WO2020119739A1 - 2-aminopyrimidine compound and application therefor - Google Patents

2-aminopyrimidine compound and application therefor Download PDF

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WO2020119739A1
WO2020119739A1 PCT/CN2019/124686 CN2019124686W WO2020119739A1 WO 2020119739 A1 WO2020119739 A1 WO 2020119739A1 CN 2019124686 W CN2019124686 W CN 2019124686W WO 2020119739 A1 WO2020119739 A1 WO 2020119739A1
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substituted
unsubstituted
alkyl
halogen
pharmaceutically acceptable
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PCT/CN2019/124686
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French (fr)
Chinese (zh)
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丁克
丁健
陆小云
耿美玉
李姗
谢华
陈灏
童林江
任小梅
冯芳
Original Assignee
暨南大学
中国科学院上海药物研究所
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Priority to CN201980077663.4A priority Critical patent/CN113166110B/en
Publication of WO2020119739A1 publication Critical patent/WO2020119739A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of chemical medicine, in particular to a 2-aminopyrimidine compound and its application.
  • Tumor molecular targeted therapy is a treatment method that selectively kills tumor cells by chemical or biological means based on key molecules closely related to tumor growth.
  • the characteristics of targeted therapy are: high specificity, strong selectivity, and lighter side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence.
  • Imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003), erlotinib (OSI774) (Genentech and OSIP, 2004), sorafenib P-toluenesulfonate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and dasatinib (BMS-354825) (Bristol-Myers Squibb, The targeted drugs represented by 2006) created a new era for cancer chemotherapy. Cancer targeted therapy has developed rapidly in just a few years.
  • targeted cancer therapy is a hot spot and development trend of cancer therapy.
  • EGFR Epidermal growth factor receptor
  • EGFR is over-activated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, and prostate cancer.
  • tumor cells such as lung cancer, breast cancer, and prostate cancer.
  • EGFR small molecule inhibitor drugs Gefitinib and Erlotinib which were marketed from 2003 to 2004, have been used in the treatment of advanced non-small cell lung cancer, further clarifying that EGFR is an effective target for the treatment of non-small cell lung cancer.
  • the first-generation EGFR small molecule inhibitors have achieved significant clinical efficacy in patients with EGFR-sensitive mutations, extending their survival. However, after 10-12 months of using the drug, most patients will develop drug resistance. Among them, more than 50% of the drug-resistant patients (carrying EGFR sensitive mutations) are due to the occurrence of drug resistance due to the T790M secondary mutation of EGFR. Compared with the L858R sensitive mutant EGFR, the L858R/T790M secondary mutant EGFR has a stronger affinity for ATP, and the first-generation drugs are all ATP competitive inhibitors, resulting in drug resistance.
  • Osimertinib (AZD9291), the third-generation irreversible inhibitor that overcomes EGFR T790M resistance, was granted accelerated approval by the US FDA in November 2015 (Cancer discovery 2014, 4(9), 1046-1061), which is clinically effective Treatment of patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) T790M mutation or resistance to other EGFR inhibitors.
  • EGFR epidermal growth factor receptor
  • Osimertinib has achieved great success in the clinical treatment of non-small cell lung cancer with EGFR T790M mutation, some beneficiary patients have developed drug resistance after 9 to 14 months of treatment (Nature Medicine 2015, 21(6), 560-2).
  • the present invention provides a 2-aminopyrimidine compound that can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M , EGFR T790M/C797S, and EGFR T790M/C797S/L858R ).
  • EGFR protein kinase resistant mutants such as EGFR T790M , EGFR T790M/C797S, and EGFR T790M/C797S/L858R .
  • A, B, C are independently selected from: N or CR 2a ;
  • R 1 , R 2 , and R 2a are independently selected from the group consisting of: H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl , Substituted or unsubstituted C 1 ⁇ C 6 alkoxy, or substituted or unsubstituted C 3 ⁇ C 6 cycloalkoxy;
  • R 3 is selected from: substituted or unsubstituted pyrazolyl, -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 or -(CH 2 ) m CR 4 R 5 R 6 ; Where m is selected from: 0, 1, 2, 3, or 4;
  • R 4 is selected from: hydrogen or C 1 ⁇ C 3 alkyl
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or R 5 , R 6 and the N or C to which they are attached together form a substituted or unsubstituted heteroatom-containing Single ring, condensed ring, spiro ring or bridge ring;
  • L is selected from: CH 2 , NH or O;
  • n is selected from: 0, 1, 2 or 3;
  • G is selected from: unsubstituted or R 10 substituted fused cycloalkyl having 8-10 ring atoms, unsubstituted or R 10 substituted fused aliphatic heterocyclic group having 8-10 ring atoms, unsubstituted or R 10 Substituted fused aromatic ring groups having 8-10 ring atoms, or unsubstituted or R 10 substituted fused aromatic heterocyclic groups having 8-10 ring atoms;
  • R 10 is independently selected from H, halogen, oxo, thio, nitro, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted Substituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy or S(O 2 )R 7 ;
  • R 7 is selected from: H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 2a is not C 1 to C 6 alkoxy.
  • the 2-aminopyrimidine compounds are:
  • G is selected from:
  • X 1 and X 2 are independently selected from: CH, C or N;
  • G is selected from the following groups:
  • G is selected from the following groups:
  • G is selected from the following groups:
  • R 10 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 7 is selected from: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl.
  • R 3 is selected from: R 8 substituted pyrazolyl, -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 , -(CH 2 ) m CR 4 R 5 R 6 ; where m is selected from: 0, 1, 2, 3 or 4;
  • R 4 is selected from: hydrogen or C 1 ⁇ C 3 alkyl
  • R 5 and R 6 are independently selected from: hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 together with N or C connected thereto form R 8 substituted 1, 2 or 3 3 to 8 membered monocyclic rings of hetero atoms, or R 5 and R 6 together with N or C connected to them form an 8 to 12 membered fused ring, spiro ring or R 8 substituted with 1, 2 or 3 heteroatoms Bridge ring, hetero atom selected from: O, N or S;
  • R 3 is selected from: -(CH 2 ) m NR 5 R 6 ; m is selected from: 0 or 1.
  • R 3 is selected from: -NR 5 R 6 ;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 and N to which they are connected together form R 8 substituted 1 or 2 heteroatoms 6-membered single ring, heteroatom selected from: O, N or S.
  • R 3 is selected from: R 8 replaced R 8 replaced R 8 replaced Or substituted by R 8 R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl substituted with R 8 .
  • R 8 is selected from the group consisting of: H, halogen, hydroxy, amino, C 1 -C 3 alkyl, -C( ⁇ O)R 9 , hydroxy substituted C 1 -C 3 alkyl, C 1 ⁇ C 3 alkoxy, -NHR 9 , -N(R 9 ) 2 , R 9 is C 1 to C 3 alkyl.
  • R 3 is selected from:
  • R 1 , R 2 and R 2a are independently selected from the group consisting of: H, halogen, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy.
  • R 1 is selected from: H, halogen, methyl, cyano, trifluoromethyl, difluoromethyl, methoxy, cyclopropyl, trifluoromethoxy;
  • R 2 and R 2a are independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, cyclopropyl, isopropyl, n- Propyl, methoxy, isopropoxy or cyclopentyloxy.
  • G is selected from When R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl, halogen-substituted or unsubstituted Substituted C 1 ⁇ C 6 alkoxy, or halogen substituted or unsubstituted C 3 ⁇ C 6 cycloalkoxy;
  • R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, or halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl.
  • G is N
  • R 1 is selected from: H, halogen, C 1 -C 6 alkyl or halogen substituted C 1 -C 6 alkyl;
  • R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy;
  • R 2a is independently selected from: H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy.
  • A, B, C are selected from C-H;
  • R 3 is selected from
  • G is selected from
  • R 1 is selected from H, halogen or halogen substituted C 1 ⁇ C 6 alkyl
  • A, B, C are selected from C-H;
  • R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy.
  • the present invention also provides the use of the above-mentioned 2-aminopyrimidine compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof in preparing mutant EGFR inhibitors.
  • the tumor is a malignant tumor with EGFR gene mutation.
  • the tumor is a malignant tumor with EGFR L858R/T790M/C797S mutation.
  • the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal Stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer or glioma.
  • the invention also provides a pharmaceutical composition for preventing and treating tumors.
  • a pharmaceutical composition includes an active ingredient and a pharmaceutically acceptable carrier.
  • the active ingredient includes the aforementioned 2-aminopyrimidine compound or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof.
  • the present invention has the following beneficial effects:
  • the 2-aminopyrimidine compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule can have an inhibitory effect on the EGFR family protease, thereby inhibiting the growth of various tumor cells. Compared with wild-type cancer cells, the compounds of the present invention have higher selectivity for mutant cancer cells.
  • the compounds of the present invention can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR T790M/C797S ), and can selectively act on EGFR L858R/T790M , EGFR Del E745_A750, and EGFR L858R/T790M/C797S lung cancer cells It can overcome the current third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) induced clinical drug resistance of non-small cell lung cancer and other tumor patients.
  • EGFR protein kinase resistant mutants such as EGFR T790M and EGFR T790M/C797S
  • Osimertinib AZD9291
  • Olmutinib HM6171
  • Rociletinib CO-1686
  • the compound of the present invention can be used to prepare anti-tumor drugs, and can overcome the resistance induced by the existing drugs gefitinib, erlotinib, especially Osimertinib (AZD9291), etc. It is a novel class that can overcome the existing EGFR case Protein kinase inhibitors that are drug-resistant, selective and have good pharmacological properties are used to treat hyperproliferative diseases such as tumors in humans and other mammals.
  • any variable for example, R 1 , R 2, etc.
  • its definition for each occurrence is independent of other definitions for each occurrence.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • the line drawn from the substituent to the ring system indicates that the indicated bond can be connected to any ring atom that can be substituted. If the ring system is polycyclic, it means that this bond is only connected to any suitable carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select substituents and substituted forms of the compounds of the present invention to provide chemically stable compounds that can be easily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If the substituent itself is substituted with more than one group, it should be understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl means a saturated alkyl group
  • alkyl group means a straight or branched chain alkyl group, such as C 1 -C 4 alkyl group means having 1 to 4 carbon atoms, Saturated linear or branched alkyl, wherein examples of linear alkyl include but are not limited to ethyl, n-propyl, etc. Examples of branched alkyl include but are not limited to isopropyl, tert-butyl, etc.;
  • cycloalkyl refers to an alkyl group having a cyclic structure, such as C 3 -C 4 cycloalkyl refers to an alkyl group having a cyclic structure having 3 to 4 carbon atoms, examples include but are not limited to cyclopropyl , Cyclobutyl, methyl substituted cyclopropyl, etc.
  • alkoxy refers to a linear or branched alkyl group containing an oxygen atom at the end. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
  • halo or halo means chlorine, fluorine, bromine, and iodine.
  • the present invention provides a compound of formula I, a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof,
  • R 1 , R 2 , R 3 and A, B, C, L, G, n are as defined above.
  • the present invention includes the free form of the compound of formula I as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to amine compounds in non-salt form.
  • the included pharmaceutically acceptable salts include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts in the free form of all compounds of formula I.
  • the free form of the specific salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable alkaline dilute aqueous solution such as NaOH dilute aqueous solution, potassium carbonate dilute aqueous solution, dilute ammonia water, and sodium bicarbonate dilute aqueous solution.
  • a suitable alkaline dilute aqueous solution such as NaOH dilute aqueous solution, potassium carbonate dilute aqueous solution, dilute ammonia water, and sodium bicarbonate dilute aqueous solution.
  • the free form is somewhat different from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are comparable to their respective free forms in other pharmaceutical aspects.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing basic or acidic moieties by conventional chemical methods.
  • salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents.
  • salts of acidic compounds are formed by reaction with appropriate inorganic or organic bases.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., as well as organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard acids Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Oxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt, etc. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases which include salts of primary, secondary and tertiary amines, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as refined Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine , Piperidine, chirp, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the deprotonated acidic part of the compound such as carboxyl group can be anionic under physiological conditions, this charge can then be protonated or alkylated with a cationic internal part such as tetravalent
  • a cationic internal part such as tetravalent
  • the compounds of the present invention can be prepared using the reactions shown in the schemes listed in the specific examples below. Therefore, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any specific substituents.
  • the number of substituents shown in the scheme does not necessarily correspond to the number used in the claims, and for clarity, it is shown that a single substituent is attached to a compound that allows multiple substituents under the definition of Formula I above.
  • the compounds provided by the present invention having the structure of Formula I and their pharmaceutically acceptable salts can be used to treat transitional proliferative diseases or symptoms such as tumors in humans or other mammals.
  • non-small cell lung cancer small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, Histocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma and other transitional proliferative diseases.
  • Drug metabolites and prodrugs metabolites of the compounds and pharmaceutically acceptable salts of the present invention, and prodrugs that can be converted into structures of the compounds and pharmaceutically acceptable salts of the present invention in vivo, Also included in the claims of this application.
  • composition also provides a pharmaceutical composition, which comprises an active ingredient in a safe and effective amount range, and a pharmaceutically acceptable carrier.
  • active ingredient in the present invention refers to the compound of the formula I described in the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof.
  • the "active ingredient” and the pharmaceutical composition described in the present invention can be used as EGFR protease inhibitors. In another preferred example, it is used to prepare a medicine for preventing and/or treating tumors.
  • the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.
  • composition here means that the components in the composition can be blended with the active ingredient of the present invention and between them without significantly reducing the efficacy of the active ingredient.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the compound of formula I of the present invention can form a complex with a macromolecular compound or a polymer by non-bonding.
  • the compound of formula I of the present invention can also be connected to a macromolecular compound or a polymer through a chemical bond as a small molecule.
  • the macromolecular compound may be biological macromolecules such as high glycans, proteins, nucleic acids, polypeptides and the like.
  • the mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:
  • Fillers or compatibilizers for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
  • Binders for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;
  • humectants for example, glycerin
  • Disintegrants for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • absorption accelerators for example, quaternary amine compounds
  • wetting agents such as cetyl alcohol and glyceryl monostearate
  • adsorbent for example, kaolin
  • Lubricants for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
  • the dosage form may also contain buffering agents.
  • the solid dosage form can also be prepared by coating and shell materials, such as casings and other materials well known in the art. They may contain an opaque agent, and the release of the active ingredient in this composition can be released in a certain part of the digestive tract in a delayed manner.
  • shell materials such as casings and other materials well known in the art. They may contain an opaque agent, and the release of the active ingredient in this composition can be released in a certain part of the digestive tract in a delayed manner.
  • embedding components that can be used are polymeric substances and waxy substances.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compound of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypoglycemic agents).
  • other therapeutic drugs such as hypoglycemic agents.
  • a safe and effective amount of the compound of the present invention is administered to a mammal in need of treatment (such as a human), wherein the dose at the time of administration is the pharmacologically effective dose, for a person of 60 kg body weight, daily
  • the dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • Combination therapy The compound of formula I can be used in combination with other drugs known to treat or improve similar conditions. When co-administered, the original drug administration method and dose remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time. Drug combination also includes taking the compound of formula I with one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or known drugs may be lower than when they are used alone.
  • Drugs or active ingredients that can be used in combination with compounds of formula I include, but are not limited to:
  • drugs or active ingredients that can be used in combination with compounds of formula I include, but are not limited to: aldesleukin, alendronic acid, interferon, atranoline, allopurinol, allopurinol Sodium, Palonosetron hydrochloride, hexamethylmelamine, aminoglutamine, amifostine, amrubicin, amaridine, anatozole, dolasetron, aranesp, arglabin, arsenic trioxide, Anoxin, 5-azacytidine, azathioprine, BCG or tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromoglycan, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, Constance, cefesone, simor interleukin, daunor
  • Such compounds can effectively inhibit the role of EGFR protein kinase resistant mutants and can be used to prepare anti-tumor drugs.
  • the synthetic route is as follows:
  • Step 4 4-(Benzo[b]thiophen-3-yl)-5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -Yl)phenyl)pyrimidine-2-amino (LS3-102)
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthesis method refers to Example 3, and the yield is 8%.
  • the synthesis method refers to Example 3, and the yield is 5%.
  • the synthesis method refers to compound HCD3, and the yield is 6%.
  • the synthetic route is as follows:
  • the synthesis method refers to Example 3, and the yield is 7%.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthesis method of the compound refers to Example 3, and the yield is 15%.
  • the synthesis method of the compound refers to Example 3, and the yield is 42%.
  • the synthesis method of the compound refers to Example 4, and the yield is 33%.
  • the synthetic route is as follows:
  • reaction solution was poured into 150 mL of water, extracted twice with 50 mL of ethyl acetate, the organic phases were combined, washed with 100 mL of saturated brine three times, dried, concentrated, and separated by flash silica gel column chromatography (mobile phase: petroleum ether: acetic acid) Ethyl ester 80:20) to give the title compound, a light yellow solid, 0.50g, yield 35%.
  • the method for synthesizing the compound refers to Example 3, Step 3, and the yield is 7%.
  • reaction solution was poured into water, the resulting solid was filtered, dissolved in dichloromethane, and separated by flash silica gel column chromatography (mobile phase methanol: dichloromethane 0:100 to 3:97) to obtain the target compound, a white solid, 43mg, yield 40%.
  • the synthesis method of the compound refers to Example 3, and the raw material is replaced by 2,4-dichloro-5-methylpyrimidine.
  • Example 3 For the synthesis method of the compound, refer to Example 3. The raw material was replaced with 2,4-dichloro-5-trifluoropyrimidine.
  • the synthesis method of the compound refers to Example 3, and the raw material is replaced by 2,4-dichloropyrimidine.
  • Example 12 For the synthesis method of the compound, refer to Example 12. The raw material was replaced with ethyl iodide in a yield of 24%.
  • the temperature is raised to 95 degrees Celsius overnight to react, then 0.016g of cyclopropylboronic acid is added, and the reaction is continued for 3 hours.
  • the reaction solution is added to 50mL of water, respectively It was extracted twice with 30 mL of ethyl acetate, the organic phase was dried, concentrated and separated by flash silica gel column chromatography (eluent is 2% methanol in dichloromethane) to obtain the title compound 0.07 g, white solid in 32% yield .
  • 2-Aminopyrimidine compounds inhibit the activity of wild-type EGFR and mutant EGFR kinase:
  • EGFR (WT) is the wild-type epidermal growth factor receptor
  • EGFR (T790M) is the epidermal growth factor receptor with the 790th amino acid mutated from threonine to methionine
  • EGFR (L858R) is the Epidermal growth factor receptor with 858 amino acid mutation from leucine to arginine
  • EGFR (L861Q) is an epidermal growth factor receptor with 861 amino acid mutation from leucine to glutamine
  • EGFR ( L858R/T790M) is an epidermal growth factor receptor with amino acid 858 mutation from leucine to glutamine and amino acid 790 mutation from threonine to methionine double mutation.
  • EGFR (L858R/T790M/C797S) has amino acid 858 mutated from leucine to glutamine, amino acid 790 mutated from threonine to methionine, 797 cysteine Triple mutant epidermal growth factor receptor mutated to serine.
  • Enzyme-Linked Immunosorbent Assay was used to detect the inhibitory effect of compounds on kinase activity.
  • EGFR WT and EGFR T790M/L858R kinase were purchased from Eurofins, and EGFR T790M/L858R/C797SR kinase was purchased from BPS Bioscience.
  • the main experimental steps are as follows: Enzyme reaction substrate Poly (Glu, Tyr) 4:1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 37 °C reaction 12- 16h coated microplate.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • ATP final concentration 5 ⁇ M
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • Table 1 lists the compound numbers (corresponding to the compound numbers in the above examples) and the detection results of the compounds' inhibitory activity on each kinase.
  • the 2-aminopyrimidine compounds of the present invention have an inhibitory effect on the EGFR triple mutant protease, thereby inhibiting the growth of various tumor cells.
  • the compound of the present invention can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR T790M/C797S ), can selectively act on EGFR L858R/T790M and EGFR L858R/T790M/C797S lung cancer cells, and can overcome the existing There are third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) induced clinical drug resistance in non-small cell lung cancer and other tumor patients.

Abstract

The present invention relates to a 2-aminopyrimidine compound and an application therefor. The structure of the 2-aminopyrimidine compound is shown in I; the compound can effectively inhibit the activity of EGFR protein kinase drug-resistant mutants (such as EGFRT790M and EGFRT790M/C797S), and can overcome the clinical drug resistance of tumour patients with non-small cell lung cancer and suchlike induced by existing third-generation selective EGFRT790M small molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), and Rociletinib (CO-1686).

Description

2-氨基嘧啶类化合物及其应用2-aminopyrimidine compounds and their applications 技术领域Technical field
本发明涉及化学医药领域，特别是涉及一种2-氨基嘧啶类化合物及其应用。The invention relates to the field of chemical medicine, in particular to a 2-aminopyrimidine compound and its application.
背景技术Background technique
肿瘤分子靶向治疗是基于对肿瘤生长密切相关的关键分子通过化学或生物学手段选择性杀伤肿瘤细胞的一种治疗方法。靶向治疗的特点为：特异性高，选择性强，毒副作用较轻；联合应用时，它可加强传统化疗、放疗的疗效，减少术后复发。以伊马替尼甲磺酸盐(STI571)(Novartis,2001)，吉非替尼(ZD1839)(AstraZeneca,2003)，厄罗替尼(OSI774)(Genentech and OSIP,2004)，索拉菲尼对甲苯磺酸盐(Bay 43-9006)(Bayer and Onyx,2005)，舒尼替尼苹果酸盐(SU11248)(Pfizer,2006)以及达沙替尼(BMS-354825)(Bristol-Myers Squibb,2006)为代表的靶向药物为肿瘤化疗开创了一个新时代。肿瘤靶向治疗在短短几年内得到了迅速发展。肿瘤靶向治疗的出现已对传统给药观念和模式构成冲击，例如，因毒副作用小，靶向药物在I期临床试验中往往无法达到剂量限制性毒性和最大耐受剂量；用靶向治疗药物时无需用最大耐受剂量即可达到满意疗效。肿瘤靶向治疗是肿瘤治疗的热点和发展趋势。Tumor molecular targeted therapy is a treatment method that selectively kills tumor cells by chemical or biological means based on key molecules closely related to tumor growth. The characteristics of targeted therapy are: high specificity, strong selectivity, and lighter side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence. Imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003), erlotinib (OSI774) (Genentech and OSIP, 2004), sorafenib P-toluenesulfonate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and dasatinib (BMS-354825) (Bristol-Myers Squibb, The targeted drugs represented by 2006) created a new era for cancer chemotherapy. Cancer targeted therapy has developed rapidly in just a few years. The emergence of targeted cancer therapy has impacted on traditional drug administration concepts and models. For example, due to small toxic and side effects, targeted drugs often fail to achieve dose-limiting toxicity and maximum tolerated dose in phase I clinical trials; use targeted therapy The drug can achieve satisfactory therapeutic effect without using the maximum tolerated dose. Tumor targeted therapy is a hot spot and development trend of cancer therapy.
