可接受的盐或溶剂合物的其他RET激酶抑制剂)的后续治疗。本文描述了示例性的RET激酶抑制剂(例如，不是本发明化合物或其药学上可接受的盐或溶剂合物的其它RET激酶抑制剂)。在一些实施方式中，RET激酶抑制剂可以选自卡博替尼，凡德他尼，阿拉替尼，索拉非尼，乐伐替尼，普纳替尼，多维替尼，舒尼替尼，福替尼(foretinib)，BLU667和BLU6864。
在一些实施方式中，本发明化合物及其药学上可接受的盐和溶剂合物可用于治疗已被鉴定为具有一种或多种RET抑制剂抗性突变(其导致对不是本发明化合物或其药学上可接受的盐或溶剂合物的RET抑制剂的抗性增加，例如在氨基酸位置804处的取代，例如V804M，V804L或V804E)。
因此，本文提供了用于治疗被诊断患有(或被鉴定为具有)癌症(例如，RET相关癌症)(例如，包括一种或多种RET抑制剂抗性突变的RET相关癌症)的患者的方法，其包括向患者给予治疗有效量的本发明化合物或其药学上可接受的盐或溶剂合物。本文还提供了用于治疗被鉴定或诊断为患有RET相关癌症的患者(例如，已经通过使用管理机构批准的例如FDA批准的测试或测定而鉴定或诊断为具有RET相关癌症的患者，所述测试或测定用于鉴定患者中或患者的活检样品中的RET基因、RET激酶或其中任何一者的表达或活性或水平的失调)(例如本文所述或本领域已知的任何RET相关癌症)(例如，包括一种或多种RET抑制剂抗性突变的RET相关癌症)的方法，包括向患者施用治疗有效量的通本发明化合物或其药学上可接受的盐或溶剂合物或其药物组合 物。
还提供了本发明化合物或其药学上可接受的盐或溶剂合物，其用于治疗患者中的癌症(例如RET相关癌症，例如具有一种或多种RET抑制剂抗性突变的RET相关癌症)，所述患者为有需要的患者或经鉴定或诊断为患有RET相关癌症的患者(例如，通过使用管理机构批准的，例如FDA批准的试剂盒鉴定或诊断为患有RET相关癌症的患者，所述试剂盒用于鉴定患者或患者的活检样品中的RET基因、RET激酶或其中任何一者的表达或活性或水平的失调)(例如，本文描述的或本领域已知的任何RET相关癌症)。还提供了本发明化合物或其药学上可接受的盐或溶剂合物在制备药物中的用途，所述药物用于治疗患者中的癌症(例如RET相关癌症，例如具有一种或多种RET抑制剂抗性突变的RET相关癌症)，所述患者经鉴定或诊断为患有RET相关癌症的患者(例如，通过使用管理机构批准的，例如FDA批准的试剂盒鉴定或诊断为患有RET相关癌症的患者，所述试剂盒用于鉴定患者或患者的活检样品中的RET基因、RET激酶或其中任何一者的表达或活性或水平的失调)(例如，本文描述的或本领域已知的任何RET相关癌症)
本文还提供了治疗对象的方法。该方法包括对从对象获得的样品进行测定以确定对象是否具有RET基因、RET蛋白或其中任何一者的表达或水平的失调(例如，一种或多种RET抑制剂抗性突变)。该方法还包括向确定具有RET基因、RET蛋白或其中任何一者的表达或活性或水平的失调(例如一种或多种RET抑制剂抗性突变)的对象施用治疗有效量的通式(I)化合物或其药学上可接受的盐或溶剂合物。在一些实施方式中，RET融合体可以选自KIF5B-RET融合体和CCDC6-RET融合体。在一些实施方式中，RET基因、RET激酶蛋白或其表达或活性的失调是导致RET融合蛋白(例如，本文所述的任何RET融合蛋白)表达的基因或者染色体易位。在一些实施方式中，RET基因、RET激酶蛋白或者其中任何一者的表达或活性或水平的失调是RET基因中的一个或多个点突变(例如，本文所述的一种或多种RET点突变中的任何)。RET基因中的一个或多个点突变可导致例如翻译具有一个或多个以下氨基酸取代的RET蛋白：M918T，M918V，C634W，V804L和V804M。在一些实施方式中，RET基因、RET激酶蛋白或者其中任何一者的表达或活性或水平的失调是的一个或多个RET抑制剂抗性突变(例如，本文所述的一种或多种RET抑制剂抗性突变的任何组合)。这些方法的一些实施方式进一步包括向对象施用另一种抗癌剂(例如另一种RET抑制剂，例如不是通式(I) 化合物或其药学上可接受的盐或溶剂合物的RET抑制剂，或是另一种本发明化合物或其药学上可接受的盐或溶剂合物的RET抑制剂)。
联合疗法
在肿瘤医学领域，通常使用不同形式的治疗的组合来治疗每个患有癌症的患者。在肿瘤医学中，除本文提供的组合物之外，此类联合治疗或疗法的其它组成可以是例如手术，放射疗法和化学治疗剂，例如激酶抑制剂，信号转导抑制剂和/或单克隆抗体。本发明化合物因此也可以用作癌症治疗的辅佐，即它们可以与一种或多种其他疗法或治疗试剂组合使用，例如通过相同或不同的机制起作用的化学治疗剂。
在本文所述的任何方法的一些实施方式中，本发明化合物(或其药学上可接受的盐或溶剂合物)与治疗有效量的至少一种其他治疗剂联用，所述至少一种其他治疗剂选自一种或多种其他疗法或治疗(例如化学治疗)试剂。其他治疗剂的非限制性示例包括：其它RET靶向治疗剂(即其他RET激酶抑制剂；不是本发明化合物或其药学上可接受的盐或溶剂合物的RET抑制剂)，受体酪氨酸激酶靶向的治疗剂，信号转导途径抑制剂，检查点抑制剂，凋亡途径调节剂(例如Obataclax)；细胞毒性化学治疗剂，血管生成靶向治疗剂，免疫靶向剂和放射疗法。
在一些实施方式中，其他RET靶向治疗剂是显示RET抑制活性的多激酶抑制剂。在一些实施方式中，其他RET靶向治疗性抑制剂对RET激酶是选择性的。示例性RET靶向治疗剂可表现出对RET激酶的抑制活性(IC50)小于约1000nM，小于约500nM，小于约200nM，小于约100nM，小于约50nM，小于约25nM，小于约10nM或小于约1nM。
RET靶向治疗剂的非限制性示例包括阿拉替尼，阿帕替尼，卡博替尼(XL-184)，多维替尼，乐伐替尼，莫泰沙尼，尼达尼布，普纳替尼，雷格拉非尼，斯塔替尼(sitravatinib)，舒尼替尼，索拉非尼，瓦他拉尼，凡德他尼，AUY-922(5-(2,4-二羟基-5-异丙基-苯基)-N-乙基-4-[4-(吗啉代甲基)苯基]异噁唑-3-甲酰胺)，BLU6864，BLU-667，DCC-2157，NVP-AST487(1-[4-[(4-乙基哌嗪-1-基)甲基]-3-(三氟甲基)苯基]-3-[4-[6-(甲氨基)嘧啶-4-基]氧苯基]脲)，PZ-1，RPI-1(1,3-二氢-5,6-二甲氧基-3-[(4-羟基苯基)亚甲基]-H-吲哚-2-酮)，RXDX-105(1-(3-(6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-3-(5-(1,1,1-三氟-2-甲基丙-2-基)异噁唑-3-基)脲)，SPP86(1-异丙基-3-(苯基乙炔基)-1H-吡唑并[3,4-d] 嘧啶-4-胺)和TG101209(N-(1,1-二甲基乙基)-3-[[5-甲基-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-4-嘧啶基]氨基]苯磺酰胺)。
因此，本文还提供了治疗癌症的方法，包括向有需要的患者给予治疗癌症的药物组合，其包括(a)本发明化合物或其药学上可接受的盐或溶剂合物，(b)其他治疗剂，和(c)任选的至少一种药学上可接受的运载体，以同时、分开或顺序用于治疗癌症，其中本发明化合物或其药学上可接受的盐或溶剂合物的量和其他治疗剂的量在治疗癌症方面共同有效。
在一些实施方式中，其他治疗剂包括以上列出的疗法或治疗剂中的任一种，所述疗法或治疗剂是对具有RET基因、RET蛋白或其中任何一者的表达或活性或水平的失调的癌症的护理标准。这些其他治疗剂可以与一个或多个剂量的通式(I)的化合物或其药学上可接受的盐或溶剂合物或其药物组合物一起给予，作为相同或分开的剂型的一部分，通过相同或不同的给予途径，和/或根据本领域技术人员已知的标准药学实践在相同或不同的给予方案中进行。
本文还提供了(i)用于治疗有需要的患者的癌症(例如，RET相关癌症(例如，具有一种或多种RET抑制剂抗性突变的RET相关癌症))的药物组合，其包含(a)本发明化合物或其药学上可接受的盐或溶剂合物，(b)至少一种其他治疗剂(例如本文所述的或本领域已知的任何示例性的其他治疗剂)，和(c)任选至少一种药学上可接受的运载体以同时、分开或顺序用于治疗癌症，其中本发明化合物或其药学上可接受的盐或溶剂合物的量和其他治疗剂的量一起有效治疗癌症；(ii)包含这种组合的药物组合物；(iii)这种组合在制备治疗癌症的药物中的用途；和(iv)商业包装或产品，其包含这种组合作为用于同时、分开或顺序使用的组合制剂；并涉及一种治疗有需要的患者的癌症的方法。