表皮生长因子受体(EGFR)，一种受体酪氨酸蛋白激酶，调控了细胞的增殖，存活，粘连，迁移与分化。EGFR在多种肿瘤细胞中过度活化或持续活化，比如肺癌，乳腺癌，前列腺癌等。大约62％的非小细胞肺癌患者存在EGFR过量表达，对EGFR的抑制能显著提高部分患者的生存期。并且，2003～2004年上市的EGFR小分子抑制剂药物Gefitinib和Erlotinib，已经被用于晚期非小细胞肺癌的治疗，进一步明确了EGFR是治疗非小细胞肺癌的有效靶点。Epidermal growth factor receptor (EGFR), a receptor tyrosine protein kinase, regulates cell proliferation, survival, adhesion, migration, and differentiation. EGFR is over-activated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, and prostate cancer. Approximately 62% of patients with non-small cell lung cancer have EGFR overexpression, and inhibition of EGFR can significantly improve the survival of some patients. In addition, the EGFR small molecule inhibitor drugs Gefitinib and Erlotinib, which were marketed from 2003 to 2004, have been used in the treatment of advanced non-small cell lung cancer, further clarifying that EGFR is an effective target for the treatment of non-small cell lung cancer.
第一代EGFR小分子抑制剂在携带EGFR敏感突变的患者中获得了显著的临床疗效，延长了他们的生存期。但获益患者在使用药物10～12个月后，大部分患者会产生耐药。其中，超过50％的耐药患者(携带EGFR敏感突变)是由于EGFR发生了T790M二次突变产生耐药。相比L858R敏感突变的EGFR，L858R/T790M二次突变的EGFR对ATP的亲和力更强，而第一代药物均是ATP竞争性抑制剂，因此导致药物耐药。第二代EGFR不可逆抑制剂虽然在临床前研究获得较好的结果，但对野生型EGFR(EGFR WT)缺乏选择性，具有较大毒性。2013年FDA批准的EGFR不可逆抑制剂Gilotrif虽然对携带激活性EGFR突变(L858R，del E746-A750)的晚期NSCLC病人有效，但在临床最大耐受剂量(MTD)下，仍无法解决EGFRT790M突变引起的临床耐药。第三代克服EGFR T790M耐药的不可逆抑制剂Osimertinib(AZD9291)，于2015年11月，获得美国FDA加速批准上市(Cancer discovery 2014,4(9), 1046-1061)，其在临床上能够有效治疗表皮生长因子受体(EGFR)T790M突变或对其它EGFR抑制剂耐药的晚期非小细胞肺癌患者。尽管Osimertinib在临床上治疗EGFRT790M突变的非小细胞肺癌取得了较大的成功，但是部分受益患者在经过9～14个月治疗后又出现了耐药的现象(Nature Medicine 2015,21(6),560-2)。经研究发现，高达40％的耐药患者由于(EGFR)C797S点突变导致了Osimertinib耐药。进一步的机制研究表明，(EGFR)C797S的点突变使797位的半胱氨酸转变为丝氨酸，导致Osimertinib无法与靶蛋白形成共价结合，最终引起耐药。目前临床尚缺乏针对新突变(C797S)单独用药有效的EGFR抑制剂。因此，迫切需要新类型，高选择性的EGFR抑制剂来解决(EGFR)C797S点突变导致的药物耐药性等问题。 The first-generation EGFR small molecule inhibitors have achieved significant clinical efficacy in patients with EGFR-sensitive mutations, extending their survival. However, after 10-12 months of using the drug, most patients will develop drug resistance. Among them, more than 50% of the drug-resistant patients (carrying EGFR sensitive mutations) are due to the occurrence of drug resistance due to the T790M secondary mutation of EGFR. Compared with the L858R sensitive mutant EGFR, the L858R/T790M secondary mutant EGFR has a stronger affinity for ATP, and the first-generation drugs are all ATP competitive inhibitors, resulting in drug resistance. Although the second-generation EGFR irreversible inhibitors obtained good results in preclinical studies, they lacked selectivity for wild-type EGFR (EGFR WT ) and had greater toxicity. Although the FDA-approved EGFR irreversible inhibitor Gilotrif was effective in advanced NSCLC patients with activated EGFR mutations (L858R, del E746-A750) in 2013, at the clinical maximum tolerated dose (MTD), it still could not solve the EGFRT790M mutation-induced Clinically resistant. Osimertinib (AZD9291), the third-generation irreversible inhibitor that overcomes EGFR T790M resistance, was granted accelerated approval by the US FDA in November 2015 (Cancer discovery 2014, 4(9), 1046-1061), which is clinically effective Treatment of patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) T790M mutation or resistance to other EGFR inhibitors. Although Osimertinib has achieved great success in the clinical treatment of non-small cell lung cancer with EGFR T790M mutation, some beneficiary patients have developed drug resistance after 9 to 14 months of treatment (Nature Medicine 2015, 21(6), 560-2). The study found that up to 40% of drug-resistant patients caused Osimertinib resistance due to (EGFR) C797S point mutation. Further mechanism research shows that the point mutation of (EGFR)C797S changes the cysteine at position 797 to serine, which prevents Osimertinib from forming a covalent bond with the target protein, which eventually causes drug resistance. At present, there is still a lack of effective EGFR inhibitors for the new mutation (C797S) alone. Therefore, new types of highly selective EGFR inhibitors are urgently needed to solve the problem of drug resistance caused by (EGFR) C797S point mutation.
发明内容Summary of the invention
基于此，本发明提供了提供一种2-氨基嘧啶类化合物，该类化合物可以有效抑制EGFR蛋白激酶耐药突变体(如EGFR T790M、EGFR T790M/C797S和EGFR T790M/C797S/L858R)的活性。 Based on this, the present invention provides a 2-aminopyrimidine compound that can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M , EGFR T790M/C797S, and EGFR T790M/C797S/L858R ).
具体技术方案如下：The specific technical solutions are as follows:
具有式I所示结构的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：A 2-aminopyrimidine compound having the structure shown in Formula I or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof:
Figure PCTCN2019124686-appb-000001
Figure PCTCN2019124686-appb-000001
式中：In the formula:
A、B、C分别独立地选自：N或C-R 2a； A, B, C are independently selected from: N or CR 2a ;
R 1、R 2、R 2a分别独立地选自：H、卤素、氰基、硝基、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷氧基、或者取代或未取代的C 3～C 6环烷氧基； R 1 , R 2 , and R 2a are independently selected from the group consisting of: H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl , Substituted or unsubstituted C 1 ～C 6 alkoxy, or substituted or unsubstituted C 3 ～C 6 cycloalkoxy;
R 3选自：取代或未取代的吡唑基、-(CH 2) mNR 5R 6、-(CH 2) mOCR 4R 5R 6或者-(CH 2) mCR 4R 5R 6；其中，m选自：0、1、2、3或4； R 3 is selected from: substituted or unsubstituted pyrazolyl, -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 or -(CH 2 ) m CR 4 R 5 R 6 ; Where m is selected from: 0, 1, 2, 3, or 4;
R 4选自：氢或C 1～C 3烷基； R 4 is selected from: hydrogen or C 1 ～C 3 alkyl;
R 5和R 6分别独立地选自：氢、取代或未取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N或C一同形成取代或未取代的含有杂原子的单环、稠环、螺环或桥环； R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or R 5 , R 6 and the N or C to which they are attached together form a substituted or unsubstituted heteroatom-containing Single ring, condensed ring, spiro ring or bridge ring;
L选自：CH 2、NH或O； L is selected from: CH 2 , NH or O;
n选自：0、1、2或3；n is selected from: 0, 1, 2 or 3;
G选自：未取代或R 10取代的具有8-10个环原子的稠环烷基、未取代或R 10取代的具有8-10个环原子的稠脂杂环基、未取代或R 10取代的具有8-10个环原子的稠芳环基、或者未取代或R 10取代的具有8-10个环原子的稠芳杂环基； G is selected from: unsubstituted or R 10 substituted fused cycloalkyl having 8-10 ring atoms, unsubstituted or R 10 substituted fused aliphatic heterocyclic group having 8-10 ring atoms, unsubstituted or R 10 Substituted fused aromatic ring groups having 8-10 ring atoms, or unsubstituted or R 10 substituted fused aromatic heterocyclic groups having 8-10 ring atoms;
R 10分别独立地选自H、卤素、氧代、硫代、氮代、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷基、取代或未取代的C 1～C 6烷氧基、或者取代或未取代的C 3～C 6环烷氧基或者S(O 2)R 7；R 7选自：H、C 1-C 6烷基或者C 3-C 6环烷基； R 10 is independently selected from H, halogen, oxo, thio, nitro, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted Substituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy or S(O 2 )R 7 ; R 7 is selected from: H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
其中，当G选自C 1～C 6烷基取代或未被取代的
Figure PCTCN2019124686-appb-000002
时，R 2a不为C 1～C 6烷氧基。 Where, when G is selected from C 1 ～C 6 alkyl substituted or unsubstituted
Figure PCTCN2019124686-appb-000002
In this case, R 2a is not C 1 to C 6 alkoxy.
在其中一些实施例中，所述2-氨基嘧啶类化合物为：In some of these embodiments, the 2-aminopyrimidine compounds are:
Figure PCTCN2019124686-appb-000003
Figure PCTCN2019124686-appb-000003
在其中一些实施例中，G选自：In some of these embodiments, G is selected from:
Figure PCTCN2019124686-appb-000004
Figure PCTCN2019124686-appb-000004
其中，X 1、X 2分别独立地选自：CH、C或N；X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10分别独立地选自：CH 2、CH、C、C＝O、C＝S、C＝NR 10、C R 10、N、NH、N R 10、NS(O 2)R 7、S、S(O)、S(O 2)或O。 Wherein, X 1 and X 2 are independently selected from: CH, C or N; X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from: CH 2 , CH, C, C=O, C=S, C=NR 10 , C R 10 , N, NH, NR 10 , NS(O 2 )R 7 , S, S(O), S(O 2 ) or O .
在其中一些实施例中，G选自以下基团：In some of these embodiments, G is selected from the following groups:
未被取代或被1-5个R 10取代的萘基、未被取代或被1-5个R 10取代的吲哚基、未被取代或被1-5个R 10取代的吲唑基、未被取代或被1-5个R 10取代的苯并噻吩基、未被取代或被1-5个R 10取代的苯并呋喃基、未被取代或被1-5个R 10取代的1,1-二氧代苯并噻吩基、未被取代或被1-5个R 10取代的1,2-苯并恶唑基、未被取代或被1-5个R 10取代的苯并咪唑基、未被取 代或被1-5个R 10取代的吡啶并吡咯基、未被取代或被1-5个R 10取代的吡唑并吡啶基、未被取代或被1-5个R 10取代的咪唑并吡啶基、未被取代或被1-5个R 10取代的噻吩并吡咯基、或者未被取代或被1-5个R 10取代的噻吩并吡唑基。 Unsubstituted or substituted with 1-5 R 10 naphthyl, unsubstituted or substituted with 1-5 R 10 indolyl, unsubstituted or substituted with 1-5 R 10 indazolyl, Unsubstituted or substituted with 1-5 R 10 benzothienyl, unsubstituted or substituted with 1-5 R 10 benzofuranyl, unsubstituted or substituted with 1-5 R 10 1 , l-dioxo-benzothienyl, unsubstituted or substituted with 1-5 R 10 group is 1,2-oxazolyl, unsubstituted or substituted with 1-5 R 10 benzimidazole Group, unsubstituted or substituted with 1-5 R 10 pyridopyrrolyl, unsubstituted or substituted with 1-5 R 10 pyrazolopyridyl, unsubstituted or substituted with 1-5 R 10 Substituted imidazopyridyl, thienopyrrolyl unsubstituted or substituted with 1-5 R 10 , or thienopyrazolyl unsubstituted or substituted with 1-5 R 10 .
在其中一些实施例中，In some of these embodiments,
G选自以下基团：G is selected from the following groups:
Figure PCTCN2019124686-appb-000005
Figure PCTCN2019124686-appb-000005
在其中一些实施例中，G选自以下基团：In some of these embodiments, G is selected from the following groups:
Figure PCTCN2019124686-appb-000006
Figure PCTCN2019124686-appb-000006
其中，R 10选自C 1～C 6烷基或C 3～C 6环烷基；R 7选自：H、C 1～C 6烷基、C 3～C 6环烷基。在其中一些实施例中，R 3选自：R 8取代的吡唑基、-(CH 2) mNR 5R 6、-(CH 2) mOCR 4R 5R 6、 -(CH 2) mCR 4R 5R 6；其中，m选自：0、1、2、3或4； Wherein, R 10 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R 7 is selected from: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl. In some of these embodiments, R 3 is selected from: R 8 substituted pyrazolyl, -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 , -(CH 2 ) m CR 4 R 5 R 6 ; where m is selected from: 0, 1, 2, 3 or 4;
R 4选自：氢或C 1～C 3烷基； R 4 is selected from: hydrogen or C 1 ～C 3 alkyl;
R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N或C一同形成R 8取代的含1、2或3个杂原子的3～8元单环，或者R 5、R 6和与其相连的N或C一同形成R 8取代的含1、2或3个杂原子的8～12元稠环、螺环或桥环，杂原子选自：O、N或者S； R 5 and R 6 are independently selected from: hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 together with N or C connected thereto form R 8 substituted 1, 2 or 3 3 to 8 membered monocyclic rings of hetero atoms, or R 5 and R 6 together with N or C connected to them form an 8 to 12 membered fused ring, spiro ring or R 8 substituted with 1, 2 or 3 heteroatoms Bridge ring, hetero atom selected from: O, N or S;
各R 8分别独立地选自：H、R 9取代或未取代的4～8元杂环基、卤素、羟基、氨基、C 1～C 3烷基、-C(＝O)NHR 9取代的C 1～C 3烷基、羟基取代的C 1～C 3烷基、C 3～C 6环烷基取代的C 1～C 3烷基、C 3～C 8杂环基取代的C 1～C 3烷基、C 1～C 3烷氧基、-NHR 9、-N(R 9) 2或者-C(＝O)R 9；R 9为C 1～C 3烷基。 Each R 8 is independently selected from: H, R 9 substituted or unsubstituted 4-8 membered heterocyclic group, halogen, hydroxy, amino, C 1 -C 3 alkyl, -C(=O)NHR 9 substituted C 1 ～C 3 alkyl, hydroxy substituted C 1 ～C 3 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～C 3 alkyl, C 3 ～C 8 heterocyclic group substituted C 1 ～ C 3 alkyl, C 1 -C 3 alkoxy, -NHR 9 , -N(R 9 ) 2 or -C(=O)R 9 ; R 9 is C 1 -C 3 alkyl.
在其中一些实施例中，In some of these embodiments,
R 3选自：-(CH 2) mNR 5R 6；m选自：0或1。 R 3 is selected from: -(CH 2 ) m NR 5 R 6 ; m is selected from: 0 or 1.
在其中一些实施例中，In some of these embodiments,
R 3选自：-NR 5R 6； R 3 is selected from: -NR 5 R 6 ;
R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N一同形成R 8取代的含1或2个杂原子的6元单环，杂原子选自：O、N或S。 R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 and N to which they are connected together form R 8 substituted 1 or 2 heteroatoms 6-membered single ring, heteroatom selected from: O, N or S.
在其中一些实施例中，R 3选自：
Figure PCTCN2019124686-appb-000007
R 8取代的
Figure PCTCN2019124686-appb-000008
R 8取代的
Figure PCTCN2019124686-appb-000009
R 8取代的
Figure PCTCN2019124686-appb-000010
或者R 8取代的
Figure PCTCN2019124686-appb-000011
R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基。 In some of these embodiments, R 3 is selected from:
Figure PCTCN2019124686-appb-000007
R 8 replaced
Figure PCTCN2019124686-appb-000008
R 8 replaced
Figure PCTCN2019124686-appb-000009
R 8 replaced
Figure PCTCN2019124686-appb-000010
Or substituted by R 8
Figure PCTCN2019124686-appb-000011
R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl substituted with R 8 .
在其中一些实施例中，R 8选自：H、卤素、羟基、氨基、C 1～C 3烷基、-C(＝O)R 9、羟基取代的C 1～C 3烷基、C 1～C 3烷氧基、-NHR 9、-N(R 9) 2、
Figure PCTCN2019124686-appb-000012
R 9为C 1～C 3烷基。 In some of these embodiments, R 8 is selected from the group consisting of: H, halogen, hydroxy, amino, C 1 -C 3 alkyl, -C(═O)R 9 , hydroxy substituted C 1 -C 3 alkyl, C 1 ~C 3 alkoxy, -NHR 9 , -N(R 9 ) 2 ,
Figure PCTCN2019124686-appb-000012
R 9 is C 1 to C 3 alkyl.
在其中一些实施例中，R 3选自： In some of these embodiments, R 3 is selected from:
Figure PCTCN2019124686-appb-000013
Figure PCTCN2019124686-appb-000013
Figure PCTCN2019124686-appb-000014
Figure PCTCN2019124686-appb-000015
或者
Figure PCTCN2019124686-appb-000016
Figure PCTCN2019124686-appb-000014
Figure PCTCN2019124686-appb-000015
or
Figure PCTCN2019124686-appb-000016
在其中一些实施例中，R 1、R 2和R 2a分别独立地选自：H、卤素、氰基、硝基、C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基、C 3～C 6环烷氧基、卤素取代的C 1～C 6烷基、卤素取代的C 1～C 6烷氧基。 In some of these embodiments, R 1 , R 2 and R 2a are independently selected from the group consisting of: H, halogen, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy.
在其中一些实施例中，R 1选自：H、卤素、甲基、氰基、三氟甲基、二氟甲基、甲氧基、环丙基、三氟甲氧基； In some of these embodiments, R 1 is selected from: H, halogen, methyl, cyano, trifluoromethyl, difluoromethyl, methoxy, cyclopropyl, trifluoromethoxy;
R 2和R 2a分别独立地选自：H、氟、氯、溴、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、环丙基、异丙基、正丙基、甲氧基、异丙氧基或环戊基氧基。 R 2 and R 2a are independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, cyclopropyl, isopropyl, n- Propyl, methoxy, isopropoxy or cyclopentyloxy.
在其中一些实施例中，G选自
Figure PCTCN2019124686-appb-000017
Figure PCTCN2019124686-appb-000018
Figure PCTCN2019124686-appb-000019
Figure PCTCN2019124686-appb-000020
时，R 2a选自：H、卤素、氰基、硝基、卤素取代或未取代的C 1～C 6烷基、卤素取代或未取代的C 3～C 6环烷基、卤素取代或未取代的C 1～C 6烷氧基、或者卤素取代或未取代的C 3～C 6环烷氧基； In some of these embodiments, G is selected from
Figure PCTCN2019124686-appb-000017
Figure PCTCN2019124686-appb-000018
Figure PCTCN2019124686-appb-000019
Figure PCTCN2019124686-appb-000020
When R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl, halogen-substituted or unsubstituted Substituted C 1 ～C 6 alkoxy, or halogen substituted or unsubstituted C 3 ～C 6 cycloalkoxy;
G选自
Figure PCTCN2019124686-appb-000021
时，R 2a选自：H、卤素、氰基、硝基、卤素取代或未取代的C 1～C 6烷基、或者卤素取代或未取代的C 3～C 6环烷基。 G is selected from
Figure PCTCN2019124686-appb-000021
In this case, R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, or halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl.
在其中一些实施例中，G为
Figure PCTCN2019124686-appb-000022
In some of these embodiments, G is
Figure PCTCN2019124686-appb-000022
R 1选自：H、卤素、C 1～C 6烷基或卤素取代的C 1～C 6烷基； R 1 is selected from: H, halogen, C 1 -C 6 alkyl or halogen substituted C 1 -C 6 alkyl;
R 2选自：H、卤素、C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基或C 3～C 6环烷氧基； R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy;
R 2a分别独立地选自：H、卤素、氰基、硝基、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷氧基、或者取代或未取代的C 3～C 6环烷氧基。 R 2a is independently selected from: H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy.
在其中一些实施例中，A、B、C选自C-H；In some of these embodiments, A, B, C are selected from C-H;
R 3选自
Figure PCTCN2019124686-appb-000023
R 3 is selected from
Figure PCTCN2019124686-appb-000023
在其中一些实施例中，G选自
Figure PCTCN2019124686-appb-000024
In some of these embodiments, G is selected from
Figure PCTCN2019124686-appb-000024
R 1选自H、卤素或者卤素取代的C 1～C 6烷基； R 1 is selected from H, halogen or halogen substituted C 1 ～C 6 alkyl;
A、B、C选自C-H；A, B, C are selected from C-H;
R 2选自：H、卤素、C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基或C 3～C 6环烷氧基。 R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy.
本发明还提供了上述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备突变型EGFR抑制剂中的应用。The present invention also provides the use of the above-mentioned 2-aminopyrimidine compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof in preparing mutant EGFR inhibitors.
上述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备防治肿瘤的药物中的应用。The application of the above-mentioned 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of drugs for preventing and treating tumors.
在其中一些实施例中，所述肿瘤为EGFR基因突变的恶性肿瘤。In some of these embodiments, the tumor is a malignant tumor with EGFR gene mutation.
在其中一些实施例中，所述肿瘤为EGFR L858R/T790M/C797S突变的恶性肿瘤。 In some of these embodiments, the tumor is a malignant tumor with EGFR L858R/T790M/C797S mutation.
在其中一些实施例中，所述肿瘤为：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌或胶质瘤。In some of these embodiments, the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal Stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer or glioma.
本发明还提供了一种防治肿瘤的药物组合物。The invention also provides a pharmaceutical composition for preventing and treating tumors.
具体技术方案如下：The specific technical solutions are as follows:
一种药物组合物，包括活性成分以及药学上可接受的载体，所述活性成分包括上述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。A pharmaceutical composition includes an active ingredient and a pharmaceutically acceptable carrier. The active ingredient includes the aforementioned 2-aminopyrimidine compound or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，可以对EGFR家族蛋白酶产生抑制作用，从而可以抑制多种肿瘤细胞的生长。对比野生型癌细胞，本发明的化合物对突变型癌细胞具有较高的选择性。本发明的化合物尤其能够有效抑制EGFR蛋白激酶耐药突变体(如EGFR T790M和EGFR T790M/C797S)的活性，能够选择性作用于EGFR L858R/T790M、EGFR Del E745_A750以及EGFR L858R/T790M/C797S肺癌细胞，可以克服现有第三代选择性EGFR T790M小分子抑制剂Osimertinib(AZD9291)，Olmutinib(HM6171)，Rociletinib(CO-1686)等诱发的非小细胞肺癌等肿瘤病人的临床耐药。 The 2-aminopyrimidine compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule can have an inhibitory effect on the EGFR family protease, thereby inhibiting the growth of various tumor cells. Compared with wild-type cancer cells, the compounds of the present invention have higher selectivity for mutant cancer cells. The compounds of the present invention can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR T790M/C797S ), and can selectively act on EGFR L858R/T790M , EGFR Del E745_A750, and EGFR L858R/T790M/C797S lung cancer cells It can overcome the current third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) induced clinical drug resistance of non-small cell lung cancer and other tumor patients.
本发明的化合物可用于制备抗肿瘤药物，并可以克服现有药物吉非替尼、厄洛替尼，尤其是Osimertinib(AZD9291)等诱发的耐药，是一类新颖的能够克服现有EGFR酪氨酸激酶抑制剂耐药的并具有选择性和良好药代性质的蛋白激酶抑制剂，可用于治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病。The compound of the present invention can be used to prepare anti-tumor drugs, and can overcome the resistance induced by the existing drugs gefitinib, erlotinib, especially Osimertinib (AZD9291), etc. It is a novel class that can overcome the existing EGFR case Protein kinase inhibitors that are drug-resistant, selective and have good pharmacological properties are used to treat hyperproliferative diseases such as tumors in humans and other mammals.
具体实施方式detailed description
以下结合具体实施例对本发明作进一步详细的说明。The present invention will be further described in detail below with reference to specific embodiments.