如本文所用，术语“药物组合”是指由多于一种活性成分的混合或组合产生并且包括活性成分的固定和非固定组合的药物疗法。术语“固定组合”是指本发明化合物或其药学上可接受的盐或溶剂合物和至少一种其他治疗剂(例如化疗剂)，其以单一组合物或剂量同时给予于患者。术语“非固定组合”意指将本发明化合物或其药学上可接受的盐或溶剂合物与至少一种其他治疗剂(例如化疗剂)配制为分开的组合物或剂量，使得它们可以以不同的介入时间限制同时、并行或顺序地给予有需要的患者，其中所述给予在患者体内提供有效水平的两种或更多种化合物。这些也适用于鸡尾酒疗法，例如三种或更多种活性成分的给予。
因此，本文还提供了治疗癌症(例如，RET相关癌症(例如，具有一种或多种RET抑制剂抗性突变的RET相关癌症))的方法，所述方法包括向有需要的患者给予药物组合用于治疗癌症，该药物组合包括(a)本发明化合物或其药学上可接受的盐或溶剂合物，(b)其他治疗剂，和(c)任选的至少一种药学上可接受的运载体，用于同时、分开或顺序使用以治疗癌症，其中其他治疗剂和本发明化合物或其药学上可接受的盐或溶剂合物的量一起有效地治疗癌症。在一个实施方式中，本发明化合物或其药学上可接受的盐或溶剂合物和其他治疗剂作为分开的剂量同时给予。在一个实施方式中，本发明化合物或其药学上可接受的盐或溶剂合物以及其他治疗剂作为分开的剂量以任何顺序，以联合治疗有效量(例如每日或间歇剂量)给予。在一个实施方式中，本发明化合物或其药学上可接受的盐或溶剂合物和其他治疗剂作为组合的剂量同时给予。
本文还提供了治疗有治疗需要的患者中由RET介导的疾病或病症(例如RET基因、RET激酶或其中任何一者的表达或活性或水平的失调，例如一种或多种RET抑制剂抗性突变)的方法，所述方法包括给予患者治疗有效量的本发明化合物或其药学上可接受的盐或溶剂合物或其药物组合物。由RET介导的疾病或病症(例如，RET基因、RET激酶或其中任何一者的表达或活性或水平的失调，例如一种或多种RET抑制剂抗性突变)可以包括任何与RET的表达或活性直接或间接相关(包括过度表达和/或异常活性水平)的疾病、紊乱或病症。在一个实施方式中，所述疾病是癌症(例如RET相关癌症)。在一个实施方式中，癌症是本文所述的任何癌症或RET相关癌症。
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。
本文所用缩略语如下表2中。
表2
APCI 大气压力化学游离法
Boc 叔丁氧碳基
MsCl 甲基磺酰氯
B 2(pin) 2 联硼酸频那醇酯
X-Phos 2-二环己基磷-2,4,6-三异丙基联苯
Pd 2(dba) 3 三(二亚苄基丙酮)二钯
PdCl 2(dppf)DCM [1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物
Pd(PPh 3) 4 四(三苯基膦)钯
NaBH 4 硼氢化钠
LiAlD4 氘化铝锂
NaH 氢化钠
KOAc 乙酸钾
Cs 2CO 3 碳酸铯
K 2CO 3 碳酸钾
Na 2CO 3 碳酸钠
DIPEA N,N-二异丙基乙胺
TEA 三乙胺
TFA 三氟乙酸
HCl 盐酸
THF 四氢呋喃
DCM 二氯甲烷
MTBE 甲基叔丁醚
DCE 1,2-二氯乙烷
DMF N,N-二甲基甲酰胺
DMA N,N-二甲基乙酰胺
Dioxane 二氧六环
DME 乙二醇二甲醚
EtOAc 乙酸乙酯
PE 石油醚
CDCl 3 氘代氯仿
DMSO 二甲基亚砜
MeOH 甲醇
中间物P1：4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4- 基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000044
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000045
步骤1 4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
氮气保护下，将Pd(PPh 3) 4(692mg)加入到6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-腈(2.5g)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(2.49g)和碳酸钠(3.15g)的二氧六环(33mL)和水(15mL)的混合溶剂中，反应在氮气保护下80℃搅拌过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到2.3g淡黄色固体。LC-MS(APCI):m/z＝254.1(M+1) +， 1H NMR(400MHz,DMSO)δ8.87(d,J＝1.0Hz,1H),8.54(s,1H),8.37(s,1H),8.10(d,J＝0.6Hz,1H),7.28(d,J＝0.8Hz,1H),4.07(s,3H),3.89(s,3H)。
步骤2 4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
室温下，将三氯化铝(4.06g)加入到4-甲氧基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(2.3g)的无水DCE(44mL)中，回流反应过夜。冷却至温室，加入DCE (25mL)稀释反应体系，用水(25mL x 2)淬灭反应。在室温下，搅拌3hrs。固体过滤，40℃真空干燥得到1.5g淡黄色固体。LC-MS(APCI):m/z＝240.1(M+1) +。
步骤3 三氟甲磺酸3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯
将N-苯基双(三氟甲磺酰亚胺)(2.46g)加入到4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(1.5g)和DIPEA(2.18mL)的DMA(12.5mL)中，反应在室温下搅拌2hrs。加入到水(150mL)中淬灭反应，固体过滤，用水(20mL x 3)洗涤。固体溶入DCM(150mL)溶液中，用无水硫酸钠干燥，滤液减压浓缩，浓缩液柱层析(PE/EtOAc＝50％)纯化得到浓缩得到2.1g土灰色固体。 1H NMR(300MHz,CDCl 3)δ8.66(d,J＝1.0Hz,1H),8.29(s,1H),7.78(s,1H),7.71(s,1H),7.56(d,J＝0.9Hz,1H),4.01(s,3H)。
步骤4 4-(6-氟吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
氮气保护下，将Pd(PPh 3) 4(155.6mg，0.13mmol)加入到三氟甲磺酸3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯(1.00g，2.70mmol)，2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶(902mg，4.04mmol)和碳酸钠(707mg，6.73mmol)的二氧六环(26mL)和水(3.4mL)混合溶剂中，反应在氮气保护下，封管90℃反应过夜。冷却至室温，加入水(25mL)，充分搅拌3hrs，固体过滤，用水(10mL x 3)和冷的MTBE(5mL x 2)洗涤，真空干燥得到740mg淡黄色固体，收率：87％。LC-MS(APCI):m/z＝319.1(M+1) +。
步骤5 3-(5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯的合成
室温下，将K 2CO 3(780mg，5.65mmol)加入到4-(6-氟吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(600mg，1.88mmol)和6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(374mg，1.88mmol)的无水DMSO(8mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc洗涤3次。合并有机层，用饱和食盐水洗涤2次，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝10％)纯化得到800mg淡黄色固体，产率：85.4％。LC-MS(APCI):m/z＝497.2(M+1) +。
步骤6 4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
冰浴下，将TFA(10mL)加入到3-(5-(3-氰基-6-(1-甲基-1H-吡唑-4-基吡唑并[1,5-a] 吡啶-4-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羧酸叔丁酯(600mg，1.21mmol)的DCM(10mL)溶液中，反应在室温下反应3hrs。减压浓缩反应液，用氨-甲醇溶液调pH为碱性，减压浓缩，浓缩液柱层析(DCM/MeOH＝12％)纯化得到425mg白色固体。LC-MS(APCI):m/z＝397.2(M+1) +。
中间物P2：4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡 唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000046
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000047
步骤1 1-(甲基-d3)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑的合成
室温下，将氘代碘甲烷(28.38mmol，1.77mL)加入到4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(5g,27.78mmol)和碳酸铯(10.11g，31.11mmol)的无水 DMF(100mL)中，反应在室温下搅拌3hrs。用EtOAc(300mL)稀释反应，分别用水(100mL x 3)和饱和食盐水(100mL x 3)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩得到4.0g淡黄色固体，收率：68.22％。LC-MS(APCI):m/z＝212.3(M+1) +。 1H NMR(500MHz,CDCl 3):δ7.76(s,1H),7.64(s,1H),1.31(s,12H).
步骤2 4-甲氧基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
氮气保护下，将Pd(PPh 3) 4(600mg,4.73mmol)加入到6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲腈(3.96g,15.78mmol)、1-(甲基-d 3)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(4.00g,18.94mmol)和碳酸钠(5.00g，47.34mmol)的二氧六环(52mL)和水(22mL)的混合溶剂中，反应在氮气保护下80℃搅拌过夜。冷却至室温，室温下剧烈搅拌2hrs，固体过滤，分别用水(100mL)和MTBE(15mL x3)洗涤，真空干燥得到3.3g淡黄色固体。LC-MS(APCI):m/z＝257.1(M+1) +。
步骤3 4-羟基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
室温下，将三氯化铝(5.12g)加入到4-甲氧基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(3.3g)的无水DCE(66mL)中，回流反应过夜。冷却至温室，加入DCE(60mL)稀释反应体系，用水(25mL x 2)淬灭反应。在室温下，搅拌3hrs。固体过滤，40℃真空干燥得到2.87g淡黄色固体。LC-MS(APCI):m/z＝243.1(M+1) +。
步骤4 三氟甲磺酸3-氰基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯
将N-苯基双(三氟甲磺酰亚胺)(4.71g)加入到4-羟基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(2.87g,11.21mmol)和DIPEA(4.17mL)的DMA(25mL)中，反应在室温下搅拌2hrs。加入到水(300mL)中淬灭反应，固体过滤，用水(50mL x 3)洗涤。固体溶入DCM(250mL)溶液中，用无水硫酸钠干燥，滤液减压浓缩，浓缩液柱层析(PE/EtOAc＝50％)纯化得到浓缩得到2.4g土灰色固体。LC-MS(APCI):m/z＝375.2(M+1) +。
步骤5 4-(6-氟吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
氮气保护下，将Pd(PPh 3) 4(185mg，0.16mmol)加入到三氟甲磺酸3-氰基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯(1.2g，3.20mmol)，2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶(1.08g，4.80mmol)和碳酸钠(1.70g，16mmol)的二氧六环(32mL)和水(8mL)混合溶剂中，反应在氮气保护下，封管90℃反应 过夜。冷却至室温，加入水(30mL)，充分搅拌3hrs，固体过滤，用水(10mL x 3)和冷的MTBE(5mL x 2)洗涤，真空干燥得到750mg淡黄色固体，收率：72.8％。LC-MS(APCI):m/z＝322.1(M+1) +。
步骤6 3-(5-(3-氰基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯的合成
室温下，将K 2CO 3(1.24g，9.00mmol)加入到4-(6-氟吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(580mg，1.80mmol)和6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(380mg，1.90mmol)的无水DMSO(9mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc洗涤3次。合并有机层，用饱和食盐水洗涤2次，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到700mg淡黄色固体，产率：77.9％。LC-MS(APCI):m/z＝500.2(M+1) +。
步骤7 4-(6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成
冰浴下，将TFA(10mL)加入到3-(5-(3-氰基-6-(1-(甲基-d 3)-1H-吡唑-4-基吡唑并[1,5-a]吡啶-4-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羧酸叔丁酯(700mg，1.40mmol)的DCM(10mL)溶液中，反应在室温下反应3hrs。减压浓缩反应液，用氨-甲醇溶液调pH为碱性，减压浓缩，浓缩液柱层析(DCM/MeOH＝12％)纯化得到560mg白色固体。LC-MS(APCI):m/z＝400.2(M+1) +。
中间物P3：(R)-2-(((3-氰基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡唑[1,5-a]吡 啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯
Figure PCTCN2019122674-appb-000048
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000049
步骤1 4-溴-6-羟基吡唑并[1,5-a]吡啶-3-甲腈的合成
氮气保护下啊，将无水三氯化铝(950mg，7.15mmol)加入到4-溴-6-甲氧基吡唑并[1,5-a]吡啶-3-甲腈(600mg，2.38mmol)的无水DCE(10mL)中，反应在75℃下搅拌过夜。冷却至室温，加入100mL的四氢呋喃稀释反应液，然后在加入十水硫酸钠(10eq)淬灭体系。在室温下搅拌8hrs后，过滤，用四氢呋喃洗涤，滤液减压浓缩。浓缩物用MTBE(2mL)打浆纯化过夜，固体过滤，用冷的MTBE(1mL)洗涤，真空干燥得到540mg固体。产率：95.7％。LC-MS(APCI):m/z＝235.9(M-1) -。