本发明所述化合物中，当任何变量(例如R 1、R 2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代形式而提供化学上稳定的 并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。 In the compound of the present invention, when any variable (for example, R 1 , R 2, etc.) occurs more than once in any component, its definition for each occurrence is independent of other definitions for each occurrence. Likewise, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. The line drawn from the substituent to the ring system indicates that the indicated bond can be connected to any ring atom that can be substituted. If the ring system is polycyclic, it means that this bond is only connected to any suitable carbon atom of the adjacent ring. It is to be understood that those of ordinary skill in the art can select substituents and substituted forms of the compounds of the present invention to provide chemically stable compounds that can be easily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If the substituent itself is substituted with more than one group, it should be understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
本文所用术语“烷基”是指饱和链状烷基，“链状烷基”是指直链或支链的烷基，如C 1-C 4烷基是指具有1至4个碳原子的饱和直链或支链的烷基，其中直链烷基的示例包括但不限于乙基，正丙基等，支链烷基的示例包括但不限于异丙基，叔丁基等； As used herein, the term "alkyl" means a saturated alkyl group, "alkyl group" means a straight or branched chain alkyl group, such as C 1 -C 4 alkyl group means having 1 to 4 carbon atoms, Saturated linear or branched alkyl, wherein examples of linear alkyl include but are not limited to ethyl, n-propyl, etc. Examples of branched alkyl include but are not limited to isopropyl, tert-butyl, etc.;
术语“环烷基”是指具有环状结构的烷基，如C 3-C 4环烷基指具有3至4个碳原子的具有环状结构的烷基，示例包括但不限于环丙基，环丁基、甲基取代环丙基等。 The term "cycloalkyl" refers to an alkyl group having a cyclic structure, such as C 3 -C 4 cycloalkyl refers to an alkyl group having a cyclic structure having 3 to 4 carbon atoms, examples include but are not limited to cyclopropyl , Cyclobutyl, methyl substituted cyclopropyl, etc.
术语“烷氧基”表示末端含有一个氧原子的直链或支链烷基，示例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。The term "alkoxy" refers to a linear or branched alkyl group containing an oxygen atom at the end. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。As used herein, "halo" or "halo" means chlorine, fluorine, bromine, and iodine.
本发明提供一种式I化合物，其药学上可接受的盐或其立体异构体或其前药分子，The present invention provides a compound of formula I, a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof,
Figure PCTCN2019124686-appb-000025
Figure PCTCN2019124686-appb-000025
其中，R 1、R 2、R 3和A、B、C、L、G、n的定义同前。 Among them, R 1 , R 2 , R 3 and A, B, C, L, G, n are as defined above.
本发明包括式I化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式I化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The present invention includes the free form of the compound of formula I as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. The included pharmaceutically acceptable salts include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts in the free form of all compounds of formula I. The free form of the specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable alkaline dilute aqueous solution such as NaOH dilute aqueous solution, potassium carbonate dilute aqueous solution, dilute ammonia water, and sodium bicarbonate dilute aqueous solution. The free form is somewhat different from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are comparable to their respective free forms in other pharmaceutical aspects.
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing basic or acidic moieties by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reaction with appropriate inorganic or organic bases.
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反 应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Therefore, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting basic compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., as well as organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard acids Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Oxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and other salts prepared.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt, etc. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases, which include salts of primary, secondary and tertiary amines, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as refined Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine , Piperidine, chirp, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
Berg等，“Pharmaceutical Salts”J.Pharm.Sci.’1977：66：1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。Berg et al., "Pharmaceutical Salts" J. Pharm. Sci. '1977: 66:1-19 describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。Since the deprotonated acidic part of the compound such as carboxyl group can be anionic under physiological conditions, this charge can then be protonated or alkylated with a cationic internal part such as tetravalent The nitrogen atoms balance out, so it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下具体实施例中所列方案显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式I的定义下允许有多取代基的化合物上。In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the present invention can be prepared using the reactions shown in the schemes listed in the specific examples below. Therefore, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any specific substituents. The number of substituents shown in the scheme does not necessarily correspond to the number used in the claims, and for clarity, it is shown that a single substituent is attached to a compound that allows multiple substituents under the definition of Formula I above.
本发明提供的具有式I结构的化合物及其药学上可接受的盐可用于治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。尤其是用于治疗或控制非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤等过渡增殖性疾病。The compounds provided by the present invention having the structure of Formula I and their pharmaceutically acceptable salts can be used to treat transitional proliferative diseases or symptoms such as tumors in humans or other mammals. Especially for the treatment or control of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, Histocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma and other transitional proliferative diseases.
药物代谢物及前药：本发明所涉及的化合物及其药学上可接受的盐的代谢产物，以及可以在体内转变为本发明所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。Drug metabolites and prodrugs: metabolites of the compounds and pharmaceutically acceptable salts of the present invention, and prodrugs that can be converted into structures of the compounds and pharmaceutically acceptable salts of the present invention in vivo, Also included in the claims of this application.
药物组合物：本发明还提供了一种药物组合物，它包含安全有效量范围内的活性成分， 以及药学上可接受的载体。本发明所述的“活性成分”是指本发明所述的式I化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。Pharmaceutical composition: The present invention also provides a pharmaceutical composition, which comprises an active ingredient in a safe and effective amount range, and a pharmaceutically acceptable carrier. The "active ingredient" in the present invention refers to the compound of the formula I described in the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof.
本发明所述的“活性成分”和药物组合物可用作EGFR蛋白酶抑制剂。在另一优选例中，用于制备预防和/或治疗肿瘤的药物。The "active ingredient" and the pharmaceutical composition described in the present invention can be used as EGFR protease inhibitors. In another preferred example, it is used to prepare a medicine for preventing and/or treating tumors.
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。"Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose. Preferably, the "one dose" is a tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。"Compatibility" here means that the components in the composition can be blended with the active ingredient of the present invention and between them without significantly reducing the efficacy of the active ingredient.
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019124686-appb-000026
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween
Figure PCTCN2019124686-appb-000026
), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
在另一优选例中，本发明式I化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中，本发明式I化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。In another preferred example, the compound of formula I of the present invention can form a complex with a macromolecular compound or a polymer by non-bonding. In another preferred embodiment, the compound of formula I of the present invention can also be connected to a macromolecular compound or a polymer through a chemical bond as a small molecule. The macromolecular compound may be biological macromolecules such as high glycans, proteins, nucleic acids, polypeptides and the like.
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:
(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;
(c)保湿剂，例如，甘油；(c) humectants, for example, glycerin;
(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(d) Disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
(e)缓溶剂，例如石蜡；(e) Slow solvents, such as paraffin wax;
(f)吸收加速剂，例如，季胺化合物；(f) absorption accelerators, for example, quaternary amine compounds;
(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;
(h)吸附剂，例如，高岭土；和(h) adsorbent, for example, kaolin; and
(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。(i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。The solid dosage form can also be prepared by coating and shell materials, such as casings and other materials well known in the art. They may contain an opaque agent, and the release of the active ingredient in this composition can be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxy substances.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredients, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavoring agents.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active ingredients, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。The composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他治疗药物(如降糖药)联合给药。The compound of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypoglycemic agents).
使用药物组合物时，是将安全有效量的本发明化合物施用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is administered to a mammal in need of treatment (such as a human), wherein the dose at the time of administration is the pharmacologically effective dose, for a person of 60 kg body weight, daily The dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
联合用药：式I化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用式I化合物。当式I化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药时的剂量较低。Combination therapy: The compound of formula I can be used in combination with other drugs known to treat or improve similar conditions. When co-administered, the original drug administration method and dose remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time. Drug combination also includes taking the compound of formula I with one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or known drugs may be lower than when they are used alone.
可以与式I化合物进行药物联用的药物或活性成分包括但不局限为：Drugs or active ingredients that can be used in combination with compounds of formula I include, but are not limited to:
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。Estrogen receptor modulator, androgen receptor modulator, retinal-like receptor modulator, cytotoxin/cytostatic agent, antiproliferative agent, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protein kinase inhibition Agents, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine Acid deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors , Integrin blocker, interferon-α, interleukin-12, COX-2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody, etc.
在一个实施方案中，可以与式I化合物进行药物联用的药物或活性成分包括但不局限为：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸 阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。In one embodiment, drugs or active ingredients that can be used in combination with compounds of formula I include, but are not limited to: aldesleukin, alendronic acid, interferon, atranoline, allopurinol, allopurinol Sodium, Palonosetron hydrochloride, hexamethylmelamine, aminoglutamine, amifostine, amrubicin, amaridine, anatozole, dolasetron, aranesp, arglabin, arsenic trioxide, Anoxin, 5-azacytidine, azathioprine, BCG or tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromoglycan, bortezomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, Constance, cefesone, simor interleukin, daunorubicin, chlorambucil, cisplatin, cladribone Bin, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin liposomes, dexamethasone, dexamethasone phosphate, estradiol valerate Alcohol, Dene interleukin 2, Depomery, Deslorellin, Derazorsen, Diethylstilbestrol, Dafukang, Docetaxel, Deoxyfluridine, Doxorubicin, Dronabinol, Chin-166-shell Glycan complexes, eligard, rabrizyme, epirubicin hydrochloride, aprepitant, epirubicin, alfaberine, erythropoietin, epiplatin, levamisole tablets, estradiol preparations, 17-β-estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, hydroxyphosphoric acid, verbifu, etoposide, fadrozole, tamoxifen preparation, filgrastim, non- Nalastine, Fiesistat, Fluuridine, Fluconazole, Fludarabine, 5-fluorodeoxyuridine nucleoside monophosphate, 5-fluorouracil, Fluoxymesterone, Flutamide, Formestane, 1-β-D-arabinofuranosylcytosine-5'-stearoyl phosphate, formustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imatinate mesylate Ni, Carmustine Waxy Rice Paper Capsules, Goserelin, Granisilone Hydrochloride, Histralin, Hemexin, Hydrocortisone, Red-Hydroxynonyladenine, Hydroxyurea, Titamisobe Mozumab, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-nl, interferon α-n3, interferon β , Interferon γ-la, interleukin-2, intron A, Iressa, irinotecan, keteri, lentinan sulfate, letrozole, formyltetrahydrofolate, leuprolide, leuprolide Ralin acetate, levamisole, levofolate calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, methylol Progesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-lyl purine, mesna sodium, methotrexate, methyllevulinate, mitifosin, minocycline , Mitomycin C, Mitotan, Mitocinone, Tralostan, Adriamycin Liposome Citrate, Nedaplatin, Pegylated Fegrastim, Oprean Interleukin, neupogen, Nirumite, tamoxifen, NSC-6315 70. Recombinant Human Interleukin 1-β, Octreotide, Ondansetron Hydrochloride, Dehydrohydrocortisone Oral Solution, Oxaliplatin, Paclitaxel, Prednisone Sodium Phosphate Preparation, Pemendase, Pyroxine Xin, Penastatin, Streptolysin, Pilocarpine Hydrochloride, Pirubicin, Pikamycin, Porphenim Sodium, Predimustine, Strepprednisolone, Prednisone, Pomeli, Procarba Umbilical, Recombinant Human Erythropoietin, Ratitrixone, Libi, Etidronate Rhenium-186, Rituxan, Diligent-A, Romopeptide, Pilocarpine Hydrochloride Tablets, Octreotide, Samo Stim, Simolastine, Cizoran, Sobuzosen, Sodium methylprednisolone, Paphos acid, Stem cell therapy, Streptozocin, Strontium chloride-89, Levothyroxine sodium, Tamoxifen, Tamsulosin, tasonamin, tastolactone, taxotere, tethisulfin, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, titipipe, thyroid stimulating hormone, tiludron Acid, topotecan, toremifene, tositumomab, trastuzumab, troxofan, tretinoin, methotrexate tablets, trimethylmelamine, trimetrisa, acetic acid Triptorelin, Triptorelin, Euphradine, Uridine, Pentarubicin, Vesilrin, Vinblastine, Vincristine, Vinblastine, Vinorelbine, Verulin, D-propimine, net statin, fulbutonin, paclitaxel protein stabilizing agent, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifen, asoprisnil, atamitan, atrason Tan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Clenato, Cyproterone Acetate, Decitabine, DN-101, Doxorubicin -MTC, dSLIM, dutasteride, edotecarin, eflunithine, ixiticon, fenretinide, histamine dihydrochloride, histidine hydrogel implant, holmium-166DOTMP, Ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanopeptide, rasoxifene, libra, lonafamib, mipraxifen, minoxidic acid Ester, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neofamil, nolatrexate, orimerson, onco-TCS, osidem, paclitaxel Polyglutamate, sodium methionate, PN-401, QS-21, kwaxiyang, R-1549, raloxifene, leopard frogase, 13-cis retinoic acid, saplatin, theocalciferol , T-138067, tarceva, docosahexaenoic acid paclitaxel, thymosin αl, garzofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, valspar Dap, vapeptide, vatalanib, verteporfin, vinflunine, Z-100, and zoledronic acid or a combination thereof.
本发明的有益之处在于：The benefits of the present invention are:
(1)提供一种结构新颖的2-氨基嘧啶类化合物。(1) Provide a novel 2-aminopyrimidine compound.
(2)该类化合物可以有效抑制EGFR蛋白激酶耐药突变体的作用，可用于制备抗肿瘤药物。(2) Such compounds can effectively inhibit the role of EGFR protein kinase resistant mutants and can be used to prepare anti-tumor drugs.
(3)该类化合物可以克服现有药物吉非替尼、厄洛替尼尤其是Osimertinib(AZD9291)等诱发的耐药，对野生型EGFR具有选择性，具有良好的药代动力学性质。(3) These compounds can overcome the resistance induced by the existing drugs gefitinib, erlotinib, especially Osimertinib (AZD9291), etc., they are selective for wild-type EGFR and have good pharmacokinetic properties.
下面结合具体实施例，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，通常按照常规条件如 Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples generally follow conventional conditions such as Sambrook et al. Molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer The recommended conditions. Unless otherwise stated, percentages and parts are calculated by weight.
除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as familiar to those skilled in the art. In addition, any methods and materials similar to or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.
实施例1Example 1
4-(苯并[b]噻吩-3-基)-5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-氨基(LS3-102)4-(benzo[b]thiophen-3-yl)-5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Phenyl)pyrimidine-2-amino (LS3-102)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000027
Figure PCTCN2019124686-appb-000027
步骤1. 4-(苯并[b]噻吩-3-基)-2,5-二氯嘧啶(3)的制备Step 1. Preparation of 4-(benzo[b]thiophen-3-yl)-2,5-dichloropyrimidine (3)
将2,4,5-三氯嘧啶(1.0g,5.5mmol)、苯并噻吩-3-硼酸(0.93g,5.23mmol)、四三苯基膦钯(0.6g,0.52mmol)和碳酸钾(1.8g,13.0mmol)溶于1,4-二氧六环/水(2:1)的混合溶剂中，氩气保护于80摄氏度反应过夜。待反应完全，反应液经硅藻土层抽滤，减压旋干大部分滤液，以二氯甲烷/水萃取三次，合并有机层，有机层用饱和食盐水洗，再用无水硫酸钠干燥后旋干，经柱层析分离得固体1.2g，收率78％。Combine 2,4,5-trichloropyrimidine (1.0g, 5.5mmol), benzothiophene-3-boronic acid (0.93g, 5.23mmol), tetratriphenylphosphine palladium (0.6g, 0.52mmol) and potassium carbonate ( 1.8g, 13.0mmol) was dissolved in a mixed solvent of 1,4-dioxane/water (2:1), and the argon gas was protected at 80°C overnight. After the reaction was completed, the reaction solution was filtered with suction through a celite layer, and most of the filtrate was spin-dried under reduced pressure, and extracted three times with dichloromethane/water. The organic layers were combined. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Spin dry and separate 1.2 g of solid by column chromatography, yield 78%.
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.30(s,1H),8.28-8.20(m,1H),7.99-7.88(m,1H),7.52-7.43(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (s, 1H), 8.30 (s, 1H), 8.28-8.20 (m, 1H), 7.99-7.88 (m, 1H), 7.52-7.43 (m, 2H ).
MS(ESI):m/z 280[M+H] +. MS(ESI): m/z 280[M+H] + .
步骤2. 1-(1-(2-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(5)的制备Step 2. Preparation of 1-(1-(2-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (5)
将2-氯-1-氟-4-硝基苯(0.5g,2.4mmol)、1-甲基-4-(哌啶-4-基)哌嗪盐酸盐(0.64g,2.87mmol)、碳酸钾(0.67g,4.8mmol)溶于15毫升乙腈溶剂中，加热至80摄氏度反应过夜。待反应完全，以二氯甲烷/水萃取三次，合并有机层，有机层用饱和食盐水洗，再用无水硫酸 钠干燥后旋干，经柱层析分离得固体0.84g，收率93％。2-chloro-1-fluoro-4-nitrobenzene (0.5g, 2.4mmol), 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (0.64g, 2.87mmol), Potassium carbonate (0.67g, 4.8mmol) was dissolved in 15ml of acetonitrile solvent and heated to 80°C to react overnight. After the reaction was completed, it was extracted three times with dichloromethane/water, and the organic layers were combined. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The solid was separated by column chromatography to obtain 0.84g of solid, yield 93%.
1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝2.8Hz,1H),8.13(dd,J 1＝9.0Hz,J 2＝2.8Hz,1H),7.27(d,J＝9.2Hz,1H),3.57(d,J＝12.3Hz,2H),2.82(t,J＝11.3Hz,2H),2.50-2.40(m,4H),2.41-2.19(m,5H),2.14(s,3H),1.88(d,J＝11.8Hz,2H),1.61-1.51(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J=2.8 Hz, 1H), 8.13 (dd, J 1 =9.0 Hz, J 2 =2.8 Hz, 1H), 7.27 (d, J= 9.2Hz, 1H), 3.57 (d, J = 12.3Hz, 2H), 2.82 (t, J = 11.3Hz, 2H), 2.50-2.40 (m, 4H), 2.41-2.19 (m, 5H), 2.14 ( s, 3H), 1.88 (d, J = 11.8 Hz, 2H), 1.61-1.51 (m, 2H).
MS(ESI):m/z 339[M+H] +. MS(ESI): m/z 339[M+H] + .
步骤3. 3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(6)的制备Step 3. Preparation of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (6)
向1-(1-(2-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(5,2.85g,8.43mmol)的乙醇、水混合溶剂(v/v＝2/1)中加入铁粉(1.42g,25.3mmol)、氯化铵(4.6g,84.3mmol)，回流反应2小时。待反应完全，硅藻土抽滤，旋干，经柱层析分离得固体2.4g，收率95％。To 1-(1-(2-chloro-4-nitrophenyl) piperidin-4-yl)-4-methylpiperazine (5, 2.85 g, 8.43 mmol) in ethanol and water mixed solvent (v/ Iron powder (1.42g, 25.3mmol) and ammonium chloride (4.6g, 84.3mmol) were added to v=2/1), and the mixture was refluxed for 2 hours. After the reaction was completed, the celite was suction filtered, spin-dried, and separated by column chromatography to obtain 2.4 g of solid, with a yield of 95%.
1H NMR(400MHz,CDCl 3)δ6.87(d,J＝8.4Hz,1H),6.74(d,J＝2.8Hz,1H),6.53(dd,J 1＝8.5Hz,J 2＝2.6Hz,1H),3.51(s,2H),3.29(d,J＝11.6Hz,2H),2.87-2.23(m,14H),1.89(d,J＝11.8Hz,2H),1.80-1.70(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 6.87 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 2.8 Hz, 1 H), 6.53 (dd, J 1 = 8.5 Hz, J 2 = 2.6 Hz , 1H), 3.51 (s, 2H), 3.29 (d, J = 11.6 Hz, 2H), 2.87-2.23 (m, 14H), 1.89 (d, J = 11.8 Hz, 2H), 1.80-1.70 (m, 2H).
MS(ESI):m/z 309[M+H] +. MS(ESI): m/z 309[M+H] + .
步骤4. 4-(苯并[b]噻吩-3-基)-5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-氨基(LS3-102)的制备Step 4. 4-(Benzo[b]thiophen-3-yl)-5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -Yl)phenyl)pyrimidine-2-amino (LS3-102)
向15毫升封管中加入4-(苯并[b]噻吩-3-基)-2,5-二氯嘧啶(3,0.1g,0.32mmol)、3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(6,0.1g,0.29mmol)、0.3毫升2.5M HCl的乙醇溶液和3毫升乙二醇单甲醚，加热至120摄氏度反应过夜。待反应完全，旋干大部分溶剂后，以二氯甲烷/水萃取三次，合并有机层，有机层用饱和食盐水洗，再用无水硫酸钠干燥后旋干，经柱层析分离得固体88mg，收率55％。To a 15 ml sealed tube, add 4-(benzo[b]thiophen-3-yl)-2,5-dichloropyrimidine (3,0.1 g, 0.32 mmol), 3-chloro-4-(4-(4 -Methylpiperazin-1-yl)piperidin-1-yl)aniline (6,0.1g,0.29mmol), 0.3 ml of 2.5M ethanol solution of HCl and 3 ml of ethylene glycol monomethyl ether, heated to 120 degrees Celsius React overnight. After the reaction was completed, after spin-drying most of the solvent, it was extracted three times with dichloromethane/water. The organic layers were combined. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then spin-dried, and 88 mg of solid was separated by column chromatography. , The yield is 55%.
1H NMR(400MHz,CDCl 3)δ8.50(s,1H),8.23-8.15(m,1H),8.12(s,1H),7.96-7.89(m,1H),7.75(d,J＝2.4Hz,1H),7.47-7.37(m,3H),7.11(s,1H),6.98(d,J＝8.8Hz,1H),3.39(d,J＝12.0Hz,2H),2.71-2.34(m,10H),2.30(s,3H),2.03-1.98(m,1H),1.92(d,J＝12.0Hz,2H),1.81-1.71(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.23-8.15 (m, 1H), 8.12 (s, 1H), 7.96-7.89 (m, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.47-7.37(m, 3H), 7.11(s, 1H), 6.98(d, J=8.8Hz, 1H), 3.39(d, J=12.0Hz, 2H), 2.71-2.34(m , 10H), 2.30 (s, 3H), 2.03-1.98 (m, 1H), 1.92 (d, J = 12.0Hz, 2H), 1.81-1.71 (m, 2H).
MS(ESI):m/z 553[M+H] +. MS(ESI): m/z 553[M+H] + .
实施例2Example 2
4-(苯并呋喃-3-基)-5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-氨基(LS3-108)4-(benzofuran-3-yl)-5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Pyrimidine-2-amino (LS3-108)
Figure PCTCN2019124686-appb-000028
Figure PCTCN2019124686-appb-000028
合成方法参照实施例1，收率51％。For the synthesis method, refer to Example 1. The yield is 51%.
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.43(s,1H),8.34(d,J＝7.5Hz,1H),7.80(d,J＝2.5Hz,1H),7.57(d,J＝8.1Hz,1H),7.41-7.39(m,1H),7.37-7.30(m,2H),7.10(s,1H),7.03(d,J＝8.7Hz,1H),3.43(d,J＝11.8Hz,2H),2.74-2.30(m,14H),1.94(d,J＝11.4Hz,2H),1.84-1.74(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.43 (s, 1H), 8.34 (d, J=7.5 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.57 (d, J=8.1Hz, 1H), 7.41-7.39(m, 1H), 7.37-7.30(m, 2H), 7.10(s, 1H), 7.03(d, J=8.7Hz, 1H), 3.43( d, J = 11.8 Hz, 2H), 2.74-2.30 (m, 14H), 1.94 (d, J = 11.4 Hz, 2H), 1.84-1.74 (m, 2H).