步骤2 (R)-2-(((4-溴-3-氰基吡唑并[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯的合成
室温下，将Cs 2CO 3(2.2g，6.75mmol)加入到4-溴-6-羟基吡唑并[1,5-a]吡啶-3-甲腈(540mg，2.25mmol)和(R)-2-(溴甲基)-4-吗啉羧酸叔丁酯(630mg，2.25mmol)的无水DMA(4mL)溶液中，反应在60℃下，氮气保护下反应过夜。冷却至室温，用DCM(50mL)稀释反应体系，分别用H 2O(25mL x 3)和饱和食盐水(25mL x 2)洗涤，有机层用无水硫酸钠干燥。减压浓缩，浓缩物用MTBE(2mL)打浆纯化，固体过滤，用冷的MTBE(1mL)洗涤，真空干燥得到630mg固体。产率：64.2％。LC-MS(APCI):m/z＝437.2(M+1) +。
步骤3 (R)-2-(((3-氰基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯的合成
氮气保护下，将PdCl 2(dppf)DCM(100mg)加入到(R)-2-(((4-溴-3-氰基吡唑并[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯(510mg，1.16mmol)，联硼酸频那醇酯(2.97g，11.68mmol)和KOAc(580mg，5.92mmol)的无水二氧六环(12mL)中。反应在氮气保护下，80℃封管反应过夜。冷却至室温，用DCM(150mL)稀释反应体系，硅胶层析过滤，用DCM(150mL)洗涤。滤液减压浓缩，浓缩物用正戊烷(50mL)打浆纯化，固体过滤，真空干燥得到400mg固体，不纯化直接用于下一步反应。LC-MS (APCI):m/z＝485.2(M+1) +。
中间物P4：4-溴-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000050
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000051
室温下，将K 2CO 3(2.2g，6.75mmol)加入到4-溴-6-羟基吡唑并[1,5-a]吡啶-3-甲腈(720mg，3.00mmol)和二甲基环氧乙烷(2.2g，30.00mmol)的无水DMF(5mL)溶液中，反应在60℃下，氮气保护下封管反应8hrs。升温至80℃反应过夜。冷却至室温，加入50mL水，搅拌1hr，固体过滤，用冷的MTBE(1mL)洗涤，真空干燥得到800mg固体。LC-MS(APCI):m/z＝310.0(M+1) +。
中间物R1：5-(氯甲基)-2-(甲氧基-d 3)吡啶
Figure PCTCN2019122674-appb-000052
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000053
步骤1 6-氯烟酸(甲基-d 3)酯的合成
冰浴下，将草酰氯(4.90g)和两滴DMF加入到6-氯烟酸(5g)的无水DCM(75mL)中，反应在室温下搅拌24hrs。加压浓缩反应液，在加入无水DCM(35mL)。冰浴下，将氘代甲醇(5mL)，自然升温，再反应30min。减压浓缩反应液，用MTBE稀释，分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝10％)纯化得到5.34g淡黄色固体。 1H NMR(500MHz,CDCl 3)δ9.04– 8.96(m,1H),8.26(dd,J＝8.3,2.4Hz,1H),7.43(dd,J＝8.3,0.5Hz,1H).
步骤2 6-(甲氧基-d 3)烟酸(甲基-d 3)酯的合成
冰浴下，将NaH(1.62g，60％)分批加入到氘代甲醇(1.34g)的无水THF(50mL)溶液中，反应在室温下搅拌反应1hrs后，再次冰浴，将6-氯烟酸(甲基-d 3)酯(5.3g)加入到反应体系体系中，反应在室温下反应4hrs。加入水淬灭反应，用EtOAc萃取，有机层用饱和食盐水洗涤。无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝30％)纯化得到4.5g淡黄色固体。LC-MS(APCI):m/z＝174.1(M+1) +。
步骤3 化合物(6-(甲氧基-d 3)吡啶-3-基)甲醇的合成
冰浴下，将四氢铝锂(402mg)加入到6-(甲氧基-d 3)烟酸(甲基-d 3)酯(1.5g)的无水四氢呋喃(30mL)溶液中，反应在室温下反应2hrs。用十水硫酸钠淬灭反应，加入四氢呋喃(150mL)，充分搅拌4hrs，过滤，用THF洗涤，滤液减压浓缩，浓缩液柱层析(PE/EtOAc＝40％)纯化得到840mg淡黄色油状物，液体产率：72.9％.LC-MS(APCI):m/z＝143.1(M+1) +。
步骤4 5-(氯甲基)-2-(甲氧基-d 3)吡啶的合成
冰浴下，将MsCl(1.02g)加入到(6-(甲氧基-d 3)吡啶-3-基)甲醇(840mg)的TEA(1.19g)的无水DCM(20mL)中，反应在室温下反应过夜，加入水淬灭反应，用DCM萃取，有机层用饱和食盐水洗涤。无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝16％)纯化得到800mg淡黄色油状物。LC-MS(APCI):m/z＝161.1(M+1) +， 1H NMR(300MHz,CDCl 3)δ8.15(d,J＝2.4Hz,1H),7.63(dd,J＝8.6,2.5Hz,1H),6.76(d,J＝8.6Hz,1H),4.55(s,2H).
中间物R2：5-(氯甲基-d 2)-2-甲氧基吡啶
Figure PCTCN2019122674-appb-000054
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000055
步骤1 (6-甲氧基吡啶-3-基)甲烷-d 2-醇的合成
冰浴下，将四氘铝锂(1.00g)加入到6-甲氧基烟酸甲酯(3.78g)的无水四氢呋喃(50mL)溶液中，反应在室温下反应2hrs。用十水硫酸钠淬灭反应，加入四氢呋喃(200mL)，充分搅拌4hrs，过滤，用THF洗涤，滤液减压浓缩，浓缩液柱层析(PE/EtOAc＝40％)纯化得到1.56g淡黄色油状物。LC-MS(APCI):m/z＝142.1(M+1) +。
步骤2 化合物5-(氯甲基-d 2)-2-甲氧基吡啶的合成
冰浴下，将MsCl(1.52g，13.27mmol)加入到(6-甲氧基吡啶-3-基)甲烷基-d 2-醇(1.56g，11.06)的TEA(1.68g，16.59mmol)的无水DCM(40mL)中，反应在室温下反应过夜，加入水淬灭反应，用DCM萃取，有机层用饱和食盐水洗涤。无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝16％)纯化得到1.2g淡黄色油状物。LC-MS(APCI):m/z＝163.1(M+1) +， 1H NMR(400MHz,CDCl 3)δ8.17(d,J＝2.3Hz,1H),7.64(dd,J＝8.6,2.5Hz,1H),6.78(d,J＝8.6Hz,1H),3.96(s,3H).
中间物R3：5-(氯甲基-d 2)-2-(甲氧基-d 3)吡啶
Figure PCTCN2019122674-appb-000056
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000057
步骤1 (6-(甲氧基-d 3)吡啶-3-基)甲烷-d 2-醇的合成
冰浴下，将四氘铝锂(444mg)加入到6-(甲氧基-d 3)烟酸(甲基-d 3)酯(1.5g)的无水四氢呋喃(30mL)溶液中，反应在室温下反应2hrs。用十水硫酸钠淬灭反应，加入四氢呋喃(150mL)，充分搅拌4hrs，过滤，用THF洗涤，滤液减压浓缩，浓缩液柱层析(PE/EtOAc＝40％)纯化得到670mg淡黄色油状物，液体产率：58.2％.LC-MS(APCI):m/z＝145.1(M+1) +.
步骤2 5-(氯甲基-d 2)-2-(甲氧基-d 3)吡啶的合成
冰浴下，将MsCl(803mg)加入到(6-(甲氧基-d 3)吡啶-3-基)甲烷-d 2-醇(670mg)的TEA(940mg)的无水DCM(20mL)中，反应在室温下反应过夜，加入水淬灭反应，用DCM萃取，有机层用饱和食盐水洗涤。无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝16％)纯化得到560mg淡黄色油状物。LC-MS(APCI):m/z＝163.1(M+1) +， 1H NMR(500MHz,CDCl 3)δ8.22–8.05(m,1H),7.63(dd,J＝8.6,2.5Hz,1H),6.76(dd,J＝8.6,0.6Hz,1H).
中间物R4：3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环 [3.1.1]庚烷
Figure PCTCN2019122674-appb-000058
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000059
步骤1 3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯的合成
室温下，将K 2CO 3加入到2,5-二氯吡嗪(2.60g，17.4mmol)和6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(3.10g，15.66mmol)的无水DMSO中，反应在85℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝15-30％)纯化得到4.0g淡黄色固体，产率：62.83％。LC-MS(APCI):m/z＝313.1(M+1) +。
步骤2 3-(5-氯吡嗪-基)-3,6-二氮杂双环[3.1.1]庚烷的合成
冰浴下，将TFA(15mL)加入到3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(2.3g，7.37mmol)的无水DCM(15mL)中，反应在室温下反应4hrs。减压浓缩反应液，残留物用饱和的碳酸氢钠溶液调pH至碱性，DCM萃取3次，并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析 (DCM/MeOH＝10％)纯化得到1.34g淡黄色固体，产率：86.5％。LC-MS(APCI):m/z＝211.1(M+1) +。
步骤3 3-(5-氯吡嗪-2-基)-6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷
室温下，将Cs 2CO 3(1.55g)加入到3-(5-氯吡嗪-基)-3,6-二氮杂双环[3.1.1]庚烷(500mg，)和5-(氯甲基-d 2)-2-甲氧基吡啶(405mg)的无水DMF(10mL)中，反应在90℃下搅拌5hrs。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到600mg淡黄色固体。LC-MS(APCI):m/z＝334.1(M+1) +。
中间物R5：3-(5-氯吡嗪-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环 [3.1.1]庚烷
Figure PCTCN2019122674-appb-000060
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000061
室温下，将Cs 2CO 3(1.55g)加入到3-(5-氯吡嗪-基)-3,6-二氮杂双环[3.1.1]庚烷(295mg)和5-(氯甲基)-2-(甲氧基-d3)吡啶(240mg)的无水DMF(5mL)中，反应在90℃下搅拌5hrs。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到320mg淡黄色固体。LC-MS(APCI):m/z＝335.1(M+1) +.
中间物R6：3-(5-氯吡嗪-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环 [3.1.1]庚烷
Figure PCTCN2019122674-appb-000062
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000063
室温下，将Cs 2CO 3(1.55g)加入到3-(5-氯吡嗪-2-基)-3,6-二氮杂双环[3.1.1]庚烷(359mg，1.85mmol)和5-(氯甲基-d 2)-2-(甲氧基-d 3)吡啶(300mg,1.85mmol)的无水DMF(5mL)中，反应在90℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到400mg淡黄色固体。LC-MS(APCI):m/z＝337.2(M+1) +。
中间物R7：6-((6-甲氧基吡啶-3-基)甲基-d 2)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷 -2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019122674-appb-000064
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000065
步骤1 3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯的合成
室温下，将K 2CO 3加入到5-溴-2-氟吡啶(919mg，5.22mmol)和6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(1.00g，5.22mmol)的无水DMSO(8mL)中，反应在90℃下搅拌24hrs。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(PE/EtOAc＝10％)纯化得到1.6g淡黄色固体，产率：86.8％。LC-MS(APCI):m/z＝354.1(M+1) +。
步骤2 3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷的合成
冰浴下，将TFA(10mL)加入到3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(1.5g，4.25mmol)的无水DCM(10mL)中，反应在室温下反应4hrs。减压浓缩反应液，残留物用饱和的碳酸氢钠溶液调pH至碱性，DCM萃取3次，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝10％)纯化得到1.05g淡黄色固体，产率：97.6％。LC-MS(APCI):m/z＝254.1(M+1) +。
步骤3 3-(5-溴吡啶-2-基)-6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷的合成
室温下，将Cs 2CO 3(1.30g，4.00mmol)加入到3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷(504mg，2.00mmol)和5-(氯甲基-d 2)-2-甲氧基吡啶(400mg,2.40mmol)的无水DMF(8mL)中，反应在90℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到540mg淡黄色固体，产率：71.6％。LC-MS(APCI):m/z＝377.0(M+1) +。
步骤4 6-((6-甲氧基吡啶-3-基)甲基-d 2)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷的合成
氮气保护下将，PdCl 2(dppf)DCM(115mmol,0.14mmol)加入到3-(5-溴吡啶-2-基)-6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷(540mg,1.43mmol)，B 2(Pin) 2(1.10g,4.29mmol)和KOAc(429mg,4.29mmol)的二氧六环(16mL)溶剂中。反应在氮气保护下，80℃过夜。冷却至室温，硅藻土过滤，EtOAc洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到250mg淡黄色固体,产率： 41.1％。LC-MS(APCI):m/z＝425.2(M+1) +。
中间物R8：6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼 烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019122674-appb-000066
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000067
步骤1 3-(5-溴吡啶-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷的合成
室温下，将Cs 2CO 3(1.30g，4.00mmol)加入到3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷(504mg，2.00mmol)和5-(氯甲基)-2-(甲氧基-d 3)吡啶(400mg,2.40mmol)的无水DMF(8mL)中，反应在90℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到470mg淡黄色固体，产率：62.3％。LC-MS(APCI):m/z＝378.1(M+1) +。
步骤2 6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷的合成
氮气保护下将，PdCl 2(dppf)DCM(100mg)加入到3-(5-溴吡啶-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(470mg,1.24mmol)，B 2(Pin) 2(950mg,3.73mmol)和KOAc(370mg,3.73mmol)的二氧六环(15mL)溶剂中。反应在氮气保护下，80℃过夜。冷却至室温，硅藻土过滤，EtOAc洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到270mg淡黄色固体,产率：51.1％。LC-MS(APCI):m/z＝426.2(M+1) +。
中间物R9：6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂 硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019122674-appb-000068
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000069
步骤1 3-(5-溴吡啶-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂二环[3.1.1]庚烷的合成
室温下，将Cs 2CO 3((1.30g，4.00mmol)加入到3-(5-溴吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷(504mg，2.00mmol)和5-(氯甲基-d 2)-2-(甲氧基-d 3)吡啶(400mg,2.40mmol)的无水DMF(8mL)中，反应在90℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到450mg淡黄色固体，产率：70.6％。LC-MS(APCI):m/z＝380.1(M+1) +。
步骤2 6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷的合成
氮气保护下将，PdCl 2(dppf)DCM(100mmol)加入到3-(5-溴吡啶-2-基)-6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂二环[3.1.1]庚烷(450mg，1.18mmol)，B 2(Pin) 2(900mg,3.55mmol)和KOAc(350mg,3.55mmol)的二氧六环(15mL)溶剂中。反应在氮气保护下，80℃过夜。冷却至室温，硅藻土过滤，EtOAc洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到236mg淡黄色固体,产率：46.7％。LC-MS(APCI):m/z＝428.1(M+1) +。
中间物R10：6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2- 基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷
Figure PCTCN2019122674-appb-000070
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000071
步骤1 3-(5-溴吡啶-2-基)-6-((6-甲氧基吡啶-3-基)基)-3,6-二氮杂双环[3.1.1]庚烷的合成
冰浴下，将一点乙酸滴加到3-(5-溴吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(1.05g，3.94mmol)和6-甲氧基烟醛(594mg，4.33mmol)的无水DCM(25mL)，反应在室温下搅拌30min，冰浴下，加入NaBH(OAc) 3(1.25g，5.91mmol)，反应搅拌过夜。用饱和碳酸氢钠溶液淬灭反应，水层用DCM(50mL x 3)萃取，合并有机层，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到1.15g淡黄色固体。LC-MS(APCI):m/z＝375.1(M+1) +， 1H NMR(400MHz,CDCl 3)δ8.26(d,J＝2.2Hz,1H),8.07(d,J＝1.9Hz,1H),7.66–7.57(m,2H),6.72(d,J＝8.5Hz,1H),6.46(d,J＝9.0Hz,1H),3.92(s,3H),3.79–3.69(m,4H),3.53(s,2H),3.48(d,J＝11.7Hz,2H),2.68(dd,J＝13.8,6.8Hz,1H),1.61(d,J＝8.6Hz,1H).