MS(ESI):m/z 537[M+H] +. MS(ESI): m/z 537[M+H] + .
实施例3Example 3
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-胺(HCD1)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl ) Pyrimidine-2-amine (HCD1)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000029
Figure PCTCN2019124686-appb-000029
步骤1.3-(2,5-二氯嘧啶-4-基)-1H-吲哚(7)的制备Step 1.3 Preparation of (2,5-dichloropyrimidin-4-yl)-1H-indole (7)
将吲哚(7.19g,0.061mol)溶解于25mL 1,2-二氯乙烷中，冰浴冷却至0℃，逐滴滴加30.7mL 3mol/L甲基碘化镁乙醚溶液。然后将2,4,5-三氯嘧啶(11.25g,0.061mol)溶解于20mL 1,2-二氯乙烷中，滴入反应体系中，滴加完成后，冰浴下反应30分钟。撤去冰浴，常温下继续反应30分钟。恢复冰浴，缓慢加入50毫升水淬灭，所得固体以质量分数为20％的冰醋酸洗涤，过滤，得标题化合物12.02g，收率74％。Dissolve indole (7.19g, 0.061mol) in 25mL of 1,2-dichloroethane, cool to 0°C in an ice bath, and add 30.7mL of 3mol/L methyl magnesium iodide ether solution dropwise. Then, 2,4,5-trichloropyrimidine (11.25g, 0.061mol) was dissolved in 20mL1,2-dichloroethane, and dropped into the reaction system. After the addition was completed, the reaction was performed under ice bath for 30 minutes. The ice bath was removed, and the reaction was continued at room temperature for 30 minutes. The ice bath was restored, and 50 ml of water was slowly added to quench. The resulting solid was washed with glacial acetic acid with a mass fraction of 20%, and filtered to obtain 12.02 g of the title compound in 74% yield.
1H NMR(400MHz,DMSO-d 6)δ12.27(s,1H),8.75(s,1H),8.74(s,1H),8.59-8.49(m,1H),7.60-7.53(m,1H),7.28(tt,J 1＝7.2Hz,J 2＝5.4Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.27 (s, 1H), 8.75 (s, 1H), 8.74 (s, 1H), 8.59-8.49 (m, 1H), 7.60-7.53 (m, 1H ), 7.28 (tt, J 1 = 7.2 Hz, J 2 = 5.4 Hz, 2H).
MS(ESI):m/z 264[M+H] +. MS(ESI): m/z 264[M+H] + .
步骤2.5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-胺(HCD1)的制备Step 2.5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indole-3- Preparation of Pyrimidine-2-amine (HCD1)
3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(6,1g,3mmol)、3-(2,5-二氯嘧啶-4-基)-1H-吲哚(7,0.85g,3mmol)和对甲苯磺酸一水合物(1.23g，6mmol)溶解于10mL 仲丁醇中，加热至100℃，过夜反应。冷却至室温后，倒入50mL水中，以50mL乙酸乙酯萃取三次。合并有机相，有机相干燥后浓缩，残余物以硅胶柱层析法纯化(二氯甲烷：甲醇＝15：1洗脱)。得标题化合物0.21g，收率12％。3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (6,1g,3mmol), 3-(2,5-dichloropyrimidine-4- Group)-1H-indole (7,0.85g, 3mmol) and p-toluenesulfonic acid monohydrate (1.23g, 6mmol) were dissolved in 10mL sec-butanol, heated to 100 ℃, overnight reaction. After cooling to room temperature, it was poured into 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15:1 elution). 0.21 g of the title compound was obtained with a yield of 12%.
1H NMR(400MHz,DMSO-d 6)δ11.94(s,1H),9.65(s,1H),8.57(d,J＝8.0Hz,1H),8.51(d,J＝2.2Hz,1H),8.47(s,1H),7.98(d,J＝2.5Hz,1H),7.57(dd,J＝8.8,2.5Hz,1H),7.51(dt,J＝8.2,0.9Hz,1H),7.24(ddd,J＝8.2,7.0,1.3Hz,1H),7.15(ddd,J＝8.1,7.0,1.1Hz,1H),7.10(d,J＝8.8Hz,1H),3.30-3.23(m,4H),3.17(d,J＝5.2Hz,1H),2.61(td,J＝11.7,2.2Hz,2H),2.39-2.24(m,1H),2.15(s,3H),1.85(d,J＝12.1Hz,2H),1.58(tt,J＝11.8,6.0Hz,2H),1.24(d,J＝3.0Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 9.65 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H) , 8.47 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.57 (dd, J = 8.8, 2.5 Hz, 1H), 7.51 (dt, J = 8.2, 0.9 Hz, 1H), 7.24 ( ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.15 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 3.30-3.23 (m, 4H) , 3.17 (d, J = 5.2 Hz, 1H), 2.61 (td, J = 11.7, 2.2 Hz, 2H), 2.39-2.24 (m, 1H), 2.15 (s, 3H), 1.85 (d, J = 12.1 Hz, 2H), 1.58 (tt, J = 11.8, 6.0 Hz, 2H), 1.24 (d, J = 3.0 Hz, 2H).
MS(ESI):m/z 536[M+H] +. MS(ESI): m/z 536[M+H] + .
实施例4Example 4
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(HCD2)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-methyl-1H-ind Indole-3-yl)pyrimidin-2-amine (HCD2)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000030
Figure PCTCN2019124686-appb-000030
步骤1. 3-(2,5-二氯嘧啶-4-基)-1-甲基-1H-吲哚(8)的制备Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (8)
将氢化钠(0.22g,9mmol)加入到冰浴下的3-(2,5-二氯嘧啶-4-基)-1H-吲哚(7,2g，8mmol)的四氢呋喃(40mL)溶液中，然后滴入碘甲烷(1.4mL,24mmol)，撤去冰浴，常温下反应90分钟。反应液浓缩，所得固体依次用水、乙酸乙酯洗涤，干燥，即得标题化合物1.9g，收率90％。Sodium hydride (0.22g, 9mmol) was added to a solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (7,2g, 8mmol) in tetrahydrofuran (40mL) under ice bath, Then, methyl iodide (1.4 mL, 24 mmol) was added dropwise, the ice bath was removed, and the reaction was performed at room temperature for 90 minutes. The reaction solution was concentrated, and the resulting solid was washed successively with water and ethyl acetate and dried to obtain 1.9 g of the title compound in 90% yield.
1H NMR(400MHz,DMSO-d 6)δ8.80(s,1H),8.74(s,1H),8.59-8.52(m,1H),7.66-7.59(m,1H),7.34(dddd,J＝17.8,8.4,7.2,1.3Hz,2H),3.96(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.74 (s, 1H), 8.59-8.52 (m, 1H), 7.66-7.59 (m, 1H), 7.34 (dddd, J = 17.8, 8.4, 7.2, 1.3 Hz, 2H), 3.96 (s, 3H).
MS(ESI):m/z 278[M+H] +. MS(ESI): m/z 278[M+H] + .
步骤2. 5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(HCD2)的制备Step 2. 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-methyl- Preparation of 1H-Indol-3-yl)pyrimidine-2-amine (HCD2)
合成方法参照实施例3，收率8％。The synthesis method refers to Example 3, and the yield is 8%.
1H NMR(400MHz,CDCl 3)δ8.55(dt,J＝7.9,1.1Hz,1H),8.35(s,1H),8.29(s,1H),7.82(d,J＝2.6Hz,1H),7.41(dq,J＝8.4,1.3,0.9Hz,2H),7.35(ddd,J＝8.2,6.9,1.3Hz,1H),7.29–7.25(m,1H),7.08(s,1H),7.04(d,J＝8.7Hz,1H),3.92(s,3H),3.45(d,J＝11.5Hz,2H),2.67(td,J＝ 13.8,11.8,3.6Hz,7H),2.34(s,3H),2.07(s,1H),1.96(d,J＝12.3Hz,2H),1.29(td,J＝7.6,7.1,3.9Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (dt, J = 7.9, 1.1 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 7.82 (d, J = 2.6 Hz, 1H) , 7.41 (dq, J = 8.4, 1.3, 0.9 Hz, 2H), 7.35 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.29–7.25 (m, 1H), 7.08 (s, 1H), 7.04 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.45 (d, J = 11.5 Hz, 2H), 2.67 (td, J = 13.8, 11.8, 3.6 Hz, 7H), 2.34 (s, 3H), 2.07 (s, 1H), 1.96 (d, J = 12.3 Hz, 2H), 1.29 (td, J = 7.6, 7.1, 3.9 Hz, 6H).
MS(ESI):m/z 550[M+H] +. MS(ESI): m/z 550[M+H] + .
实施例5Example 5
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(萘-2-基)嘧啶-2-胺(HCD3)合成路线如下：5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(naphthalen-2-yl)pyrimidine- The synthetic route of 2-amine (HCD3) is as follows:
Figure PCTCN2019124686-appb-000031
Figure PCTCN2019124686-appb-000031
步骤1. 2,5-二氯-4-(萘-2-基)嘧啶(10)的制备Step 1. Preparation of 2,5-dichloro-4-(naphthalen-2-yl)pyrimidine (10)
4,4,5,5-四甲基-2-(萘-2-基)-1,3,2-二氧杂硼烷(1g，4mmol)、2,4,5-三氯嘧啶(1.44g,8mmol)、碳酸钾(1.36g,10mmol)及四三苯基膦钯(0.23g,0.2mmol)加入到一个干燥的双口瓶中，将瓶内空气置换为氩气三次，用注射器向其中加入20mL二氧六环以及10mL水，65℃下反应3小时。反应冷却至室温后，向体系中加入30mL水淬灭，以30mL乙酸乙酯萃取，有机相干燥后浓缩，残余物以硅胶柱层析法分离(石油醚洗脱)，得标题化合物1.07g，收率49％。4,4,5,5-tetramethyl-2-(naphthalen-2-yl)-1,3,2-dioxaborolane (1g, 4mmol), 2,4,5-trichloropyrimidine (1.44 g, 8mmol), potassium carbonate (1.36g, 10mmol) and tetratriphenylphosphine palladium (0.23g, 0.2mmol) were added to a dry two-necked bottle, the bottle of air was replaced with argon three times, using a syringe to 20mL of dioxane and 10mL of water were added and reacted at 65°C for 3 hours. After the reaction was cooled to room temperature, 30 mL of water was added to the system to quench, extracted with 30 mL of ethyl acetate, the organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (eluted with petroleum ether) to obtain the title compound 1.07 g, The yield was 49%.
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.49(d,J＝1.1Hz,1H),7.99(dd,J＝5.2,1.5Hz,3H),7.93(ddd,J＝7.5,1.8,0.8Hz,1H),7.66-7.55(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.49 (d, J=1.1 Hz, 1H), 7.99 (dd, J=5.2, 1.5 Hz, 3H), 7.93 (ddd, J= 7.5, 1.8, 0.8Hz, 1H), 7.66-7.55 (m, 2H).
MS(ESI):m/z 274[M+H] +. MS(ESI): m/z 274[M+H] + .
步骤2.5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(萘-2-基)嘧啶-2-胺(HCD3)的制备Step 2.5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(naphthalen-2-yl)pyrimidine Preparation of 2-Amine (HCD3)
合成方法参照实施例3，收率5％。The synthesis method refers to Example 3, and the yield is 5%.
1H NMR(400MHz,CDCl 3)δ8.49(s,1H),8.44(q,J＝1.1Hz,1H),8.01-7.94(m,3H),7.96-7.88(m,1H),7.86(d,J＝2.6Hz,1H),7.65–7.53(m,2H),7.42(dd,J＝8.7,2.6Hz,1H),7.32(s,1H),7.00(d,J＝8.7Hz,1H),3.47–3.36(m,2H),3.18(s,2H),2.90(d,J＝35.0Hz,6H),2.66(td,J＝11.7,10.9,3.7Hz,5H),1.98(d,J＝12.1Hz,3H),1.83(d,J＝12.0Hz,2H),1.33-1.23(m,3H),1.20(d,J＝6.2Hz,1H),0.99-0.87(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.44 (q, J=1.1 Hz, 1H), 8.01-7.94 (m, 3H), 7.96-7.88 (m, 1H), 7.86 ( d, J=2.6 Hz, 1H), 7.65–7.53 (m, 2H), 7.42 (dd, J=8.7, 2.6 Hz, 1H), 7.32 (s, 1H), 7.00 (d, J=8.7 Hz, 1H ), 3.47–3.36 (m, 2H), 3.18 (s, 2H), 2.90 (d, J = 35.0 Hz, 6H), 2.66 (td, J = 11.7, 10.9, 3.7 Hz, 5H), 1.98 (d, J = 12.1 Hz, 3H), 1.83 (d, J = 12.0 Hz, 2H), 1.33-1.23 (m, 3H), 1.20 (d, J = 6.2 Hz, 1H), 0.99-0.87 (m, 1H).
MS(ESI):m/z 547[M+H] +. MS(ESI): m/z 547[M+H] + .
实施例6Example 6
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(萘-1-基)嘧啶-2-胺(HCD4)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(naphthalene-1-yl)pyrimidine- 2-amine (HCD4)
Figure PCTCN2019124686-appb-000032
Figure PCTCN2019124686-appb-000032
合成方法参照化合物HCD3，收率6％。The synthesis method refers to compound HCD3, and the yield is 6%.
1H NMR(400MHz,CDCl 3)δ8.55(s,1H),8.01(dt,J＝7.9,1.2Hz,1H),7.98-7.94(m,1H),7.72-7.68(m,2H),7.61(dd,J＝7.9,7.1Hz,1H),7.59-7.50(m,3H),7.43(dd,J＝8.7,2.6Hz,1H),7.20(s,1H),7.00(d,J＝8.7Hz,1H),3.40(d,J＝11.4Hz,3H),2.70(s,5H),2.63(td,J＝11.8,2.1Hz,2H),2.55(s,4H),2.34(s,4H),1.94(d,J＝12.2Hz,2H),0.97-0.83(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (s, 1H), 8.01 (dt, J=7.9, 1.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.72-7.68 (m, 2H), 7.61 (dd, J = 7.9, 7.1 Hz, 1H), 7.59-7.50 (m, 3H), 7.43 (dd, J = 8.7, 2.6 Hz, 1H), 7.20 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 3.40 (d, J = 11.4Hz, 3H), 2.70 (s, 5H), 2.63 (td, J = 11.8, 2.1Hz, 2H), 2.55 (s, 4H), 2.34 (s, 4H), 1.94 (d, J = 12.2 Hz, 2H), 0.97-0.83 (m, 2H).
MS(ESI):m/z 547[M+H] +. MS(ESI): m/z 547[M+H] + .
实施例7Example 7
5-氯-N 2-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N 4-(萘-2-基)嘧啶-2,4-二胺(HCD5) 5-chloro-N 2 -(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(naphthalen-2-yl) Pyrimidine-2,4-diamine (HCD5)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000033
Figure PCTCN2019124686-appb-000033
步骤1. 2,5-二氯-N-(萘-2-基)嘧啶-4-胺(12)的制备Step 1. Preparation of 2,5-dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine (12)
向圆底烧瓶中加入2,4,5-三氯嘧啶(0.54g,3mmol)、2-萘胺(11,0.42g,3mmol)、碳酸钾(0.5g,4mmol)、四丁基溴化铵(0.1g,0.3mmol)及10mL DMF，65℃下反应15小时。反应液倒入100mL水中，过滤浑浊液，所得固体以硅胶柱层析法纯化(石油醚洗脱)，得目标化合物0.4g，收率49％。Add 2,4,5-trichloropyrimidine (0.54g, 3mmol), 2-naphthylamine (11,0.42g, 3mmol), potassium carbonate (0.5g, 4mmol), tetrabutylammonium bromide to the round bottom flask (0.1g, 0.3mmol) and 10mL DMF, react at 65℃ for 15 hours. The reaction solution was poured into 100 mL of water, and the turbid liquid was filtered. The obtained solid was purified by silica gel column chromatography (eluted with petroleum ether) to obtain the target compound 0.4 g, with a yield of 49%.
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),8.23(d,J＝2.2Hz,1H),7.90–7.80(m,3H),7.63(dd,J＝8.8,2.3Hz,1H),7.49(dddd,J＝21.4,8.2,6.9,1.4Hz,2H),7.42(s,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 7.90–7.80 (m, 3H), 7.63 (dd, J=8.8, 2.3 Hz, 1H), 7.49 (dddd, J = 21.4, 8.2, 6.9, 1.4 Hz, 2H), 7.42 (s, 1H).
MS(ESI):m/z 289[M+H] +. MS(ESI): m/z 289[M+H] + .
步骤2. 5-氯-N 2-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N 4-(萘-2-基)嘧啶-2,4-二胺(HCD5)的制备 Step 2. 5-chloro-N 2 -(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(naphthalene-2 -Yl)pyrimidine-2,4-diamine (HCD5)
合成方法参照实施例3，收率7％。The synthesis method refers to Example 3, and the yield is 7%.
1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),9.06(s,1H),8.25(s,1H),8.19(s,1H),7.99-7.86(m,2H),7.83-7.73(m,2H),7.72-7.66(m,1H),7.59-7.39(m,3H),6.85(d,J＝8.8Hz,1H),3.17(d,J＝11.1Hz,2H),2.42-2.23(m,4H),2.16(s,3H),1.88-1.77(m,2H),1.53(qd,J＝12.0,3.8Hz,2H),1.24(t,J＝7.2Hz,7H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (s, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.99-7.86 (m, 2H), 7.83-7.73 (m, 2H), 7.72-7.66 (m, 1H), 7.59-7.39 (m, 3H), 6.85 (d, J = 8.8Hz, 1H), 3.17 (d, J = 11.1Hz, 2H) , 2.42-2.23(m, 4H), 2.16(s, 3H), 1.88-1.77(m, 2H), 1.53(qd, J=12.0, 3.8Hz, 2H), 1.24(t, J=7.2Hz, 7H ).
MS(ESI):m/z 562[M+H] +. MS(ESI): m/z 562[M+H] + .
实施例8Example 8
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-1-基)嘧啶-2-胺(HCD6)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indol-1-yl ) Pyrimidine-2-amine (HCD6)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000034
Figure PCTCN2019124686-appb-000034
化合物13的合成方法参照实施例7步骤1，收率为17％。 1H NMR(400MHz,CDCl 3)δ8.70(dq,J＝8.4,0.9Hz,1H),8.64(s,1H),8.17(d,J＝3.7Hz,1H),7.64(ddd,J＝7.7,1.3,0.7Hz,1H),7.39(ddd,J＝8.4,7.2,1.4Hz,1H),7.29(ddd,J＝8.2,7.3,1.1Hz,1H),6.75(dd,J＝3.7,0.8Hz,1H).MS(ESI):m/z 263[M+H] +. For the synthesis method of compound 13, refer to Step 1 of Example 7, and the yield was 17%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (dq, J=8.4, 0.9 Hz, 1H), 8.64 (s, 1H), 8.17 (d, J=3.7 Hz, 1H), 7.64 (ddd, J= 7.7, 1.3, 0.7Hz, 1H), 7.39 (ddd, J=8.4, 7.2, 1.4Hz, 1H), 7.29 (ddd, J=8.2, 7.3, 1.1Hz, 1H), 6.75 (dd, J=3.7, 0.8Hz, 1H).MS(ESI): m/z 263[M+H] + .
化合物HCD6的合成方法参照实施例3，收率为13％。 1H NMR(400MHz,DMSO-d 6)δ9.47(s,1H),8.48(s,1H),8.35(d,J＝8.3Hz,1H),8.09(d,J＝3.6Hz,1H),7.74(d,J＝2.5Hz,1H),7.60(d,J＝7.5Hz,1H),7.52(dd,J＝8.7,2.5Hz,1H),7.25(d,J＝8.7Hz,1H),7.21-7.12(m,1H),7.09(ddd,J＝8.4,7.1,1.4Hz,1H),6.73(d,J＝3.6Hz,1H),2.78-2.65(m,2H),2.37-2.23(m,2H),1.63(d,J＝11.8Hz,2H),1.32(d,J＝15.2Hz,1H),1.25(d,J＝9.7Hz,9H),0.91-0.81(m,2H).MS(ESI):m/z 536[M+H] +. For the synthesis method of compound HCD6, refer to Example 3, and the yield was 13%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.48 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.09 (d, J=3.6 Hz, 1H) , 7.74 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.52 (dd, J = 8.7, 2.5 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H) , 7.21-7.12 (m, 1H), 7.09 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 2.78-2.65 (m, 2H), 2.37-2.23 (m, 2H), 1.63 (d, J = 11.8 Hz, 2H), 1.32 (d, J = 15.2 Hz, 1H), 1.25 (d, J = 9.7 Hz, 9H), 0.91-0.81 (m, 2H) .MS(ESI):m/z 536[M+H] + .
实施例9Example 9
4-(1H-苯并[d]咪唑-1-基)-5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD7)4-(1H-Benzo[d]imidazol-1-yl)-5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Group) phenyl) pyrimidine-2-amine (HCD7)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000035
Figure PCTCN2019124686-appb-000035
化合物14的合成方法参照实施例7，收率为90％。 1H NMR(400MHz,CDCl 3)δ8.82(s,1H),8.79(s,1H),8.07-8.03(m,1H),7.94-7.88(m,1H),7.50-7.46(m,2H).MS(ESI):m/z 264[M+H] +. For the synthesis method of compound 14, refer to Example 7, and the yield was 90%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 8.79 (s, 1H), 8.07-8.03 (m, 1H), 7.94-7.88 (m, 1H), 7.50-7.46 (m, 2H ).MS(ESI):m/z 264[M+H] + .
化合物HCD7的合成方法参照实施例3，收率为7％。 1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.85(s,1H),8.80(s,1H),7.89(d,J＝2.5Hz,1H),7.88-7.85(m,1H),7.82-7.79(m,1H),7.54(dd,J＝8.8,2.6Hz,1H),7.39(td,J＝7.4,6.2,4.1Hz,2H),7.10(d,J＝8.8Hz,1H),3.24(d,J ＝11.6Hz,2H),2.64-2.55(m,5H),2.46-2.22(m,4H),2.18(s,4H),2.08-1.97(m,1H),1.87-1.79(m,2H),1.56(dd,J＝11.9,3.6Hz,2H),0.86(t,J＝6.7Hz,1H).MS(ESI):m/z 537[M+H] +. The synthesis method of the compound HCD7 refers to Example 3, and the yield is 7%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 7.89 (d, J=2.5 Hz, 1H), 7.88-7.85 ( m, 1H), 7.82-7.79 (m, 1H), 7.54 (dd, J = 8.8, 2.6 Hz, 1H), 7.39 (td, J = 7.4, 6.2, 4.1 Hz, 2H), 7.10 (d, J = 8.8Hz, 1H), 3.24 (d, J = 11.6Hz, 2H), 2.64-2.55 (m, 5H), 2.46-2.22 (m, 4H), 2.18 (s, 4H), 2.08-1.97 (m, 1H ), 1.87-1.79 (m, 2H), 1.56 (dd, J = 11.9, 3.6 Hz, 2H), 0.86 (t, J = 6.7 Hz, 1H). MS (ESI): m/z 537 (M+H ] + .
实施例10Example 10
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-2-胺(HCD8)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-pyrrolo[2,3 -b]pyridin-3-yl)pyrimidin-2-amine (HCD8)
Figure PCTCN2019124686-appb-000036
Figure PCTCN2019124686-appb-000036
化合物的合成方法参照实施例3，收率为15％。The synthesis method of the compound refers to Example 3, and the yield is 15%.