步骤2 6-((6-甲氧基吡啶-3-基)甲基)-3-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷的合成
氮气保护下将，PdCl 2(dppf)DCM(228mg，0.28mmol)加入到3-(5-溴吡啶-2-基)-6-((6-甲氧基吡啶-3-基)基)-3,6-二氮杂双环[3.1.1]庚烷(1.05g，2.80mmol)，B 2(Pin) 2(2.13g,8.40mmol)和KOAc(825mg，8.40mmol)的二氧六环(28mL)溶剂中。反应在氮气保护下，80℃过夜。冷却至室温，硅藻土过滤，EtOAc洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝5％)纯化得到840mg淡黄色固体,产率：71.1％。 LC-MS(APCI):m/z＝423.4(M+1) +。
实施例1 4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基) 吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000072
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000073
室温下，将Cs 2CO 3(392mg)加入到中间物P1(160mg,60％)和中间物R1(76mg)的无水DMF(5mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到68mg白色固体，纯度：99.36％(HPLC)。LC-MS(APCI):m/z＝521.4(M+1) +。
实施例2 4-(6-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡 啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000074
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000075
室温下，将Cs 2CO 3(488mg，1.50mmol)加入到中间物P1(200mg，0.50mmol,60％)和中间物R2(100mg,0.60mmol)的无水DMF(5mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到90mg白色固体，纯度：99.74％(HPLC)。LC-MS(APCI):m/z＝520.4(M+1) +。
实施例3 4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基) 吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000076
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000077
室温下，将Cs 2CO 3(592mg)加入到中间物P1(160mg,60％)和中间物R3(80mg)的无水DMF(5mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到40mg白色固体，纯度：98.84％(HPLC)。LC-MS(APCI):m/z＝523.4(M+1) +。
实施例4 4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基) 吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000078
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000079
室温下，将Cs 2CO 3(196mg，0.60mmol)加入到中间物P2(80mg，0.20mmol)和中间物R1(38mg,0.24mmol)的无水DMF(3mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到63mg白色固体，产率：60.2％，纯度：98.51％(HPLC)。LC-MS(APCI):m/z＝524.4(M+1) +。
实施例5 4-(6-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡 啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000080
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000081
室温下，将Cs 2CO 3(1.6g，3.00mmol)加入到中间物P2(400mg，1.00mmol,纯度30％)和中间物R2(160mg,1.00mmol)的无水DMF(5mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到50mg白色固体，纯度：99.29％(HPLC)。LC-MS(APCI):m/z＝523.4(M+1) +。
实施例6 4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基) 吡啶-3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000082
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000083
室温下，将Cs 2CO 3(196mg，0.60mmol)加入到中间物P2(80mg，0.2mmol)和中间物R3(40mg,0.24mmol)的无水DMF(3mL)中，反应在95℃下搅拌过夜。冷却至室温，加H 2O稀释反应体系，用EtOAc萃取3次。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到33mg白色固体，产率：31.5％，纯度：98.95％(HPLC)。LC-MS(APCI):m/z＝526.4(M+1) +。
实施例7 4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶 -3-基)-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000084
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000085
氮气保护下，将Pd 2(dba) 2(37mg)和X-phos(38mg)加入到中间物R10(204mg，0.48mmol)，三氟甲磺酸3-氰基-6-(1-(甲基-d 3)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯(150mg，0.40mmol)和碳酸钠(216mg，2.06mmol)的二氧六环(4mL)和水(1mL)的混合溶剂中，反应在氮气保护下，85℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到140mg白色固体。纯度：93.99％(HPLC)。LC-MS(APCI):m/z＝521.4(M+1) +。
实施例8 4-(5-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡 嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000086
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000087
步骤1 (2R)-2-(((3-氰基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯的合成
氮气保护下将，Pd 2(dba) 3(20mg)和X-Phos(20mg)加入到中间物R4(80mg)，中间物P3(100mg)和K 3PO 4(127mg)的二氧六环(2mL)和水(0.5mL)的混合溶剂中。反应在氮气保护下，封管反应在80℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到45mg淡黄色固体。LC-MS(APCI):m/z＝656.4(M+1) +。
步骤2 4-(5-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈的合成
冰浴下，将TFA(1mL)加入到(2R)-2-(((3-氰基-4-(5-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯(45mg)的DCM(2mL)溶液中，反应在室温下反应2hrs。减压浓缩反应液，用氨-甲醇溶液调pH为碱性，减压浓缩，浓缩液柱层析(DCM/MeOH＝10％)纯化得到30mg灰色固体。纯度：96.45％(HPLC)。LC-MS(APCI):m/z＝556.4(M+1) +。
实施例9 4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基) 吡嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000088
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000089
步骤1 (2R)-2-(((3-氰基-4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯的合成
氮气保护下将，Pd 2(dba) 3(35mg)和X-Phos(35mg)加入到中间物R5(120mg)，中间物P3(150mg)和K 3PO 4(220mg)的二氧六环(2mL)和水(0.5mL)的混合溶剂中。反应在氮气保护下，封管反应在80℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到60mg淡黄色固体。LC-MS(APCI):m/z＝657.3(M+1) +。
步骤2 4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈的合成
冰浴下，将TFA(1mL)加入到(2R)-2-(((3-氰基-4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯(60mg)的DCM(2mL)溶液中，反应在室温下反应2hrs。减压浓缩反应液，用氨-甲醇溶液调pH为碱性，减压浓缩，浓缩液柱层析(DCM/MeOH＝10％)纯化得到36mg灰色固体。纯度：98.00％(HPLC)。LC-MS(APCI):m/z＝557.2(M+1) +。
实施例10 4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3- 基)吡嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000090
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000091
步骤1 (2R)-2-(((3-氰基-4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯的合成
氮气保护下将，Pd 2(dba) 3(35mg)和X-Phos(35mg)加入到中间物R6(120mg)，中间物P3(150mg)和K 3PO 4(220mg)的二氧六环(2mL)和水(0.5mL)的混合溶剂中。反应在氮气保护下，封管反应在80℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到98mg淡黄色固体。LC-MS(APCI):m/z＝659.3(M+1) +。
步骤2 4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)-6-(((R)-吗啉-2-基)甲氧基))吡唑并[1,5-a]吡啶-3-甲腈的合成
冰浴下，将TFA(1mL)加入到(2R)-2-(((3-氰基-4-(5-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡嗪-2-基)吡唑[1,5-a]吡啶-6-基)氧基)甲基)吗啉-4-羧酸叔丁酯(98mg)的DCM(2mL)溶液中，反应在室温下反应2hrs。减压浓缩反应液，用氨-甲醇溶液调pH为碱性，减压浓缩，浓缩液柱层析(DCM/MeOH＝10％)纯化得到35mg灰色固体。纯度：97.92％(HPLC)。LC-MS(APCI):m/z＝559.2(M+1) +。
实施例11 6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基-d 2)-3,6-二氮 杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000092
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000093
氮气保护下将，Pd(PPh 3) 4(60mg，0.05mmol)加入到中间物R7(250mg，0.59mmol)，中间物P4(150mg，0.48mmol)和K 2CO 3(166mg，1.2mmol)的二氧六环(9mL)和水(3mL)的混合溶剂中。反应在氮气保护下，85℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯 化得到110mg淡黄色固体。收率：43.5％。纯度：96.61％(HPLC)。LC-MS(APCI):m/z＝528.1(M+1) +。 1H NMR(500MHz,DMSO)δ8.70(s,1H),8.61(s,1H),8.47–8.38(m,1H),8.09(s,1H),7.86(d,J＝8.6Hz,1H),7.70(d,J＝7.2Hz,1H),7.32(s,1H),6.87–6.73(m,2H),4.74(s,1H),3.90(s,2H),3.84(s,3H),3.79–3.65(m,4H),3.63–3.50(m,2H),2.50–2.44(m,1H),1.65–1.54(m,1H),1.25(s,6H).