1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.60(dd,J＝4.8,2.0Hz,2H),8.55(s,1H),8.18-8.10(m,2H),8.09(dd,J＝7.8,1.7Hz,1H),7.30(dd,J＝7.8,4.7Hz,1H),7.18(d,J＝8.8Hz,1H),6.76(d,J＝3.9Hz,1H),3.30(d,J＝11.4Hz,2H),2.71-2.59(m,2H),2.44-2.24(m,0H),2.17(d,J＝4.7Hz,3H),1.86(d,J＝12.2Hz,2H),1.58(d,J＝10.5Hz,2H),1.24(d,J＝6.2Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.60 (dd, J=4.8, 2.0 Hz, 2H), 8.55 (s, 1H), 8.18-8.10 (m, 2H), 8.09 (dd, J = 7.8, 1.7 Hz, 1H), 7.30 (dd, J = 7.8, 4.7 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 3.9 Hz, 1H) ), 3.30 (d, J = 11.4 Hz, 2H), 2.71-2.59 (m, 2H), 2.44-2.24 (m, 0H), 2.17 (d, J = 4.7 Hz, 3H), 1.86 (d, J = 12.2Hz, 2H), 1.58 (d, J = 10.5Hz, 2H), 1.24 (d, J = 6.2Hz, 1H).
MS(ESI):m/z 537[M+H] +. MS(ESI): m/z 537[M+H] + .
实施例11Example 11
5-氯-N-(2,5-二氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-氨基(LS 3-128)5-chloro-N-(2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indole- 3-yl)pyrimidine-2-amino (LS 3-128)
Figure PCTCN2019124686-appb-000037
Figure PCTCN2019124686-appb-000037
化合物的合成方法参照实施例3，收率为42％。The synthesis method of the compound refers to Example 3, and the yield is 42%.
1H NMR(400MHz,CDCl 3)δ8.52(s,1H),8.43(d,J＝8.4Hz,1H),8.37(s,1H),8.32(s,1H),7.41(d,J＝8.0Hz,1H),7.26(s,1H),7.24-7.16(m,2H),7.04(s,1H),3.35(d,J＝15.2Hz,2H),2.72-2.21(m,14H),1.91(d,J＝12.0Hz,2H),1.72(dt,J＝11.7,8.5Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (s, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.41 (d, J= 8.0Hz, 1H), 7.26(s, 1H), 7.24-7.16(m, 2H), 7.04(s, 1H), 3.35(d, J=15.2Hz, 2H), 2.72-2.21(m, 14H), 1.91 (d, J = 12.0 Hz, 2H), 1.72 (dt, J = 11.7, 8.5 Hz, 2H).
MS(ESI):m/z 570[M+H] +. MS(ESI): m/z 570[M+H] + .
实施例12Example 12
5-氯-N-(2-氯-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-氨基(LS 3-135)5-chloro-N-(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-methyl Yl-1H-indol-3-yl)pyrimidine-2-amino (LS 3-135)
Figure PCTCN2019124686-appb-000038
Figure PCTCN2019124686-appb-000038
化合物的合成方法参照实施例4，收率为33％。The synthesis method of the compound refers to Example 4, and the yield is 33%.
1H NMR(400MHz,CDCl 3)δ8.53(t,J＝8.0Hz,1H),8.34(s,1H),8.28(s,1H),8.24(s,1H),7.39(d,J＝8.4Hz,1H),7.35-7.29(m,2H),7.24-7.14(m,1H),7.04(s,1H),3.90(s,3H),3.16(d,J＝12.0Hz,2H),2.75-2.23(m,16H),2.04-1.92(m,3H),1.76-1.69(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (t, J=8.0 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.39 (d, J= 8.4Hz, 1H), 7.35-7.29(m, 2H), 7.24-7.14(m, 1H), 7.04(s, 1H), 3.90(s, 3H), 3.16(d, J=12.0Hz, 2H), 2.75-2.23 (m, 16H), 2.04-1.92 (m, 3H), 1.76-1.69 (m, 2H).
MS(ESI):m/z 564[M+H] +. MS(ESI): m/z 564[M+H] + .
实施例13Example 13
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(吡唑并[1,5-a]吡啶-3-基)嘧啶-2-胺(HCD9)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(pyrazolo[1,5- a)pyridin-3-yl)pyrimidin-2-amine (HCD9)
合成路线如下：The synthetic route is as follows:
Figure PCTCN2019124686-appb-000039
Figure PCTCN2019124686-appb-000039
步骤1.(Z)-4-(2-丁烯基)-2,5-二氯嘧啶(15)的制备Step 1. Preparation of (Z)-4-(2-butenyl)-2,5-dichloropyrimidine (15)
向一个干燥的100mL双颈瓶中，依次加入3.7g(20mmol)2,4,5-三氯嘧啶(1)，2.1g(20mmol)乙烯丁基醚，2.13g(20mmol)三乙胺以及20mL聚乙二醇。将瓶内空气置换为氩气，重复操作两次后，加入0.16g(0.6mmol)醋酸钯，再将瓶内气体置换为氩气。将混合物置于50摄氏度油浴下反应过夜。反应结束后，冷却至室温，将混合物倒入100mL水中，以40mL乙酸乙酯萃取，重复一次，有机相合并、干燥、浓缩后，以快速硅胶柱层析法分离(流动相为石油醚：乙酸乙酯100：0至95：5)。得标题化合物，无色液体，1.3g，收率26％。To a dry 100 mL double-necked flask, add 3.7 g (20 mmol) 2,4,5-trichloropyrimidine (1), 2.1 g (20 mmol) ethylene butyl ether, 2.13 g (20 mmol) triethylamine and 20 mL Polyethylene glycol. Replace the air in the bottle with argon. After repeating the operation twice, add 0.16 g (0.6 mmol) of palladium acetate, and then replace the gas in the bottle with argon. The mixture was placed in an oil bath at 50 degrees Celsius to react overnight. After the reaction was completed, it was cooled to room temperature, the mixture was poured into 100 mL of water, extracted with 40 mL of ethyl acetate, and repeated once. After the organic phases were combined, dried, and concentrated, they were separated by flash silica gel column chromatography (mobile phase: petroleum ether: acetic acid) Ethyl ester 100:0 to 95:5). The title compound was obtained as a colorless liquid, 1.3g, and the yield was 26%.
1H NMR(400MHz,CDCl 3)δ8.33(s,1H),8.08(d,J＝12.0Hz,1H),6.10(d,J＝12.0Hz,1H),4.04(t,J＝6.5Hz,2H),1.75(ddt,J＝8.9,7.8,6.4Hz,2H),1.53–1.41(m,2H),0.98(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 8.08 (d, J=12.0 Hz, 1H), 6.10 (d, J=12.0 Hz, 1H), 4.04 (t, J=6.5 Hz , 2H), 1.75 (ddt, J = 8.9, 7.8, 6.4Hz, 2H), 1.53-1.41 (m, 2H), 0.98 (t, J = 7.4Hz, 3H).
MS(ESI):m/z 247[M+H] +. MS(ESI): m/z 247[M+H] + .
步骤2. 3-(2,5-二氯嘧啶-4-基)吡唑并[1,5-a]吡啶(16)的制备Step 2. Preparation of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (16)
向一个干燥的100mL圆底烧瓶中，依次加入1.3g(5.2mmol)(Z)-4-(2-丁烯基)-2,5-二氯嘧啶(15)，1.2g(5.2mmol)碘化-1-氨基吡啶，2.0g(12.5mmol)碳酸钾以及50mL DMF，在110摄氏度下反应2小时。反应液倒入150mL水中，分别以50mL乙酸乙酯萃取两次，有机相合并，再分别以100mL饱和食盐水洗三次，干燥，浓缩，以快速硅胶柱层析法分离(流动相为石油醚：乙酸乙酯80：20)，得标题化合物，淡黄色固体，0.50g，收率35％。Into a dry 100mL round bottom flask, sequentially add 1.3g (5.2mmol) (Z)-4-(2-butenyl)-2,5-dichloropyrimidine (15), 1.2g (5.2mmol) iodine 1-aminopyridine, 2.0 g (12.5 mmol) of potassium carbonate and 50 mL of DMF were reacted at 110 degrees Celsius for 2 hours. The reaction solution was poured into 150 mL of water, extracted twice with 50 mL of ethyl acetate, the organic phases were combined, washed with 100 mL of saturated brine three times, dried, concentrated, and separated by flash silica gel column chromatography (mobile phase: petroleum ether: acetic acid) Ethyl ester 80:20) to give the title compound, a light yellow solid, 0.50g, yield 35%.
1H NMR(400MHz,CDCl 3)δ9.08(s,1H),8.77(dt,J＝9.0,1.2Hz,1H),8.63(dt,J＝6.9,1.1Hz,1H),8.53(s,1H),7.56(ddd,J＝9.0,6.9,1.2Hz,1H),7.10(td,J＝6.9,1.4Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.08 (s, 1H), 8.77 (dt, J=9.0, 1.2 Hz, 1H), 8.63 (dt, J=6.9, 1.1 Hz, 1H), 8.53 (s, 1H), 7.56 (ddd, J = 9.0, 6.9, 1.2 Hz, 1H), 7.10 (td, J = 6.9, 1.4 Hz, 1H).
MS(ESI):m/z 265[M+H] +. MS(ESI): m/z 265[M+H] + .
步骤3. 5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(吡唑并[1,5-a]吡啶-3-基)嘧啶-2-胺(HCD9)的制备Step 3. 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(pyrazolo[1 , 5-a]pyridin-3-yl)pyrimidin-2-amine (HCD9)
向一个干燥的50mL圆底烧瓶中，依次加入0.40g(1.5mmol)3-(2,5-二氯嘧啶-4-基)吡唑并[1,5-a]吡啶(16)、0.46g(1.5mmol)3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(6)、0.34g(2mmol)对甲苯磺酸一水合物以及10mL仲戊醇，混合物置于120摄氏度油浴下回流，约48小时后，TLC指示反应结束。冷却至室温后，将反应液倒入50mL水中，分别以20mL乙酸乙酯萃取两次，合并有机相、干燥浓缩后以快速硅胶柱层析法分离(流动相为甲醇：二氯甲烷＝0：100至7：93)，得标题化合物，淡黄色固体，50mg，收率6％。To a dry 50 mL round bottom flask, add 0.40 g (1.5 mmol) 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (16), 0.46 g (1.5mmol) 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (6), 0.34g (2mmol) p-toluenesulfonic acid monohydrate and 10 mL of sec-amyl alcohol, the mixture was placed under an oil bath at 120 degrees Celsius and refluxed. After about 48 hours, TLC indicated that the reaction was completed. After cooling to room temperature, the reaction solution was poured into 50 mL of water and extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried and concentrated, and separated by flash silica gel column chromatography (mobile phase: methanol: dichloromethane = 0: 100 to 7:93) to give the title compound, light yellow solid, 50 mg, yield 6%.
1H NMR(400MHz,CDCl 3)δ9.00(s,1H),8.59(dt,J＝6.9,1.1Hz,1H),8.54(dt,J＝8.9,1.2Hz,1H),8.38(s,1H),7.86(d,J＝2.6Hz,1H),7.42-7.35(m,1H),7.33-7.29(m,1H),7.08(s,1H),7.05(d,J＝8.6Hz,1H),6.99(td,J＝6.8,1.4Hz,1H),3.45(d,J＝11.5Hz,2H),2.75(s,5H),2.72-2.63(m,2H),2.38(s,3H),2.30-2.19(m,2H),2.04(t,J＝6.3Hz,2H),1.49-1.35(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, 1H), 8.59 (dt, J=6.9, 1.1 Hz, 1H), 8.54 (dt, J=8.9, 1.2 Hz, 1H), 8.38 (s, 1H), 7.86 (d, J = 2.6Hz, 1H), 7.42-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.08 (s, 1H), 7.05 (d, J = 8.6Hz, 1H ), 6.99 (td, J = 6.8, 1.4 Hz, 1H), 3.45 (d, J = 11.5 Hz, 2H), 2.75 (s, 5H), 2.72-2.63 (m, 2H), 2.38 (s, 3H) , 2.30-2.19 (m, 2H), 2.04 (t, J = 6.3 Hz, 2H), 1.49-1.35 (m, 4H).
MS(ESI):m/z 537[M+H] +. MS(ESI): m/z 537[M+H] + .
实施例14Example 14
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲唑-1-基)嘧啶-2-胺(HCD10)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indazol-1-yl ) Pyrimidine-2-amine (HCD10)
Figure PCTCN2019124686-appb-000040
Figure PCTCN2019124686-appb-000040
合成方法参照实施例7，收率20％。For the synthesis method, refer to Example 7. The yield is 20%.
1H NMR(400MHz,CDCl 3)δ8.55(s,1H),8.33(s,1H),8.20(d,J＝8.5Hz,1H),7.83(d,J＝ 8.0Hz,1H),7.79(d,J＝2.6Hz,1H),7.52(ddd,J＝8.4,7.0,1.2Hz,1H),7.39-7.32(m,2H),7.18(s,1H),7.03(d,J＝8.7Hz,1H),3.44(d,J＝11.4Hz,2H),2.87-2.57(m,7H),2.38(s,4H),1.97(d,J＝11.4Hz,3H),1.81(tt,J＝12.0,6.1Hz,3H),1.29(d,J＝12.6Hz,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.52 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 7.39-7.32 (m, 2H), 7.18 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.44 (d, J = 11.4 Hz, 2H), 2.87-2.57 (m, 7H), 2.38 (s, 4H), 1.97 (d, J = 11.4 Hz, 3H), 1.81 (tt, J = 12.0, 6.1 Hz, 3H), 1.29 (d, J = 12.6 Hz, 2H).
MS(ESI):m/z 537[M+H] +. MS(ESI): m/z 537[M+H] + .
实施例15Example 15
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(HCD11)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(imidazo[1,2-a ]Pyridin-3-yl)pyrimidin-2-amine (HCD11)
Figure PCTCN2019124686-appb-000041
Figure PCTCN2019124686-appb-000041
步骤1. 3-(2,5-二氯嘧啶-4-基)咪唑并[1,2-a]吡啶(17)的制备Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine(17)
将0.7g(2.8mmol)(Z)-4-(2-丁烯基)-2,5-二氯嘧啶(15)溶解于由2mL水以及6mL二氧六环配成的溶液中，向其中加入0.61g(3.3mmol)溴代丁二酰亚胺以及0.27g(2.8mmol)吡啶-2-胺，85摄氏度下反应5小时。反应液冷却至室温后，加入50mL水并分别用20mL乙酸乙酯萃取两次，有机相干燥，浓缩，以快速硅胶柱层析法分离(流动相为石油醚：乙酸乙酯80：20)，得标题化合物，白色固体，0.45g，收率60％。Dissolve 0.7 g (2.8 mmol) (Z)-4-(2-butenyl)-2,5-dichloropyrimidine (15) in a solution made up of 2 mL of water and 6 mL of dioxane. 0.61 g (3.3 mmol) bromosuccinimide and 0.27 g (2.8 mmol) pyridin-2-amine were added and reacted at 85 degrees Celsius for 5 hours. After the reaction solution was cooled to room temperature, 50 mL of water was added and extracted twice with 20 mL of ethyl acetate, the organic phase was dried, concentrated, and separated by flash silica gel column chromatography (mobile phase is petroleum ether: ethyl acetate 80:20), The title compound was obtained as a white solid, 0.45g, and the yield was 60%.
1H NMR(400MHz,CDCl 3)δ9.89(dt,J＝7.0,1.2Hz,1H),9.03(s,1H),8.63(s,1H),7.85(dt,J＝8.9,1.2Hz,1H),7.55(ddd,J＝9.0,6.8,1.3Hz,1H),7.17(td,J＝7.0,1.4Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (dt, J=7.0, 1.2 Hz, 1H), 9.03 (s, 1H), 8.63 (s, 1H), 7.85 (dt, J=8.9, 1.2 Hz, 1H), 7.55 (ddd, J=9.0, 6.8, 1.3Hz, 1H), 7.17 (td, J=7.0, 1.4Hz, 1H).
MS(ESI):m/z 265[M+H] +. MS(ESI): m/z 265[M+H] + .
步骤2. 5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(HCD11)的制备Step 2. 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(imidazo[1, Preparation of 2-a]pyridin-3-yl)pyrimidin-2-amine (HCD11)
化合物的合成方法参照实施例13步骤3，收率为7％。The method for synthesizing the compound refers to Example 3, Step 3, and the yield is 7%.
1H NMR(400MHz,CDCl 3)δ9.64(dt,J＝7.1,1.2Hz,1H),8.86(s,1H),8.45(s,1H),7.86-7.74(m,2H),7.46-7.40(m,1H),7.32(dd,J＝8.7,2.6Hz,1H),7.15(s,1H),7.05(d,J＝8.7Hz,1H),6.93(td,J＝6.9,1.3Hz,1H),3.46(d,J＝11.3Hz,2H),2.86(s,4H),2.69(t,J＝11.5Hz,2H),2.48(s,3H),2.00(d,J＝12.3Hz,3H),1.35(d,J＝34.2Hz,3H),0.97-0.70(m,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (dt, J=7.1, 1.2 Hz, 1H), 8.86 (s, 1H), 8.45 (s, 1H), 7.86-7.74 (m, 2H), 7.46 7.40 (m, 1H), 7.32 (dd, J = 8.7, 2.6 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.93 (td, J = 6.9, 1.3 Hz , 1H), 3.46 (d, J = 11.3 Hz, 2H), 2.86 (s, 4H), 2.69 (t, J = 11.5 Hz, 2H), 2.48 (s, 3H), 2.00 (d, J = 12.3 Hz , 3H), 1.35 (d, J = 34.2Hz, 3H), 0.97-0.70 (m, 3H).
MS(ESI):m/z 537[M+H] +. MS(ESI): m/z 537[M+H] + .
实施例16Example 16
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-胺(HCD12)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-isopropyl-1H- Indole-3-yl)pyrimidine-2-amine (HCD12)
Figure PCTCN2019124686-appb-000042
Figure PCTCN2019124686-appb-000042
将0.1g(0.18mmol)5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-胺(HCD1)溶解于10mL DMF中，冰浴冷却至0℃，加入0.02g(0.56mmol)60％NaH，撤去冰浴，室温下反应10分钟，滴入0.062g(0.36mmol)2-碘代丙烷，继续反应30分钟。将反应液倒入水中，所得固体过滤，溶解于二氯甲烷中，以快速硅胶柱层析法分离(流动相甲醇：二氯甲烷0:100至3:97)纯化得目标化合物，白色固体，43mg，收率40％。0.1 g (0.18 mmol) 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H -Indol-3-yl)pyrimidin-2-amine (HCD1) was dissolved in 10mL DMF, cooled to 0°C in an ice bath, added 0.02g (0.56mmol) 60% NaH, removed the ice bath, and reacted at room temperature for 10 minutes, 0.062 g (0.36 mmol) of 2-iodopropane was added dropwise, and the reaction was continued for 30 minutes. The reaction solution was poured into water, the resulting solid was filtered, dissolved in dichloromethane, and separated by flash silica gel column chromatography (mobile phase methanol: dichloromethane 0:100 to 3:97) to obtain the target compound, a white solid, 43mg, yield 40%.
1H NMR(400MHz,CDCl 3)δ8.55(dt,J＝7.8,1.1Hz,1H),8.42(s,1H),8.36(s,1H),7.84(d,J＝2.6Hz,1H),7.47(d,J＝8.2Hz,1H),7.42(dd,J＝8.7,2.6Hz,1H),7.33(ddd,J＝8.3,7.0,1.3Hz,1H),7.28-7.24(m,1H),7.04(d,J＝8.7Hz,1H),6.99(s,1H),4.78(p,J＝6.7Hz,1H),3.45(d,J＝11.4Hz,2H),2.75-2.64(m,5H),2.52(s,5H),2.33(s,3H),1.96(d,J＝12.3Hz,2H),1.82(tt,J＝13.0,6.6Hz,2H),1.65(s,3H),1.63(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (dt, J=7.8, 1.1 Hz, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.84 (d, J=2.6 Hz, 1H) , 7.47 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 8.7, 2.6 Hz, 1H), 7.33 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.28-7.24 (m, 1H) ), 7.04 (d, J = 8.7 Hz, 1H), 6.99 (s, 1H), 4.78 (p, J = 6.7 Hz, 1H), 3.45 (d, J = 11.4 Hz, 2H), 2.75-2.64 (m , 5H), 2.52 (s, 5H), 2.33 (s, 3H), 1.96 (d, J = 12.3 Hz, 2H), 1.82 (tt, J = 13.0, 6.6 Hz, 2H), 1.65 (s, 3H) ,1.63(s,3H).
MS(ESI):m/z 578[M+H] +. MS(ESI): m/z 578[M+H] + .
实施例17Example 17
N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)-5-甲基嘧啶-2-胺(HCD274)N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl)-5- Methylpyrimidine-2-amine (HCD274)
Figure PCTCN2019124686-appb-000043
Figure PCTCN2019124686-appb-000043
化合物的合成方法参照实施例3，原料以2,4-二氯-5-甲基嘧啶代替。The synthesis method of the compound refers to Example 3, and the raw material is replaced by 2,4-dichloro-5-methylpyrimidine.
1H NMR(400MHz,DMSO-d 6)δ11.71(d,J＝2.9Hz,1H),8.44–8.33(m,1H),8.19(s,1H),7.96(d,J＝3.0Hz,1H),7.61–7.41(m,1H),7.27–7.07(m,2H),6.87(d,J＝8.5Hz,1H),6.63(d,J＝2.6Hz,1H),6.47(dd,J＝8.5,2.6Hz,1H),5.01(s,1H),3.79(s,3H),3.10(d,J＝11.1Hz,2H),2.51(d,J＝1.9Hz,7H),2.33(s,4H),1.86(d,J＝12.0Hz,2H),1.72–1.49(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.71 (d, J=2.9 Hz, 1H), 8.44–8.33 (m, 1H), 8.19 (s, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.61–7.41(m, 1H), 7.27–7.07(m, 2H), 6.87(d, J=8.5Hz, 1H), 6.63(d, J=2.6Hz, 1H), 6.47(dd, J = 8.5, 2.6 Hz, 1H), 5.01 (s, 1H), 3.79 (s, 3H), 3.10 (d, J = 11.1 Hz, 2H), 2.51 (d, J = 1.9 Hz, 7H), 2.33 (s , 4H), 1.86 (d, J=12.0Hz, 2H), 1.72-1.49 (m, 2H).
MS(ESI):m/z 517[M+H] +. MS(ESI): m/z 517[M+H] + .
实施例18Example 18
N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)-5-三氟甲基嘧啶-2-胺(HCD239)N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl)-5- Trifluoromethylpyrimidine-2-amine (HCD239)
Figure PCTCN2019124686-appb-000044
Figure PCTCN2019124686-appb-000044
化合物的合成方法参照实施例3,原料以2,4-二氯-5-三氟嘧啶代替。For the synthesis method of the compound, refer to Example 3. The raw material was replaced with 2,4-dichloro-5-trifluoropyrimidine.
1H NMR(400MHz,DMSO-d 6)δ11.89(d,J＝3.0Hz,1H),10.11(s,1H),8.77(s,1H),8.30(s,1H),8.01(d,J＝2.5Hz,1H),7.89(d,J＝2.8Hz,1H),7.71–7.59(m,1H),7.51(d,J＝8.1Hz,1H),7.23(ddd,J＝8.2,7.0,1.2Hz,1H),7.14(t,J＝7.4Hz,1H),7.09(d,J＝8.8Hz,1H),3.29–3.18(m,2H),2.70–2.54(m,3H),2.30(dd,J＝18.8,8.1Hz,5H),2.15(s,3H),1.90–1.79(m,2H),1.56(qd,J＝11.9,3.7Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (d, J=3.0 Hz, 1H), 10.11 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.71–7.59 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.23 (ddd, J = 8.2, 7.0 , 1.2Hz, 1H), 7.14 (t, J = 7.4Hz, 1H), 7.09 (d, J = 8.8Hz, 1H), 3.29-3.18 (m, 2H), 2.70-2.54 (m, 3H), 2.30 (dd, J = 18.8, 8.1 Hz, 5H), 2.15 (s, 3H), 1.90-1.79 (m, 2H), 1.56 (qd, J = 11.9, 3.7 Hz, 2H).
MS(ESI):m/z 570[M+H] +. MS(ESI): m/z 570[M+H] + .
实施例19Example 19
N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-胺(HCD224)N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H-indol-3-yl)pyrimidine-2 -Amine (HCD224)
Figure PCTCN2019124686-appb-000045
Figure PCTCN2019124686-appb-000045
化合物的合成方法参照实施例3，原料以2,4-二氯嘧啶代替。The synthesis method of the compound refers to Example 3, and the raw material is replaced by 2,4-dichloropyrimidine.
1H NMR(400MHz,DMSO-d 6)δ11.83(d,J＝2.9Hz,1H),9.45(s,1H),8.61(d,J＝7.7Hz,1H),8.37–8.29(m,2H),8.13(d,J＝2.5Hz,1H),7.59(dd,J＝8.8,2.5Hz,1H),7.51–7.43(m,1H),7.29(d,J＝5.4Hz,1H),7.21(ddd,J＝8.1,7.1,1.5Hz,1H),7.16(ddd,J＝8.2,7.1,1.4Hz,1H),7.11(d,J＝8.8Hz,1H),3.66–3.55(m,1H),3.25(d,J＝11.2Hz,2H),2.60(td,J＝11.7,2.2Hz,2H),2.35–2.22(m,7H),2.14(s,3H),1.88–1.81(m,2H),1.78–1.72(m,1H),1.57(qd,J＝11.9,3.7Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.83 (d, J=2.9 Hz, 1H), 9.45 (s, 1H), 8.61 (d, J=7.7 Hz, 1H), 8.37–8.29 (m, 2H), 8.13 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.51-7.43 (m, 1H), 7.29 (d, J = 5.4 Hz, 1H), 7.21 (ddd, J = 8.1, 7.1, 1.5 Hz, 1H), 7.16 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 3.66-3.55 (m, 1H), 3.25 (d, J = 11.2 Hz, 2H), 2.60 (td, J = 11.7, 2.2 Hz, 2H), 2.35–2.22 (m, 7H), 2.14 (s, 3H), 1.88–1.81 (m , 2H), 1.78-1.72 (m, 1H), 1.57 (qd, J = 11.9, 3.7Hz, 2H).
MS(ESI):m/z 502[M+H] +. MS(ESI): m/z 502[M+H] + .
实施例20Example 20
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-乙基-1H-吲哚-3-基)嘧啶-2-胺(HCD229)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-ethyl-1H-ind Indole-3-yl)pyrimidin-2-amine (HCD229)
Figure PCTCN2019124686-appb-000046
Figure PCTCN2019124686-appb-000046
化合物的合成方法参照实施例12，原料以碘乙烷代替，收率24％。For the synthesis method of the compound, refer to Example 12. The raw material was replaced with ethyl iodide in a yield of 24%.
1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.61(d,J＝12.0Hz,2H),8.48(s,1H),7.99(d,J＝2.5Hz,1H),7.64–7.55(m,2H),7.29(ddd,J＝8.2,7.0,1.3Hz,1H),7.18(td,J＝7.4,1.0Hz,1H),7.10(d,J＝8.8Hz,1H),4.37(q,J＝7.2Hz,2H),3.28(d,J＝11.3Hz,2H),2.87(s,6H),2.69–2.56(m,2H),1.96–1.79(m,2H),1.63(d,J＝12.9Hz,2H),1.43(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.61 (d, J=12.0 Hz, 2H), 8.48 (s, 1H), 7.99 (d, J=2.5 Hz, 1H) , 7.64–7.55 (m, 2H), 7.29 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.18 (td, J = 7.4, 1.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H ), 4.37 (q, J = 7.2 Hz, 2H), 3.28 (d, J = 11.3 Hz, 2H), 2.87 (s, 6H), 2.69–2.56 (m, 2H), 1.96–1.79 (m, 2H) , 1.63 (d, J = 12.9 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).
MS(ESI):m/z 564[M+H] +. MS(ESI): m/z 564[M+H] + .
实施例21Example 21
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-环丙基-1H-吲哚-3-基)嘧啶-2-胺(HCD215)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-cyclopropyl-1H- Indole-3-yl)pyrimidine-2-amine (HCD215)
Figure PCTCN2019124686-appb-000047
Figure PCTCN2019124686-appb-000047
将0.2g(0.37mmol)5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1H-吲哚-3-基)嘧啶-2-胺(HCD1),0.067g(0.37mmol)醋酸铜，0.032g(0.37mmol)环丙基硼酸以及0.13g(1.12mmol)DMAP溶解于5ml甲苯中，将体系中气体置换为氩气后，加入0.1mL 2M NaHMDS的四氢呋喃溶液。加毕，将体系中气体置换为干燥的空气后，升温至95摄氏度过夜反应，然后补加0.016g环丙基硼酸，继续反应3小时，原料基本转化完全后，反应液加入到50mL水中，分别以30mL乙酸乙酯萃取两次，有机相干燥、浓缩后以快速硅胶柱层析分离(洗脱剂为2％甲醇的二氯甲烷溶液)，得标题化合物0.07g，白色固体，收率32％。0.2g (0.37mmol) 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1H -Indol-3-yl)pyrimidin-2-amine (HCD1), 0.067g (0.37mmol) copper acetate, 0.032g (0.37mmol) cyclopropylboronic acid and 0.13g (1.12mmol) DMAP dissolved in 5ml toluene, After replacing the gas in the system with argon, 0.1mL of 2M NaHMDS in tetrahydrofuran was added. After the addition is completed, after replacing the gas in the system with dry air, the temperature is raised to 95 degrees Celsius overnight to react, then 0.016g of cyclopropylboronic acid is added, and the reaction is continued for 3 hours. After the raw materials are basically converted, the reaction solution is added to 50mL of water, respectively It was extracted twice with 30 mL of ethyl acetate, the organic phase was dried, concentrated and separated by flash silica gel column chromatography (eluent is 2% methanol in dichloromethane) to obtain the title compound 0.07 g, white solid in 32% yield .
1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.55(d,J＝8.0Hz,1H),8.49(s,1H),8.39(s,1H),7.98(d,J＝2.5Hz,1H),7.69(d,J＝8.2Hz,1H),7.56(dd,J＝8.7,2.6Hz,1H),7.39–7.28(m,1H),7.21(t,J＝7.5Hz,1H),7.09(d,J＝8.8Hz,1H),3.61(tt,J＝7.1,3.8Hz,1H),3.25(d,J＝11.2Hz,2H),2.66–2.51(m,6H),2.43–2.19(m,5H),2.15(s,3H),1.91–1.80(m,2H),1.57(qd,J＝11.9,3.7Hz,2H),1.16(tt,J＝6.8,3.4Hz,2H),1.06(dd,J＝4.8,2.5Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.56 (dd, J=8.7, 2.6 Hz, 1H), 7.39–7.28 (m, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.61 (tt, J = 7.1, 3.8 Hz, 1H), 3.25 (d, J = 11.2 Hz, 2H), 2.66-2.51 (m, 6H ), 2.43-2.19 (m, 5H), 2.15 (s, 3H), 1.91-1.80 (m, 2H), 1.57 (qd, J = 11.9, 3.7 Hz, 2H), 1.16 (tt, J = 6.8, 3.4 Hz, 2H), 1.06 (dd, J=4.8, 2.5Hz, 2H).
13C NMR(101MHz,DMSO-d 6)δ158.33,157.99,157.82,144.14,137.67,136.70,133.88,128.16,127.19,123.66,123.32,122.03,121.30,121.11,119.38,115.88,111.21,110.52, 61.21,55.67(2C),51.73(2C),48.99(2C),46.24,28.82(2C),28.08,6.53(2C). 13 C NMR (101MHz, DMSO-d 6 ) δ158.33,157.99,157.82,144.14,137.67,136.70,133.88,128.16,127.19,123.66,123.32,122.03,121.30,121.11,119.38,115.88,111.21,110.52,61.21,55.67 (2C), 51.73 (2C), 48.99 (2C), 46.24, 28.82 (2C), 28.08, 6.53 (2C).
MS(ESI):m/z 576[M+H] +. MS(ESI): m/z 576[M+H] + .
实施例22Example 22
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD1D)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(ethylsulfonyl) -1H-indol-3-yl)pyrimidine-2-amine (HCD1D)
Figure PCTCN2019124686-appb-000048
Figure PCTCN2019124686-appb-000048
步骤1. 3-(2,5-二氯嘧啶-4-基)-1-(乙基磺基)-1H-吲哚(18)的制备Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indole (18)
将3-(2,5-二氯嘧啶-4-基)-1H-吲哚(7,0.50g,1.9mmol)溶解于5mL DMF中，冷却至0摄氏度后，缓慢加入(0.15g,3.8mmol)60％氢化钠，保持在该温度反应15分钟后，加入(0.2mL,2.8mmol)乙基磺酰氯，恢复室温反应3h后。反应液以50mL水淬灭，所得白色固体抽滤，水洗，然后分散在甲醇中搅拌、过滤，即得标题化合物0.15g,白色固体，产率23％。Dissolve 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (7,0.50g, 1.9mmol) in 5mL DMF, after cooling to 0 degrees Celsius, slowly add (0.15g, 3.8mmol ) 60% sodium hydride, keeping the temperature for 15 minutes, adding (0.2mL, 2.8mmol) ethylsulfonyl chloride, and returning to room temperature for 3h. The reaction solution was quenched with 50 mL of water, and the resulting white solid was filtered with suction, washed with water, then dispersed in methanol, stirred, and filtered to obtain the title compound 0.15 g, white solid, with a yield of 23%.
步骤2. 5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD1D)的制备Step 2. 5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(ethyl Preparation of sulfo)-1H-indol-3-yl)pyrimidine-2-amine (HCD1D)
化合物的合成方法参照实施例3，步骤2，收率17％。For the synthesis method of the compound, refer to Example 3, Step 2, and the yield was 17%.
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.65(s,1H),8.46(s,2H),7.99–7.90(m,2H),7.56(dd,J＝8.8,2.6Hz,1H),7.50(ddd,J＝8.5,7.2,1.3Hz,1H),7.43–7.37(m,1H),7.09(d,J＝8.8Hz,1H),3.81(q,J＝7.3Hz,2H),3.28–3.18(m,2H),2.70–2.51(m,6H),2.32(d,J＝17.9Hz,5H),2.16(s,3H),1.83(d,J＝10.8Hz,2H),1.56(qd,J＝12.0,3.7Hz,2H),1.14(t,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.65 (s, 1H), 8.46 (s, 2H), 7.99–7.90 (m, 2H), 7.56 (dd, J=8.8 , 2.6Hz, 1H), 7.50(ddd, J=8.5, 7.2, 1.3Hz, 1H), 7.43-7.37(m, 1H), 7.09(d, J=8.8Hz, 1H), 3.81(q, J= 7.3Hz, 2H), 3.28–3.18(m, 2H), 2.70–2.51(m, 6H), 2.32(d, J=17.9Hz, 5H), 2.16(s, 3H), 1.83(d, J=10.8 Hz, 2H), 1.56 (qd, J = 12.0, 3.7Hz, 2H), 1.14 (t, J = 7.3Hz, 3H).
13C NMR(101MHz,DMSO-d 6)δ158.76,158.41,144.44,136.31,134.75,130.91,130.10,128.36,128.16,125.90,124.39,123.77,121.45,121.18,119.51,117.13,115.84,113.33,61.19,55.59(2C),51.67(2C),48.98,48.91(2C),46.14,28.79(2C),8.30. 13 C NMR (101MHz, DMSO-d 6 ) δ158.76,158.41,144.44,136.31,134.75,130.91,130.10,128.36,128.16,125.90,124.39,123.77,121.45,121.18,119.51,117.13,115.84,113.33,61.19,55.59 (2C), 51.67 (2C), 48.98, 48.91 (2C), 46.14, 28.79 (2C), 8.30.
MS(ESI):m/z 628[M+H] +. MS(ESI): m/z 628[M+H] + .
实施例23Example 23
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(甲基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD1E)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(methylsulfonyl) -1H-indol-3-yl)pyrimidine-2-amine (HCD1E)
Figure PCTCN2019124686-appb-000049
Figure PCTCN2019124686-appb-000049
化合物的合成方法参照实施例22。Refer to Example 22 for the compound synthesis method.
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.66(s,1H),8.50(s,2H),8.00–7.93(m,2H),7.55(dd,J＝8.8,2.5Hz,1H),7.51(ddd,J＝8.4,7.2,1.3Hz,1H),7.40(t,J＝7.5Hz,1H),7.10(d,J＝8.8Hz,1H),3.65(s,3H),3.25(d,J＝11.5Hz,2H),2.68–2.51(m,6H),2.46–2.22(m,5H),2.15(s,3H),1.84(d,J＝12.0Hz,2H),1.57(qd,J＝11.9,3.7Hz,2H). 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.66 (s, 1H), 8.50 (s, 2H), 8.00–7.93 (m, 2H), 7.55 (dd, J=8.8, 2.5Hz, 1H), 7.51(ddd, J=8.4, 7.2, 1.3Hz, 1H), 7.40(t, J=7.5Hz, 1H), 7.10(d, J=8.8Hz, 1H), 3.65(s, 3H), 3.25 (d, J = 11.5 Hz, 2H), 2.68-2.51 (m, 6H), 2.46-2.22 (m, 5H), 2.15 (s, 3H), 1.84 (d, J = 12.0 Hz, 2H ), 1.57 (qd, J = 11.9, 3.7 Hz, 2H).
13C NMR(101MHz,DMSO-d 6)δ158.79,158.40,144.47,136.30(2C),134.42,130.48,128.42,128.17,125.84,124.35,123.85,121.47,121.19,119.54,116.97,115.83,113.27,61.20,55.67(2C),51.69(2C),48.98(2C),46.23,41.88,28.80(2C). 13 C NMR (101MHz, DMSO-d 6 ) δ158.79,158.40,144.47,136.30(2C),134.42,130.48,128.42,128.17,125.84,124.35,123.85,121.47,121.19,119.54,116.97,115.83,113.27,61.20, 55.67(2C), 51.69(2C), 48.98(2C), 46.23, 41.88, 28.80(2C).
MS(ESI):m/z 614[M+H] +. MS(ESI): m/z 614[M+H] + .
实施例24Example 24
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(环丙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD244)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(cyclopropylsulfonyl )-1H-indol-3-yl)pyrimidine-2-amine (HCD244)
Figure PCTCN2019124686-appb-000050
Figure PCTCN2019124686-appb-000050
化合物的合成方法参照实施例22。Refer to Example 22 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.66(s,1H),8.46(s,2H),8.05–7.88(m,2H),7.56(dd,J＝8.8,2.5Hz,1H),7.54–7.47(m,1H),7.40(t,J＝7.6Hz,1H),7.11(d,J＝8.8Hz,1H),3.26(d,J＝10.7Hz,2H),2.73–2.51(m,11H),2.31(s,3H),1.87(d,J＝12.0Hz,2H),1.66–1.48(m,2H),1.36(dt,J＝6.6,3.2Hz,2H),1.24(s,1H),1.18(tt,J＝7.9,3.4Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.66 (s, 1H), 8.46 (s, 2H), 8.05–7.88 (m, 2H), 7.56 (dd, J=8.8 , 2.5Hz, 1H), 7.54–7.47 (m, 1H), 7.40 (t, J = 7.6Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 3.26 (d, J = 10.7Hz, 2H ), 2.73–2.51 (m, 11H), 2.31 (s, 3H), 1.87 (d, J=12.0Hz, 2H), 1.66–1.48 (m, 2H), 1.36 (dt, J=6.6, 3.2Hz, 2H), 1.24 (s, 1H), 1.18 (tt, J=7.9, 3.4Hz, 2H).
13C NMR(101MHz,DMSO-d 6)δ158.76,158.40,144.36,136.36,134.70,130.61,128.45,128.16(2C),125.89,124.38,123.68,121.46,121.23,119.52,117.20,116.09,113.52,61.14,54.88(2C),51.56(2C),48.27(2C),45.29,31.75,28.64(2C),6.69(2C). 13 C NMR (101 MHz, DMSO-d 6 ) δ 158.76, 158.40, 144.36, 136.36, 134.70, 130.61, 128.45, 128.16 (2C), 125.89, 124.38, 123.68, 121.46, 121.23, 119.52, 117.20, 116.09, 113.52, 61.14, 54.88(2C), 51.56(2C), 48.27(2C), 45.29, 31.75, 28.64(2C), 6.69(2C).
MS(ESI):m/z 640[M+H] +. MS(ESI): m/z 640[M+H] + .
实施例25Example 25
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(异丙基磺基)-1H- 吲哚-3-基)嘧啶-2-胺(HCD248)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(isopropylsulfonyl )-1H-indol-3-yl)pyrimidine-2-amine (HCD248)
Figure PCTCN2019124686-appb-000051
Figure PCTCN2019124686-appb-000051
化合物的合成方法参照实施例22。Refer to Example 22 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.66(s,1H),8.43(d,J＝3.9Hz,2H),8.02–7.85(m,2H),7.56(dd,J＝8.8,2.5Hz,1H),7.50(ddd,J＝8.4,7.1,1.3Hz,1H),7.40(t,J＝7.6Hz,1H),7.10(d,J＝8.8Hz,1H),4.03–3.89(m,1H),3.25(d,J＝11.4Hz,2H),2.60(td,J＝11.8,2.2Hz,6H),2.30(dtd,J＝15.0,7.9,7.4,4.3Hz,5H),2.15(s,3H),1.87–1.76(m,2H),1.57(tt,J＝11.8,5.9Hz,2H),1.28(s,3H),1.26(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.91(s, 1H), 8.66(s, 1H), 8.43(d, J=3.9Hz, 2H), 8.02-7.85(m, 2H), 7.56( dd, J = 8.8, 2.5 Hz, 1H), 7.50 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H) ), 4.03-3.89 (m, 1H), 3.25 (d, J = 11.4 Hz, 2H), 2.60 (td, J = 11.8, 2.2 Hz, 6H), 2.30 (dtd, J = 15.0, 7.9, 7.4, 4.3 Hz, 5H), 2.15 (s, 3H), 1.87–1.76 (m, 2H), 1.57 (tt, J = 11.8, 5.9 Hz, 2H), 1.28 (s, 3H), 1.26 (s, 3H).
13C NMR(101MHz,DMSO-d 6)δ158.75,158.42,144.47(2C),136.30,135.17,131.18,128.24,128.15,125.93,124.39,123.67,121.46,121.19,119.51,117.23,115.91,113.56,61.20,56.35,55.68(2C),51.69(2C),48.99(2C),46.25,28.80(2C),16.32(2C). 13 C NMR (101 MHz, DMSO-d 6 ) δ 158.75, 158.42, 144.47 (2C), 136.30, 135.17, 131.18, 128.24, 128.15, 125.93, 124.39, 123.67, 121.46, 121.19, 119.51, 117.23, 115.91, 113.56, 61.20, 56.35, 55.68 (2C), 51.69 (2C), 48.99 (2C), 46.25, 28.80 (2C), 16.32 (2C).
MS(ESI):m/z 642[M+H] +. MS(ESI): m/z 642[M+H] + .
实施例26Example 26
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(丙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD247)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(propylsulfonyl) -1H-indol-3-yl)pyrimidine-2-amine (HCD247)
Figure PCTCN2019124686-appb-000052
Figure PCTCN2019124686-appb-000052
化合物的合成方法参照实施例22。Refer to Example 22 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.65(s,1H),8.47(d,J＝6.8Hz,2H),8.00–7.86(m,2H),7.56(dd,J＝8.8,2.5Hz,1H),7.50(ddd,J＝8.4,7.1,1.3Hz,1H),7.40(t,J＝7.6Hz,1H),7.10(d,J＝8.8Hz,1H),3.85–3.72(m,2H),3.24(d,J＝11.5Hz,2H),2.60(td,J＝11.8,2.3Hz,3H),2.49(s,3H),2.29(dddd,J＝19.5,15.9,7.8,4.2Hz,5H),2.14(s,3H),1.87–1.76(m,2H),1.67–1.49(m,4H),0.89(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.65 (s, 1H), 8.47 (d, J = 6.8 Hz, 2H), 8.00–7.86 (m, 2H), 7.56 ( dd, J = 8.8, 2.5 Hz, 1H), 7.50 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H) ), 3.85-3.72 (m, 2H), 3.24 (d, J = 11.5 Hz, 2H), 2.60 (td, J = 11.8, 2.3 Hz, 3H), 2.49 (s, 3H), 2.29 (dddd, J = 19.5, 15.9, 7.8, 4.2 Hz, 5H), 2.14 (s, 3H), 1.87–1.76 (m, 2H), 1.67–1.49 (m, 4H), 0.89 (t, J=7.4 Hz, 3H).
13C NMR(101MHz,DMSO-d 6)δ158.75,158.41,156.53,144.47,136.30,134.70,130.71,128.35,128.16,125.90,124.38,123.79,121.47,121.17,119.52,117.10,115.90,113.33,61.20,55.67(2C),55.48,51.69(2C),48.99(2C),46.25,28.80(2C),17.20,12.53. 13 C NMR (101MHz, DMSO-d 6 ) δ158.75,158.41,156.53,144.47,136.30,134.70,130.71,128.35,128.16,125.90,124.38,123.79,121.47,121.17,119.52,117.10,115.90,113.33,61.20,55.67 (2C), 55.48, 51.69 (2C), 48.99 (2C), 46.25, 28.80 (2C), 17.20, 12.53.
MS(ESI):m/z 642[M+H] +. MS(ESI): m/z 642[M+H] + .
实施例27Example 27
5-氯-N-(3-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(环己基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD260)5-chloro-N-(3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(cyclohexylsulfo) -1H-indol-3-yl)pyrimidine-2-amine (HCD260)
Figure PCTCN2019124686-appb-000053
Figure PCTCN2019124686-appb-000053
化合物的合成方法参照实施例22。Refer to Example 22 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.65(s,1H),8.44(d,J＝19.9Hz,2H),8.05–7.91(m,2H),7.56(dd,J＝8.7,2.6Hz,1H),7.53–7.45(m,1H),7.40(t,J＝7.6Hz,1H),7.10(d,J＝8.8Hz,1H),3.81(tt,J＝12.0,3.5Hz,1H),3.25(d,J＝11.8Hz,2H),2.60(td,J＝11.8,2.2Hz,6H),2.44–2.21(m,5H),2.16(s,3H),1.86(td,J＝13.9,13.2,7.0Hz,4H),1.74(dt,J＝13.5,3.3Hz,2H),1.57(qd,J＝12.0,5.3Hz,4H),1.49–1.40(m,2H),1.27–1.21(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.65 (s, 1H), 8.44 (d, J = 19.9 Hz, 2H), 8.05–7.91 (m, 2H), 7.56 ( dd, J=8.7, 2.6Hz, 1H), 7.53–7.45(m, 1H), 7.40(t, J=7.6Hz, 1H), 7.10(d, J=8.8Hz, 1H), 3.81(tt, J = 12.0, 3.5Hz, 1H), 3.25 (d, J = 11.8Hz, 2H), 2.60 (td, J = 11.8, 2.2Hz, 6H), 2.44–2.21 (m, 5H), 2.16 (s, 3H) , 1.86 (td, J = 13.9, 13.2, 7.0 Hz, 4H), 1.74 (dt, J = 13.5, 3.3 Hz, 2H), 1.57 (qd, J = 12.0, 5.3 Hz, 4H), 1.49-1.40 (m , 2H), 1.27–1.21 (m, 2H).