实施例12 6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基)-3,6-二 氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000094
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000095
氮气保护下将，Pd(PPh 3) 4(60mg，0.05mmol)加入到中间物R8(270mg，0.63mmol)，中间物P4(150mg，0.48mmol)和K 2CO 3(170mg，1.2mmol)的二氧六环(9mL)和水(3mL)的混合溶剂中。反应在氮气保护下，85℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到70mg淡黄色固体。纯度：96.83％(HPLC)。LC-MS(APCI):m/z＝529.2(M+1) +。 1H NMR(500MHz,DMSO)δ8.69(s,1H),8.61(s,1H),8.48–8.36(m,1H),8.08(s,1H),7.86(dd,J＝8.8,1.8Hz,1H),7.69(dd,J＝8.2,1.3Hz,1H),7.32(s,1H),6.86–6.72(m,2H),4.74(s,1H),3.90(s,2H),3.79–3.66(m,4H),3.61–3.46(m,4H),2.53–2.43(m,1H),1.63–1.57(m,1H),1.25(s,6H).
实施例13 6-(2-羟基-2-甲基丙氧基)-4-(6-(6-((6-(甲氧基-d 3)吡啶-3-基)甲基-d 2)-3,6- 二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈
Figure PCTCN2019122674-appb-000096
采用以下路线进行合成：
Figure PCTCN2019122674-appb-000097
氮气保护下将，Pd(PPh 3) 4(60mg，0.05mmol)加入到中间物R9(236mg，0.55mmol)，中间物P4(150mg，0.48mmol)和K 2CO 3(166mg，1.2mmol)的二氧六环(9mL)和水(3mL)的混合溶剂中。反应在氮气保护下，85℃过夜。冷却至室温，硅藻土过滤，DCM洗涤滤饼，滤液减压浓缩，浓缩液柱层析(DCM/MeOH＝6％)纯化得到120mg淡黄色固体。收率：47.2％。纯度：96.12％(HPLC)。LC-MS(APCI):m/z＝531.2(M+1) +。 1H NMR(500MHz,DMSO)δ8.70(s,1H),8.61(s,1H),8.43(s,1H),8.08(s,1H),7.86(d,J＝8.5Hz,1H),7.70(d,J＝7.9Hz,1H),7.32(s,1H),6.85–6.71(m,2H),4.74(s,1H),3.90(s,2H),3.79–3.65(m,4H),3.63–3.48(m,2H),2.51–2.51(m,1H),1.64–1.54(m,J＝8.3Hz,1H),1.25(s,6H).
生物活性测试。
(1)代谢稳定性评价
微粒体实验：人肝微粒体(HLM)：0.5mg/mL，Xenotech；大鼠肝微粒体(RLM)：0.5mg/mL，Xenotech；小鼠肝微粒体(MLM)：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物和对照品化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL小鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体或者小鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2019122674-appb-000098
t 1/2(min)；CL int(μL/min/mg)。
在上述体外稳定性实验中测试了本发明化合物，发现本发明化合物具有优异的代谢稳定性。代表性实施例的肝微粒体实验结果归纳于下表3中。
表3
Figure PCTCN2019122674-appb-000099
(2)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治疗效果。
(3)激酶抑制作用
试剂和耗材：Ret wt(Carna,目录号08-159-10ug)，RET(V804M),Active(Signalchem,目录号R02-12GG)，HTRF KinEASE-TK试剂盒(Cisbio,目录号62TK0PEC)，CEP-32496(MCE,目录号HY-15200)，ATP(Sigma,目录号A7699)，DMSO(Sigma,目录号D8418-1L)，DTT(Sigma,目录号D0632)，MgCl 2(Sigma,目录号M1028)，384孔板(Labcyte,目录号P-05525-BC)。
具体实验方法：
化合物配制：将受试化合物溶于DMSO配成10mM母液。然后，在DMSO中等梯度3倍稀释，稀释十次。加药时再用缓冲液稀释10倍。
Ret wt及RET V804M激酶检测：在5x激酶缓冲液A中，将Ret wt或RET V804M激酶与预先稀释配制的不同浓度的化合物混合10分钟，每个浓度双复孔。加入对应底物及ATP，室温反应20分钟(其中设置阴阳性对照：阴性为空白对照，阳性为CEP-32496)。反应完毕加入检测试剂(HTRF KinEASE-TK试剂盒内的试剂)，室温孵育30分钟后，通过Envision酶标仪检测，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，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Ret wt和RET V804M具有强效的活性。代表性实施例化合物的结果归纳于如下表4中。
表4
实施例编号 Ret wt IC50(nM) RET V804M IC50(nM)
1 0.06 0.17
2 0.16 0.16
3 0.17 0.29
4 0.12 0.33
5 0.11 0.23
6 0.07 0.36
7 0.18 0.21
8 0.36 7.32
9 0.37 4.30
10 0.23 4.91
11 0.15 3.20
12 0.17 3.25
13 0.06 0.27
(4)细胞毒性实验
检测实施例化合物对Ba/F 3 parental，Ba/F 3 KIF5B-RET，Ba/F 3 KIF5B-RET V804M细胞活性的抑制效应。
耗材及试剂：胎牛血清FBS(GIBCO，目录号10099141)、
Figure PCTCN2019122674-appb-000100
Luminescent Cell Viability Assay(Promega,Cat#G7572)、96孔透明平底黑壁板(
Figure PCTCN2019122674-appb-000101
Cat#3603)。
实验方法：
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.调整细胞浓度为3000个细胞/每孔；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10μM，9个浓度，3.16倍稀释，在接种细胞的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.将已加药的96孔板中的细胞置于37℃、5％CO 2、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(10μL)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 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。
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％。
在上述细胞毒性实验中测试了本发明化合物，发现本发明化合物对细胞系Ba/F 3 KIF5B-RET和Ba/F 3 KIF5B-RET V804M具有强效的活性以及优于Ba/F 3 parental的优异选择性。代表性实施例化合物对癌细胞的体外增殖的抑制作用的结果归纳于如下表5中。
表5
Figure PCTCN2019122674-appb-000102
Figure PCTCN2019122674-appb-000103
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 (10)

  1. 一种式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2019122674-appb-100001
    其中，
    Y选自CH或N，其任选被氘、卤素或三氟甲基取代；
    W选自CR 9R 10；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自氢或氘；
    Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢、氘、卤素或三氟甲基；
    X选自CH 3、CD 3、CHD 2或CH 2D；
    Z选自：
    Figure PCTCN2019122674-appb-100002
    其任选被1、2、3、4、5、6、7、8或9个氘取代；
    *表示与母核相连的键；
    附加条件是，上述化合物至少含有一个氘原子。
  2. 根据权利要求1所述的化合物，其为式(II-A)化合物：
    Figure PCTCN2019122674-appb-100003