13C NMR(101MHz,DMSO-d 6)δ158.75,158.42,144.48(2C),136.29,135.20,131.13,128.18,128.15,125.89,124.36,123.70,121.50,121.19,119.55,117.18,115.83,113.61,63.17,61.19,55.63(2C),51.68(2C),48.95(2C),46.18,28.79(2C),26.81,26.21,24.76,24.38(2C). 13 C NMR (101 MHz, DMSO-d 6 ) δ 158.75, 158.42, 144.48 (2C), 136.29, 135.20, 131.13, 128.18, 128.15, 125.89, 124.36, 123.70, 121.50, 121.19, 119.55, 117.18, 115.83, 113.61, 63.17, 61.19, 55.63 (2C), 51.68 (2C), 48.95 (2C), 46.18, 28.79 (2C), 26.81,26.21,24.76, 24.38 (2C).
MS(ESI):m/z 682[M+H] +. MS(ESI): m/z 682[M+H] + .
实施例28Example 28
5-氯-N-(2,5-二氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2791)5-chloro-N-(2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(ethyl Sulfo)-1H-indol-3-yl)pyrimidine-2-amine (HCD2791)
Figure PCTCN2019124686-appb-000054
Figure PCTCN2019124686-appb-000054
步骤1. 2,5-二氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(19)的制备Step 1. Preparation of 2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (19)
化合物的合成方法参照实施例1,步骤2。For the method of compound synthesis, refer to Example 1 and Step 2.
1H NMR(400MHz,DMSO-d 6)δ6.98(s,1H),6.86(s,1H),5.28(s,2H),3.15–3.01(m,2H),2.59–2.51(m,6H),2.43–2.17(m,5H),2.14(s,3H),1.84–1.74(m,2H),1.57–1.45(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.98 (s, 1H), 6.86 (s, 1H), 5.28 (s, 2H), 3.15–3.01 (m, 2H), 2.59–2.51 (m, 6H ), 2.43–2.17(m, 5H), 2.14(s, 3H), 1.84–1.74(m, 2H), 1.57–1.45(m, 2H).
步骤2. 5-氯-N-(2,5-二氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2791)的制备Step 2. 5-chloro-N-(2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1- Preparation of (ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD2791)
化合物的合成方法参照实施例3,步骤2，收率22％。For the compound synthesis method, refer to Example 3, Step 2, and the yield was 22%.
1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.50(d,J＝11.0Hz,2H),8.44–8.38(m,1H),8.07–7.94(m,1H),7.51(s,1H),7.49–7.40(m,2H),7.10(s,1H),3.45(q,J＝7.3Hz,4H),2.83(s,5H),2.66(td,J＝11.7,2.1Hz,6H),2.45(s,3H),2.00(d,J＝12.1Hz,2H),1.80(tt,J＝12.1,5.9Hz,2H),1.33(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.50 (d, J=11.0 Hz, 2H), 8.44–8.38 (m, 1H), 8.07–7.94 (m, 1H), 7.51 (s, 1H), 7.49-7.40 (m, 2H), 7.10 (s, 1H), 3.45 (q, J = 7.3Hz, 4H), 2.83 (s, 5H), 2.66 (td, J = 11.7, 2.1 Hz, 6H), 2.45 (s, 3H), 2.00 (d, J = 12.1 Hz, 2H), 1.80 (tt, J = 12.1, 5.9 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H).
MS(ESI):m/z 662[M+H] +. MS(ESI): m/z 662[M+H] + .
实施例29Example 29
5-氯-N-(2,3-二氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2793)5-chloro-N-(2,3-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-(ethyl Sulfo)-1H-indol-3-yl)pyrimidine-2-amine (HCD2793)
Figure PCTCN2019124686-appb-000055
Figure PCTCN2019124686-appb-000055
化合物的合成方法参照实施例28。Refer to Example 28 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.49(d,J＝8.3Hz,2H),8.33(dd,J＝22.2,8.5Hz,2H),7.99(d,J＝8.3Hz,1H),7.82(d,J＝7.9Hz,1H),7.58(s,1H),7.53–7.43(m,1H),7.36(t,J＝7.6Hz,1H),7.22(d,J＝7.9Hz,1H),6.99(d,J＝9.0Hz,1H),3.44(p,J＝7.5Hz,4H),3.06(s,4H),2.71(q,J＝14.1,11.5Hz,5H),2.38(s,2H),2.07(s,1H),1.83(s,3H),1.32(t,J＝7.4Hz,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J=8.3 Hz, 2H), 8.33 (dd, J=22.2, 8.5 Hz, 2H), 7.99 (d, J=8.3 Hz, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.58 (s, 1H), 7.53-7.43 (m, 1H), 7.36 (t, J = 7.6Hz, 1H), 7.22 (d, J = 7.9Hz, 1H) ), 6.99 (d, J = 9.0 Hz, 1H), 3.44 (p, J = 7.5 Hz, 4H), 3.06 (s, 4H), 2.71 (q, J = 14.1, 11.5 Hz, 5H), 2.38 (s , 2H), 2.07 (s, 1H), 1.83 (s, 3H), 1.32 (t, J = 7.4Hz, 4H).
MS(ESI):m/z 662[M+H] +. MS(ESI): m/z 662[M+H] + .
实施例30Example 30
5-氯-N-(5-氯-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2892)5-chloro-N-(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1- (Ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD2892)
Figure PCTCN2019124686-appb-000056
Figure PCTCN2019124686-appb-000056
步骤1. 5-氯-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(20)的制备Step 1. Preparation of 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (20)
化合物的合成方法参照实施例1,步骤2。For the method of compound synthesis, refer to Example 1 and Step 2.
1H NMR(400MHz,Chloroform-d)δ6.74(s,1H),6.56(s,1H),3.85(s,3H),3.66(s,2H),3.33(dt,J＝13.1,2.8Hz,2H),2.85(s,4H),2.75(s,4H),2.63(td,J＝11.7,2.2Hz,3H),2.45(s,3H),1.97(d,J＝12.1Hz,2H),1.81(qd,J＝11.9,3.8Hz,2H). 1 H NMR (400 MHz, Chloroform-d) δ 6.74 (s, 1H), 6.56 (s, 1H), 3.85 (s, 3H), 3.66 (s, 2H), 3.33 (dt, J=13.1, 2.8 Hz , 2H), 2.85 (s, 4H), 2.75 (s, 4H), 2.63 (td, J = 11.7, 2.2 Hz, 3H), 2.45 (s, 3H), 1.97 (d, J = 12.1 Hz, 2H) , 1.81 (qd, J=11.9, 3.8Hz, 2H).
步骤2. 5-氯-N-(5-氯-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2892)的制备Step 2. 5-chloro-N-(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4- Preparation of (1-(ethylsulfo)-1H-indol-3-yl)pyrimidine-2-amine (HCD2892)
将5-氯-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(20)(0.33g,0.98mmol)，3-(2,5-二氯嘧啶-4-基)-1-(乙基磺基)-1H-吲哚(18)(0.35g,0.98mmol),和碳酸钠(0.38g,2.92mmol)溶解于10mL二氧六环中，将溶剂脱气并将体系中气体置换为氩气。然后向其中加入三二亚苄基丙酮二钯(0.11g,0.098mmol)，BINAP(0.08g,0.098mmol)，再次置换气体为氩气后，80摄氏度下反应8h。反应结束后，加入50mL水，混合物用40mL乙酸乙酯萃取，有机相干燥、浓缩后，残余物以快速硅胶柱层析法分离，洗脱剂为2％甲醇的二氯甲烷溶液，得目标化合物，黄色固体，0.11g,收率17％。5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (20) (0.33 g, 0.98 mmol), 3-( 2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indole (18) (0.35g, 0.98mmol), and sodium carbonate (0.38g, 2.92mmol) were dissolved in 10mL In dioxane, the solvent is degassed and the gas in the system is replaced with argon. Then, tridibenzylideneacetone dipalladium (0.11 g, 0.098 mmol) and BINAP (0.08 g, 0.098 mmol) were added thereto. After replacing the gas with argon again, the reaction was carried out at 80 degrees Celsius for 8 hours. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with 40 mL of ethyl acetate. After the organic phase was dried and concentrated, the residue was separated by flash silica gel column chromatography. The eluent was 2% methanol in dichloromethane to obtain the target compound. , Yellow solid, 0.11g, yield 17%.
1H NMR(400MHz,Chloroform-d)δ8.55(s,1H),8.48(s,1H),8.47–8.39(m,2H),8.04–7.93(m,1H),7.66(s,1H),7.49–7.42(m,2H),6.66(s,1H),3.93(s,3H),3.44(q,J＝7.6,7.1Hz,4H),2.80(s,4H),2.73–2.62(m,5H),2.54–2.45(m,2H),2.41(s,3H),1.99(d,J＝12.1Hz,2H),1.83(qd,J＝11.9,3.8Hz,2H),1.32(t,J＝7.5Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ 8.55 (s, 1H), 8.48 (s, 1H), 8.47–8.39 (m, 2H), 8.04–7.93 (m, 1H), 7.66 (s, 1H) , 7.49–7.42(m, 2H), 6.66(s, 1H), 3.93(s, 3H), 3.44(q, J=7.6, 7.1Hz, 4H), 2.80(s, 4H), 2.73–2.62(m , 5H), 2.54-2.45 (m, 2H), 2.41 (s, 3H), 1.99 (d, J = 12.1 Hz, 2H), 1.83 (qd, J = 11.9, 3.8 Hz, 2H), 1.32 (t, J=7.5Hz, 3H).
MS(ESI):m/z 658[M+H] +. MS(ESI): m/z 658[M+H] + .
实施例31Example 31
5-氯-N-(5-氯-2-异丙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD2891)5-chloro-N-(5-chloro-2-isopropoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1 -(Ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD2891)
Figure PCTCN2019124686-appb-000057
Figure PCTCN2019124686-appb-000057
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.53(s,1H),8.46(s,1H),8.26(d,J＝8.1Hz,1H),7.92(d,J＝8.4Hz,1H),7.87(s,1H),7.47(ddd,J＝8.4,7.1,1.3Hz,1H),7.29(t,J＝7.6Hz,1H),6.83(s,1H),4.64(p,J＝6.0Hz,1H),3.79(q,J＝7.3Hz,2H),2.74–2.53(m,7H),2.46–2.32(m,4H),2.23(d,J＝6.7Hz,3H),1.88(d,J＝12.2Hz,2H),1.59(dt,J＝12.1,6.1Hz,2H),1.23(s,3H),1.21(s,3H),1.13(t,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.47 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 4.64 (p, J = 6.0 Hz, 1H), 3.79 (q, J = 7.3 Hz, 2H), 2.74-2.53 (m, 7H), 2.46-2.32 (m, 4H), 2.23 (d, J = 6.7 Hz , 3H), 1.88 (d, J = 12.2 Hz, 2H), 1.59 (dt, J = 12.1, 6.1 Hz, 2H), 1.23 (s, 3H), 1.21 (s, 3H), 1.13 (t, J = 7.3Hz, 3H).
13C NMR(101MHz,DMSO-d 6)δ159.15,158.90,156.34,149.50,146.52,134.70,130.88, 128.41,125.84,125.35,125.27,124.24,123.75,118.87,116.76,115.80,113.26,107.71,71.58,61.19,55.30(2C),51.49(2C),48.95,48.62(3C),28.69(2C),22.26(2C),8.28. 13 C NMR (101MHz, DMSO-d 6 ) δ159.15, 158.90, 156.34, 149.50, 146.52, 134.70, 130.88, 128.41, 125.84, 125.35, 125.27, 124.24, 123.75, 118.87, 116.76, 115.80, 113.26, 107.71, 71.58, 61.19 , 55.30 (2C), 51.49 (2C), 48.95, 48.62 (3C), 28.69 (2C), 22.26 (2C), 8.28.
MS(ESI):m/z 686[M+H] +. MS(ESI): m/z 686[M+H] + .
实施例32Example 32
5-氯-N-(5-氯-2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD346)5-chloro-N-(5-chloro-2-ethoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1- (Ethylsulfonyl)-1H-indol-3-yl)pyrimidin-2-amine (HCD346)
Figure PCTCN2019124686-appb-000058
Figure PCTCN2019124686-appb-000058
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.49(s,1H),8.48–8.43(m,2H),8.03–7.95(m,1H),7.68(s,1H),7.51–7.41(m,2H),6.66(s,1H),4.15(qd,J＝7.1,2.4Hz,2H),3.50–3.38(m,4H),2.74(s,9H),2.55–2.40(m,2H),2.36(s,3H),1.96(d,J＝11.3Hz,2H),1.82(qd,J＝11.9,3.7Hz,2H),1.50(t,J＝7.0Hz,3H),1.34(d,J＝7.3Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.48–8.43 (m, 2H), 8.03–7.95 (m, 1H), 7.68 (s, 1H) , 7.51–7.41(m, 2H), 6.66(s, 1H), 4.15(qd, J=7.1, 2.4Hz, 2H), 3.50–3.38(m, 4H), 2.74(s, 9H), 2.55–2.40 (m, 2H), 2.36 (s, 3H), 1.96 (d, J = 11.3 Hz, 2H), 1.82 (qd, J = 11.9, 3.7 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H) , 1.34 (d, J = 7.3 Hz, 3H).
MS(ESI):m/z 672[M+H] +. MS(ESI): m/z 672[M+H] + .
实施例33Example 33
5-氯-N-(5-氯-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD347)5-chloro-N-(5-chloro-2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-( Ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD347)
Figure PCTCN2019124686-appb-000059
Figure PCTCN2019124686-appb-000059
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.53(s,1H),8.50(s,1H),8.16(s,1H),7.89(d,J＝8.4Hz,1H),7.48(s,1H),7.44(ddd,J＝8.5,7.1,1.3Hz,1H),7.20(t,J＝7.6Hz,1H),7.06(s,1H),3.77(q,J＝7.3Hz,2H),3.31(s,2H),2.66(td,J＝11.7,2.2Hz,2H),2.53(d,J＝8.6Hz,4H),2.47–2.24(m,5H),2.19(s,3H),2.16(s,3H),1.91–1.75(m,2H),1.61(tt,J＝11.9,6.1Hz,2H),1.11(t,J＝7.3Hz,3H).1H NMR (400MHz, DMSO-d6) δ 9.17 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 8.4Hz, 1H) , 7.48 (s, 1H), 7.44 (ddd, J = 8.5, 7.1, 1.3 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 3.77 (q, J = 7.3 Hz, 2H), 3.31 (s, 2H), 2.66 (td, J = 11.7, 2.2 Hz, 2H), 2.53 (d, J = 8.6 Hz, 4H), 2.47-2.24 (m, 5H), 2.19 (s , 3H), 2.16 (s, 3H), 1.91-1.75 (m, 2H), 1.61 (tt, J = 11.9, 6.1 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H).
13C NMR(101MHz,DMSO-d 6)δ160.06,159.06,156.32,147.22,134.66,134.07,133.58, 130.91,128.66,128.49,125.82,124.96,124.08(2C),122.63,116.11,115.86,113.16,61.16,55.68(2C),51.57(2C),48.99(2C),48.93,46.24,28.81(2C),18.29,8.26. 13 C NMR (101 MHz, DMSO-d 6 ) δ 160.06, 159.06, 156.32, 147.22, 134.66, 134.07, 133.58, 130.91, 128.66, 128.49, 125.82, 124.96, 124.08 (2C), 122.63, 116.11, 115.86, 113.16, 61.16, 55.68(2C), 51.57(2C), 48.99(2C), 48.93, 46.24, 28.81(2C), 18.29, 8.26.
MS(ESI):m/z 642[M+H] +. MS(ESI): m/z 642[M+H] + .
实施例34Example 34
5-氯-N-(5-氯-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4151)5-chloro-N-(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1- (Ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD4151)
Figure PCTCN2019124686-appb-000060
Figure PCTCN2019124686-appb-000060
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.54(s,1H),8.51(s,1H),8.16(d,J＝6.0Hz,1H),7.89(d,J＝8.4Hz,1H),7.47–7.41(m,1H),7.16(d,J＝4.0Hz,2H),6.97(s,1H),3.78(t,J＝7.3Hz,2H),3.73(s,3H),3.46(d,J＝1.9Hz,2H),2.64–2.53(m,5H),2.40–2.25(m,4H),2.16(s,3H),1.89–1.78(m,2H),1.58(td,J＝12.0,3.8Hz,2H),1.11(t,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 7.47–7.41(m, 1H), 7.16(d, J=4.0Hz, 2H), 6.97(s, 1H), 3.78(t, J=7.3Hz, 2H), 3.73( s, 3H), 3.46 (d, J = 1.9 Hz, 2H), 2.64–2.53 (m, 5H), 2.40–2.25 (m, 4H), 2.16 (s, 3H), 1.89–1.78 (m, 2H) , 1.58 (td, J = 12.0, 3.8 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H).
MS(ESI):m/z 658[M+H] +. MS(ESI): m/z 658[M+H] + .
实施例35Example 35
5-氯-N-(5-氯-2-异丙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4152)5-chloro-N-(5-chloro-2-isopropoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1 -(Ethylsulfonyl)-1H-indol-3-yl)pyrimidine-2-amine (HCD4152)
Figure PCTCN2019124686-appb-000061
Figure PCTCN2019124686-appb-000061
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ9.20(s,1H),8.53(s,1H),8.50(s,1H),8.21–8.07(m,1H),7.88(d,J＝8.4Hz,1H),7.43(t,J＝7.8Hz,1H),7.14(d,J＝12.7Hz,2H),6.95(s,1H),4.52(p,J＝6.0Hz,1H),3.77(q,J＝7.3Hz,3H),3.51(s,2H),2.61–2.53(m,5H),2.41–2.24(m,6H),2.16(d,J＝4.4Hz,3H),1.92–1.85(m,2H),1.55(dd,J＝11.9,3.8Hz,2H),1.20(s,3H),1.18(s,3H),1.12(d,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.20 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.21–8.07 (m, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.43 (t, J = 7.8Hz, 1H), 7.14 (d, J = 12.7Hz, 2H), 6.95 (s, 1H), 4.52 (p, J = 6.0Hz, 1H), 3.77 ( q, J = 7.3Hz, 3H), 3.51 (s, 2H), 2.61-2.53 (m, 5H), 2.41-2.24 (m, 6H), 2.16 (d, J = 4.4Hz, 3H), 1.92-1.85 (m, 2H), 1.55 (dd, J = 11.9, 3.8 Hz, 2H), 1.20 (s, 3H), 1.18 (s, 3H), 1.12 (d, J = 7.3 Hz, 3H).
MS(ESI):m/z 686[M+H] +. MS(ESI): m/z 686[M+H] + .
实施例36Example 36
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD323)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(2-methoxy-5-methyl-4-(4-(4-methyl Piperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2-amine (HCD323)
Figure PCTCN2019124686-appb-000062
Figure PCTCN2019124686-appb-000062
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.51–8.47(m,1H),8.46(s,1H),8.44(s,1H),8.25(s,1H),7.99(dt,J＝8.4,0.9Hz,1H),7.64(s,1H),7.46(ddd,J＝8.4,7.2,1.3Hz,1H),7.38(ddd,J＝8.2,7.3,1.1Hz,1H),6.65(s,1H),3.91(s,3H),3.45(q,J＝7.4Hz,2H),3.21(d,J＝11.6Hz,2H),2.94(s,8H),2.73–2.63(m,3H),2.52(s,3H),2.20(s,3H),2.05(d,J＝14.0Hz,2H),1.79(q,J＝11.8Hz,2H),1.33(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.51–8.47 (m, 1H), 8.46 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.99 (dt, J=8.4, 0.9Hz, 1H), 7.64(s, 1H), 7.46(ddd, J=8.4, 7.2, 1.3Hz, 1H), 7.38(ddd, J=8.2, 7.3, 1.1Hz, 1H), 6.65(s, 1H ), 3.91 (s, 3H), 3.45 (q, J = 7.4Hz, 2H), 3.21 (d, J = 11.6Hz, 2H), 2.94 (s, 8H), 2.73-2.63 (m, 3H), 2.52 (s, 3H), 2.20 (s, 3H), 2.05 (d, J = 14.0 Hz, 2H), 1.79 (q, J = 11.8 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H).
MS(ESI):m/z 638[M+H] +. MS(ESI): m/z 638[M+H] + .
实施例37Example 37
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(2-乙氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD3531)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(2-ethoxy-5-methyl-4-(4-(4-methyl Piperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2-amine (HCD3531)
Figure PCTCN2019124686-appb-000063
Figure PCTCN2019124686-appb-000063
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.49(dt,J＝8.0,1.0Hz,1H),8.45(s,1H),8.43(s,1H),8.26(s,1H),7.98(dt,J＝8.3,0.9Hz,1H),7.67(s,1H),7.45(ddd,J＝8.4,7.2,1.3Hz,1H),7.37(ddd,J＝8.2,7.2,1.1Hz,1H),6.66(s,1H),4.12(q,J＝6.9Hz,2H),3.44(q,J＝7.4Hz,2H),3.21–3.09(m,2H),2.74–2.50(m,10H),2.39(td,J＝7.6,3.8Hz,1H),2.34(s,3H),2.19(s,3H),2.00–1.91(m,2H),1.74(qd,J＝11.9,3.8Hz,2H),1.47(t,J＝7.0Hz,3H),1.31(d,J＝7.2Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.49 (dt, J=8.0, 1.0 Hz, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.98 (dt , J = 8.3, 0.9 Hz, 1H), 7.67 (s, 1H), 7.45 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.37 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 6.66(s, 1H), 4.12(q, J=6.9Hz, 2H), 3.44(q, J=7.4Hz, 2H), 3.21–3.09(m, 2H), 2.74–2.50(m, 10H), 2.39 (td, J=7.6, 3.8Hz, 1H), 2.34(s, 3H), 2.19(s, 3H), 2.00–1.91(m, 2H), 1.74(qd, J=11.9, 3.8Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.31 (d, J = 7.2 Hz, 3H).
13C NMR(101MHz,Chloroform-d)δ158.22,158.07,156.66,146.65,146.13,134.86,130.43,128.84,125.44,124.63,124.14,124.00,123.58,121.56,117.28,116.75,112.80,103.37,64.50,61.94,55.33(2C),52.17(2C),49.04(2C),48.99,45.92,29.07(2C),17.18, 15.05,8.16. 13 C NMR (101MHz, Chloroform-d) δ158.22,158.07,156.66,146.65,146.13,134.86,130.43,128.84,125.44,124.63,124.14,124.00,123.58,121.56,117.28,116.75,112.80,103.37,64.50,61.94, 55.33(2C), 52.17(2C), 49.04(2C), 48.99, 45.92, 29.07(2C), 17.18, 15.05, 8.16.
MS(ESI):m/z 652[M+H] +. MS(ESI): m/z 652[M+H] + .