    其中，
    W选自CR 9R 10；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10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或CH 2D；
    附加条件是，上述化合物至少含有一个氘原子；
    优选地，R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10是氢；
    优选地，X 1是CD 3；
    优选地，X 2是CD 3；
    优选地，R 1和R 2是氘；
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
  3. 根据权利要求1所述的化合物，其为式(II-B)化合物：
    Figure PCTCN2019122674-appb-100004
    其中，
    W选自CR 9R 10；
    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和R 19各自独立地选自氢或氘；
    X选自CH 3、CD 3、CHD 2或CH 2D；
    附加条件是，上述化合物至少含有一个氘原子；
    优选地，R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10是氢；
    优选地，R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18和R 19是氢；
    优选地，X是CD 3；
    优选地，R 1和R 2是氘；
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
  4. 根据权利要求3所述的化合物，其为式(II-B-a)化合物：
    Figure PCTCN2019122674-appb-100005
    其中，
    W选自CR 9R 10；
    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和R 19各自独立地选自氢或氘；
    X选自CH 3、CD 3、CHD 2或CH 2D；
    附加条件是，上述化合物至少含有一个氘原子；
    优选地，R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10是氢；
    优选地，R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18和R 19是氢；
    优选地，X是CD 3；
    优选地，R 1和R 2是氘；
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
  5. 根据权利要求1所述的化合物，其为式(II-C)化合物：
    Figure PCTCN2019122674-appb-100006
    其中，
    W选自CR 9R 10；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 20和R 21各自独立地选自氢或氘；
    X、X 3和X 4各自独立地选自CH 3、CD 3、CHD 2或CH 2D；
    附加条件是，上述化合物至少含有一个氘原子；
    优选地，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10是氢；
    优选地，R 20和R 21是氢
    优选地，X 3和X 4是CH 3；
    优选地，X是CD 3；
    优选地，R 1和R 2是氘；
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
  6. 根据权利要求1所述的化合物，其选自下式化合物：
    Figure PCTCN2019122674-appb-100007
    Figure PCTCN2019122674-appb-100008
    Figure PCTCN2019122674-appb-100009
    Figure PCTCN2019122674-appb-100010
    Figure PCTCN2019122674-appb-100011
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。
  7. 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1-6中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物；
    优选地，其还包含另外的治疗剂；
    优选地，所述另外的治疗剂选自细胞毒性化学治疗剂，激酶靶向治疗剂，细胞凋亡调节剂或信号转导抑制剂；
    优选地，所述另外的治疗剂选自一种或多种激酶靶向治疗剂。
  8. 制备权利要求1-6中任一项所述的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求7所述的药物组合物用于治疗RET相关癌症的药物的用途。
  9. 权利要求8的用途，其中所述RET相关癌症是RET基因、RET激酶蛋白或其中任何一者的表达或活性或水平失调的癌症；
    优选地，其中所述RET基因、RET激酶蛋白或其中任何一者的表达或活性或水平失调是RET基因中的一个或多个点突变；
    优选地，其中RET基因中的一个或多个点突变导致翻译具有一个或多个下述氨基酸取代的RET蛋白：S32L,D34S,L40P,P64L,R67H,R114H,V145G,V292M,G321R,R330Q,T338I,R360W,F393L,A510V,E511K,C515S,C531R,G533C,G533S,G550E,V591I,G593E,I602V,R600Q,K603Q,K603E,Y606C,C609Y,C609S,C609G,C609R,C609F,C609W,C611R,C611S,C611G,C611Y,C611F,C611W,C618S,C618Y,C618R,C618Y,C618G,C618F,C618W,F619F,C620S,C620W,C620R,C620G,C620L,C620Y,C620F,E623K,D624N,C630A,C630R,C630S,C630Y,C630F,D631N,D631Y,D631A,D631G,D631V,D631E,E632K,E632G,C634W,C634Y,C634S,C634R,C634F,C634G,C634L,C634A,C634T,R635G,T636P,T636M,A640G,A641S,A641T,V648I,S649L,A664D,H665Q,K666E,K666M,K666N,S686N,G691S,R694Q,M700L,V706M,V706A,E713K,G736R,G748C,A750P,S765P,P766S,P766M,E768Q,E768D,L769L,R770Q,D771N,N777S,V778I,Q781R,L790F,Y791F,V804L,V804M,V804E,E805K,Y806E,Y806F,Y806S,Y806G,Y806C,E818K,S819I,G823E,Y826M,R833C,P841L,P841P,E843D,R844W,R844Q,R844L,M848T,I852M,A866W,R873W,A876V,L881V,A883F,A883S,A883T,E884K,R886W,S891A,R897Q,D898V,E901K,S904F,S904C,K907E, K907M,R908K,G911D,R912P,R912Q,M918T,M918V,M918L,A919V,E921K,S922P,S922Y,T930M,F961L,R972G,R982C,M1009V,D1017N,V1041G或M1064T；
    优选地，其中所述RET基因、RET激酶蛋白或其中任何一者的表达或活性或水平失调是RET基因融合体；
    优选地，其中所述RET融合体选自：BCR-RET,CLIP1-RET,KIF5B-RET,CCDC6-RET,NCOA4-RET,TRIM33-RET,ERC1-RET,ELKS-RET,RET-ELKS,FGFR1OP-RET,RET-MBD1,RET-RAB61P2,RET-PCM1,RET-PPKAR1A,RET-TRIM24,RET-RFG9,RFP-RET,RET-GOLGA5,HOOK3-RET,KTN1-RET,TRIM27-RET,AKAP13-RET,FKBP15-RET,SPECC1L-RET,TBL1XR1/RET,CEP55-RET,CUX1-RET,KIAA1468-RET,PPKAR1A-RET,RFG8/RET,RET/RFG8,H4-RET,ACBD5-RET,PTCex9-RET,MYH13-RET,PIBF1-RET,KIAA1217-RET或MPRIP-RET。
  10. 权利要求8或9用途，其中所述RET相关癌症选自：肺癌、乳头状甲状腺癌、甲状腺髓样癌，分化的甲状腺癌、复发性甲状腺癌、难治性分化型甲状腺癌、2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B)，嗜铬细胞瘤、甲状旁腺增生、乳腺癌、胰腺癌、结直肠癌、乳头状肾细胞癌、胃肠粘膜神经节细胞瘤或宫颈癌；
    优选地，其中所述癌症选自RET融合体肺癌、RET融合体乳头状甲状腺癌或甲状腺髓样癌；
    优选地，其中所述肺癌是小细胞肺癌、非小细胞肺癌、细支气管肺癌或肺腺癌。
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