实施例38Example 38
5-氯-N-(5-氯-2-甲氧基-4-吗啉苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4181)5-chloro-N-(5-chloro-2-methoxy-4-morpholinephenyl)-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidine-2- Amine (HCD4181)
Figure PCTCN2019124686-appb-000064
Figure PCTCN2019124686-appb-000064
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ8.74(s,1H),8.58(s,1H),8.47(s,1H),8.29(d,J＝8.3Hz,1H),7.91(dt,J＝8.4,0.9Hz,1H),7.80(s,1H),7.47(ddd,J＝8.4,7.2,1.3Hz,1H),7.37–7.26(m,1H),6.88(s,1H),3.84(s,3H),3.83–3.73(m,6H),3.08–2.90(m,4H),1.12(d,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.91 (dt, J = 8.4, 0.9 Hz, 1H), 7.80 (s, 1H), 7.47 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.37–7.26 (m, 1H), 6.88 (s, 1H), 3.84 (s, 3H), 3.83–3.73 (m, 6H), 3.08–2.90 (m, 4H), 1.12 (d, J=7.3Hz, 3H).
MS(ESI):m/z 562[M+H] +. MS(ESI): m/z 562[M+H] + .
实施例39Example 39
5-氯-N-(5-氯-2-甲氧基-4-(哌嗪-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4182)5-chloro-N-(5-chloro-2-methoxy-4-(piperazin-1-yl)phenyl)-4-(1-(ethylsulfo)-1H-indole-3- Group) pyrimidine-2-amine (HCD4182)
Figure PCTCN2019124686-appb-000065
Figure PCTCN2019124686-appb-000065
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,DMSO-d 6)δ8.73(s,1H),8.57(s,1H),8.47(s,1H),8.28(d,J＝7.9Hz,1H),7.91(d,J＝8.4Hz,1H),7.76(s,1H),7.46(t,J＝7.8Hz,1H),7.30(t,J＝7.7Hz,1H),6.83(s,1H),3.83(s,3H),3.78(q,J＝7.3Hz,3H),2.91(dt,J＝26.6,4.3Hz,8H),1.12(t,J＝7.3Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.76 (s, 1H), 7.46 (t, J = 7.8Hz, 1H), 7.30 (t, J = 7.7Hz, 1H), 6.83 (s, 1H), 3.83 (s, 3H), 3.78 (q, J = 7.3 Hz, 3H), 2.91 (dt, J = 26.6, 4.3 Hz, 8H), 1.12 (t, J = 7.3 Hz, 3H).
MS(ESI):m/z 561[M+H] +. MS(ESI): m/z 561[M+H] + .
实施例40Example 40
(1-(2-氯-4-((5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-5-甲氧基苯基)哌啶-4-基)甲醇(HCD4184)(1-(2-chloro-4-((5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy Phenyl) piperidin-4-yl) methanol (HCD4184)
Figure PCTCN2019124686-appb-000066
Figure PCTCN2019124686-appb-000066
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.51–8.37(m,3H),8.02–7.93(m,1H),7.68(s,1H),7.49–7.40(m,2H),6.69(s,1H),3.93(s,3H),3.60(d,J＝6.2Hz,2H),3.49–3.37(m,4H),2.67(t,J＝11.6Hz,2H),1.98–1.75(m,3H),1.54(d,J＝9.1Hz,1H),1.32–1.28(m,5H),0.95–0.83(m,1H). 1 H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.51–8.37 (m, 3H), 8.02–7.93 (m, 1H), 7.68 (s, 1H), 7.49–7.40 (m, 2H), 6.69(s, 1H), 3.93(s, 3H), 3.60(d, J=6.2Hz, 2H), 3.49–3.37(m, 4H), 2.67(t, J=11.6Hz, 2H), 1.98–1.75 (m, 3H), 1.54 (d, J = 9.1 Hz, 1H), 1.32–1.28 (m, 5H), 0.95–0.83 (m, 1H).
MS(ESI):m/z 590[M+H] +. MS(ESI): m/z 590[M+H] + .
实施例41Example 41
5-氯-N-(5-氯-4-(4-(二甲氨基)哌啶-1-基)-2-甲氧基苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4185)5-chloro-N-(5-chloro-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-4-(1-(ethylsulfonyl)- 1H-Indol-3-yl)pyrimidin-2-amine (HCD4185)
Figure PCTCN2019124686-appb-000067
Figure PCTCN2019124686-appb-000067
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.55(s,1H),8.52–8.40(m,3H),8.01–7.95(m,1H),7.67(s,1H),7.48–7.43(m,2H),6.67(s,1H),3.93(s,3H),3.44(q,J＝7.3Hz,4H),2.72–2.66(m,2H),2.47(q,J＝4.2,3.6Hz,1H),2.42(s,6H),1.98(d,J＝11.1Hz,2H),1.81(qd,J＝11.7,3.8Hz,2H),1.34–1.30(m,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.52–8.40 (m, 3H), 8.01–7.95 (m, 1H), 7.67 (s, 1H), 7.48–7.43 (m, 2H), 6.67(s, 1H), 3.93(s, 3H), 3.44(q, J=7.3Hz, 4H), 2.72-2.66(m, 2H), 2.47(q, J=4.2, 3.6Hz, 1H ), 2.42 (s, 6H), 1.98 (d, J = 11.1 Hz, 2H), 1.81 (qd, J = 11.7, 3.8 Hz, 2H), 1.34-1.30 (m, 3H).
13C NMR(101MHz,Chloroform-d)δ158.23,157.68,156.91,147.28,144.04,134.79,130.55,128.66,125.50,124.58,124.52,123.35,120.46,120.22,117.99,116.53,112.81,103.06,62.15,56.00,51.42(2C),48.98,41.23(2C),28.20(2C),8.17. 13 C NMR (101MHz, Chloroform-d) δ158.23,157.68,156.91,147.28,144.04,134.79,130.55,128.66,125.50,124.58,124.52,123.35,120.46,120.22,117.99,116.53,112.81,103.06,62.15,56.00, 51.42(2C), 48.98, 41.23(2C), 28.20(2C), 8.17.
MS(ESI):m/z 603[M+H] +. MS(ESI): m/z 603[M+H] + .
实施例42Example 42
1-(4-(2-氯-4-((5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-5-甲氧基苯基)哌嗪-1-基)乙烷-1-酮(HCD4186)1-(4-(2-chloro-4-((5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5- Methoxyphenyl)piperazin-1-yl)ethane-1-one (HCD4186)
Figure PCTCN2019124686-appb-000068
Figure PCTCN2019124686-appb-000068
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.59(s,1H),8.49(s,1H),8.45(d,J＝7.9Hz,2H),8.02–7.95(m,1H),7.71(s,1H),7.51–7.41(m,2H),6.63(s,1H),3.93(s,3H),3.86–3.78(m,2H),3.67(t,J＝4.8Hz,2H),3.45(q,J＝7.4Hz,2H),3.04(dt,J＝10.1,4.8Hz,4H),2.17(s,3H),1.32(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.49 (s, 1H), 8.45 (d, J=7.9 Hz, 2H), 8.02–7.95 (m, 1H), 7.71 (s , 1H), 7.51–7.41(m, 2H), 6.63(s, 1H), 3.93(s, 3H), 3.86–3.78(m, 2H), 3.67(t, J=4.8Hz, 2H), 3.45( q, J = 7.4Hz, 2H), 3.04 (dt, J = 10.1, 4.8Hz, 4H), 2.17 (s, 3H), 1.32 (t, J = 7.4Hz, 3H).
13C NMR(101MHz,Chloroform-d)δ169.19,158.20,157.58,156.98,147.31,142.85,134.80,130.60,128.63,125.52,125.34,124.50,123.28,120.39,120.36,118.19,116.45,112.85,103.11,56.06,51.94,51.17,49.00,46.72,41.78,21.43,8.17.13CNMR(101MHz, Chloroform-d) δ169.19,158.20,157.58,156.98,147.31,142.85,134.80,130.60,128.63,125.52,125.34,124.50,123.28,120.39,120.36,118.19,116.45,112.85,103.11,56.06,51 ,51.17,49.00,46.72,41.78,21.43,8.17.
MS(ESI):m/z 603[M+H] +. MS(ESI): m/z 603[M+H] + .
实施例43Example 43
2-氯-N4-(5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-基)-N1-(2-(二甲氨基)乙基)-5-甲氧基-N1-甲苯-1,4-二胺(HCD4192)2-chloro-N4-(5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl Group)-5-methoxy-N1-toluene-1,4-diamine (HCD4192)
Figure PCTCN2019124686-appb-000069
Figure PCTCN2019124686-appb-000069
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.50(s,1H),8.48–8.37(m,2H),8.03–7.96(m,1H),7.70(s,1H),7.51–7.43(m,2H),6.76(s,1H),3.95(s,3H),3.45(q,J＝7.4Hz,2H),3.24(t,J＝7.2Hz,2H),2.84(s,3H),2.67(t,J＝7.2Hz,2H),2.39(s,6H),1.33(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.50 (s, 1H), 8.48–8.37 (m, 2H), 8.03–7.96 (m, 1H), 7.70 (s, 1H) , 7.51–7.43 (m, 2H), 6.76 (s, 1H), 3.95 (s, 3H), 3.45 (q, J = 7.4Hz, 2H), 3.24 (t, J = 7.2Hz, 2H), 2.84 ( s, 3H), 2.67 (t, J = 7.2Hz, 2H), 2.39 (s, 6H), 1.33 (t, J = 7.4Hz, 3H).
MS(ESI):m/z 577[M+H] +. MS(ESI): m/z 577[M+H] + .
实施例44Example 44
1-(2-氯-4-((5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-5-甲氧基苯基)哌啶-4-酮(HCD426)1-(2-chloro-4-((5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy Phenyl) piperidin-4-one (HCD426)
Figure PCTCN2019124686-appb-000070
Figure PCTCN2019124686-appb-000070
化合物的合成方法参照实施例30。Refer to Example 30 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),8.50(s,1H),8.50–8.38(m,2H),8.08–7.90(m,1H),7.73(s,1H),7.55–7.39(m,2H),6.70(s,1H),3.95(s,3H),3.46(q,J＝7.4Hz,2H),3.37(t,J＝6.0Hz,3H),2.69(t,J＝6.0Hz,3H),1.33(t,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.50 (s, 1H), 8.50–8.38 (m, 2H), 8.08–7.90 (m, 1H), 7.73 (s, 1H) , 7.55-7.39 (m, 2H), 6.70 (s, 1H), 3.95 (s, 3H), 3.46 (q, J = 7.4Hz, 2H), 3.37 (t, J = 6.0Hz, 3H), 2.69 ( t, J = 6.0 Hz, 3H), 1.33 (t, J = 7.4 Hz, 3H).
MS(ESI):m/z 574[M+H] +. MS(ESI): m/z 574[M+H] + .
实施例45Example 45
5-氯-N-(5-氯-2-甲氧基-4-(4-吗啉哌啶-1-基)苯基)-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-胺(HCD4261)5-chloro-N-(5-chloro-2-methoxy-4-(4-morpholinpiperidin-1-yl)phenyl)-4-(1-(ethylsulfo)-1H-ind Indole-3-yl)pyrimidin-2-amine (HCD4261)
Figure PCTCN2019124686-appb-000071
Figure PCTCN2019124686-appb-000071
将1-(2-氯-4-((5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-5-甲氧基苯基)哌啶-4-酮(HCD426)(0.1g,0.17mmol)，吗啉(0.03g,0.34mmol),三乙酰氧基硼氢化钠(0.04g,0.20mmol)以及冰醋酸(12mg,0.2mmol)溶解混合于5mL二氯乙烷中，50摄氏度下反应过夜，然后再补加0.03g吗啉以及0.04g三乙酰氧基硼氢化钠，继续反应五小时。向反应液中加入饱和碳酸氢钠溶液，以乙酸乙酯萃取，有机相干燥、浓缩后，残余物以快速硅胶柱层析法分离，洗脱剂为2％甲醇的二氯甲烷溶液，得目标化合物，黄色固体，0.073g,收率65％。1-(2-chloro-4-((5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy Phenyl) piperidin-4-one (HCD426) (0.1g, 0.17mmol), morpholine (0.03g, 0.34mmol), sodium triacetoxyborohydride (0.04g, 0.20mmol) and glacial acetic acid (12mg , 0.2mmol) was dissolved and mixed in 5mL of dichloroethane, and reacted at 50 degrees Celsius overnight, then added 0.03g of morpholine and 0.04g of sodium triacetoxyborohydride, and continued the reaction for five hours. Saturated sodium bicarbonate solution was added to the reaction solution and extracted with ethyl acetate. After the organic phase was dried and concentrated, the residue was separated by flash silica gel column chromatography. The eluent was 2% methanol in dichloromethane to obtain the target. Compound, yellow solid, 0.073g, yield 65%.
1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.49(s,1H),8.49–8.42(m,2H),7.99(ddt,J＝7.4,3.5,1.8Hz,1H),7.67(s,1H),7.51–7.41(m,2H),6.67(s,1H),3.94(s,3H),3.81(d,J＝5.4Hz,4H),3.52–3.35(m,4H),2.80–2.59(m,6H),2.43(s,1H),1.99(d,J＝12.1Hz,2H),1.83(tt,J＝12.8,6.4Hz,2H),1.36–1.30(m,4H). 1 H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.49 (s, 1H), 8.49–8.42 (m, 2H), 7.99 (ddt, J=7.4, 3.5, 1.8 Hz, 1H) , 7.67 (s, 1H), 7.51-7.41 (m, 2H), 6.67 (s, 1H), 3.94 (s, 3H), 3.81 (d, J = 5.4 Hz, 4H), 3.52-3.35 (m, 4H) ), 2.80-2.59 (m, 6H), 2.43 (s, 1H), 1.99 (d, J = 12.1 Hz, 2H), 1.83 (tt, J = 12.8, 6.4 Hz, 2H), 1.36-1.30 (m, 4H).
MS(ESI):m/z 645[M+H] +. MS(ESI): m/z 645[M+H] + .
实施例46Example 46
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯 基)嘧啶-2-胺(HCD3511)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(4-(4-(4-methylpiperazin-1-yl)piperidine-1 -Yl)phenyl)pyrimidin-2-amine (HCD3511)
Figure PCTCN2019124686-appb-000072
Figure PCTCN2019124686-appb-000072
化合物的合成方法参照实施例3。Refer to Example 3 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.43(s,1H),8.39(dt,J＝8.2,1.2Hz,1H),7.97(dt,J＝8.4,1.0Hz,1H),7.51–7.47(m,2H),7.44(ddd,J＝8.4,7.2,1.3Hz,1H),7.34(ddd,J＝8.2,7.2,1.0Hz,1H),7.07(s,1H),7.00–6.93(m,2H),3.78–3.66(m,2H),3.43(q,J＝7.4Hz,2H),2.73(td,J＝12.4,2.6Hz,6H),2.51(d,J＝15.1Hz,3H),2.46–2.36(m,2H),2.33(s,3H),2.01–1.94(m,2H),1.71(td,J＝12.1,3.9Hz,2H),1.32(d,J＝7.3Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.43 (s, 1H), 8.39 (dt, J=8.2, 1.2 Hz, 1H), 7.97 (dt, J=8.4, 1.0 Hz , 1H), 7.51–7.47 (m, 2H), 7.44 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.34 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 7.07 (s, 1H ), 7.00–6.93(m, 2H), 3.78–3.66(m, 2H), 3.43(q, J=7.4Hz, 2H), 2.73(td, J=12.4, 2.6Hz, 6H), 2.51(d, J = 15.1 Hz, 3H), 2.46-2.36 (m, 2H), 2.33 (s, 3H), 2.01-1.94 (m, 2H), 1.71 (td, J = 12.1, 3.9 Hz, 2H), 1.32 (d , J=7.3Hz, 3H).
MS(ESI):m/z 594[M+H] +. MS(ESI): m/z 594[M+H] + .
实施例47Example 47
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(3-氟-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD3512)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(3-fluoro-4-(4-(4-methylpiperazin-1-yl) Piperidin-1-yl)phenyl)pyrimidine-2-amine (HCD3512)
Figure PCTCN2019124686-appb-000073
Figure PCTCN2019124686-appb-000073
化合物的合成方法参照实施例3。Refer to Example 3 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.46(d,J＝2.0Hz,2H),8.40(d,J＝7.3Hz,1H),8.03–7.95(m,1H),7.59(dd,J＝14.2,2.6Hz,1H),7.49–7.43(m,1H),7.38(ddd,J＝8.3,7.2,1.1Hz,1H),7.25(s,1H),7.19–7.13(m,1H),6.94(t,J＝9.1Hz,1H),3.53–3.47(m,2H),3.44(q,J＝7.4Hz,2H),2.77–2.63(m,6H),2.52(d,J＝16.8Hz,3H),2.43(ddd,J＝11.5,7.8,3.8Hz,2H),2.34(s,3H),1.99–1.90(m,2H),1.79(qd,J＝12.1,4.0Hz,2H),1.32(d,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J=2.0 Hz, 2H), 8.40 (d, J=7.3 Hz, 1H), 8.03–7.95 (m, 1H), 7.59 (dd, J = 14.2, 2.6 Hz, 1H), 7.49–7.43 (m, 1H), 7.38 (ddd, J=8.3, 7.2, 1.1 Hz, 1H), 7.25 (s, 1H), 7.19–7.13 (m, 1H), 6.94(t, J=9.1Hz, 1H), 3.53–3.47(m, 2H), 3.44(q, J=7.4Hz, 2H), 2.77–2.63(m, 6H), 2.52(d, J=16.8Hz , 3H), 2.43 (ddd, J = 11.5, 7.8, 3.8 Hz, 2H), 2.34 (s, 3H), 1.99-1.90 (m, 2H), 1.79 (qd, J = 12.1, 4.0 Hz, 2H), 1.32 (d, J = 7.4 Hz, 3H).
MS(ESI):m/z 612[M+H] +. MS(ESI): m/z 612[M+H] + .
实施例48Example 48
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(3-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD3513)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(3-methoxy-4-(4-(4-methylpiperazine-1- Yl)piperidin-1-yl)phenyl)pyrimidine-2-amine (HCD3513)
Figure PCTCN2019124686-appb-000074
Figure PCTCN2019124686-appb-000074
化合物的合成方法参照实施例3。Refer to Example 3 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.45(t,J＝2.1Hz,2H),8.39(d,J＝8.0Hz,1H),7.97(d,J＝8.3Hz,1H),7.44(ddd,J＝8.4,7.2,1.4Hz,1H),7.37–7.30(m,2H),7.16–7.10(m,1H),7.06(dd,J＝8.5,2.4Hz,1H),6.94(d,J＝8.5Hz,1H),3.76(s,3H),3.54(d,J＝11.9Hz,2H),3.44(q,J＝7.3Hz,2H),2.69(s,7H),2.54–2.36(m,4H),2.32(s,3H),1.96–1.89(m,2H),1.84(dd,J＝12.0,3.8Hz,2H),1.31(d,J＝1.6Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (t, J=2.1 Hz, 2H), 8.39 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.44 ( ddd, J=8.4, 7.2, 1.4 Hz, 1H), 7.37–7.30 (m, 2H), 7.16–7.10 (m, 1H), 7.06 (dd, J=8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.76 (s, 3H), 3.54 (d, J = 11.9 Hz, 2H), 3.44 (q, J = 7.3 Hz, 2H), 2.69 (s, 7H), 2.54-2.36 ( m, 4H), 2.32 (s, 3H), 1.96-1.89 (m, 2H), 1.84 (dd, J = 12.0, 3.8Hz, 2H), 1.31 (d, J = 1.6Hz, 3H).
MS(ESI):m/z 624[M+H] +. MS(ESI): m/z 624[M+H] + .
实施例49Example 49
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(3-异丙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD3514)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(3-isopropoxy-4-(4-(4-methylpiperazine-1 -Yl)piperidin-1-yl)phenyl)pyrimidin-2-amine (HCD3514)
Figure PCTCN2019124686-appb-000075
Figure PCTCN2019124686-appb-000075
化合物的合成方法参照实施例3。Refer to Example 3 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.42(s,1H),8.37(d,J＝8.0Hz,1H),7.98(dt,J＝8.4,0.9Hz,1H),7.45(ddd,J＝8.4,7.2,1.3Hz,1H),7.35(td,J＝7.6,1.1Hz,1H),7.26(d,J＝2.4Hz,1H),7.10(d,J＝7.2Hz,1H),7.09–7.04(m,1H),6.89(d,J＝8.5Hz,1H),4.51(h,J＝6.1Hz,1H),3.62–3.51(m,2H),3.43(q,J＝7.4Hz,2H),2.80–2.47(m,10H),2.37(td,J＝9.6,7.5,3.9Hz,1H),2.33(s,3H),1.96(d,J＝11.7Hz,2H),1.80–1.71(m,2H),1.29(d,J＝7.4Hz,3H),1.27(s,3H),1.26(s,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.42 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.98 (dt, J=8.4, 0.9 Hz, 1H ), 7.45 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 7.2Hz, 1H), 7.09–7.04(m, 1H), 6.89(d, J=8.5Hz, 1H), 4.51(h, J=6.1Hz, 1H), 3.62–3.51(m, 2H), 3.43( q, J = 7.4Hz, 2H), 2.80-2.47 (m, 10H), 2.37 (td, J = 9.6, 7.5, 3.9Hz, 1H), 2.33 (s, 3H), 1.96 (d, J = 11.7Hz , 2H), 1.80-1.71 (m, 2H), 1.29 (d, J = 7.4Hz, 3H), 1.27 (s, 3H), 1.26 (s, 3H).
MS(ESI):m/z 652[M+H] +. MS(ESI): m/z 652[M+H] + .
实施例50Example 50
5-氯-4-(1-(乙基磺基)-1H-吲哚-3-基)-N-(3-环戊氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2-胺(HCD3515)5-chloro-4-(1-(ethylsulfo)-1H-indol-3-yl)-N-(3-cyclopentyloxy-4-(4-(4-methylpiperazine-1 -Yl)piperidin-1-yl)phenyl)pyrimidine-2-amine (HCD3515)
Figure PCTCN2019124686-appb-000076
Figure PCTCN2019124686-appb-000076
化合物的合成方法参照实施例3。Refer to Example 3 for the compound synthesis method.
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),8.41(s,1H),8.36(dt,J＝8.0,1.0Hz,1H),7.97(dt,J＝8.3,1.0Hz,1H),7.44(ddd,J＝8.4,7.2,1.3Hz,1H),7.34(ddd,J＝8.2,7.2,1.1Hz,1H),7.28(s,1H),7.15(s,1H),7.03(dd,J＝8.5,2.4Hz,1H),6.87(d,J＝8.5Hz,1H),4.70(dq,J＝5.6,2.9Hz,1H),3.54(d,J＝11.5Hz,2H),3.43(q,J＝7.4Hz,2H),2.71(s,4H),2.63–2.48(m,6H),2.39(td,J＝7.7,4.0Hz,1H),2.34(s,3H),1.95(d,J＝11.4Hz,2H),1.83(d,J＝12.6Hz,2H),1.75(dt,J＝18.2,7.3Hz,6H),1.51(s,2H),1.31(d,J＝7.4Hz,3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.36 (dt, J=8.0, 1.0 Hz, 1H), 7.97 (dt, J=8.3, 1.0 Hz , 1H), 7.44 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.34 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 7.03 (dd, J = 8.5, 2.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 4.70 (dq, J = 5.6, 2.9 Hz, 1H), 3.54 (d, J = 11.5 Hz, 2H ), 3.43 (q, J=7.4Hz, 2H), 2.71(s, 4H), 2.63–2.48(m, 6H), 2.39(td, J=7.7, 4.0Hz, 1H), 2.34(s, 3H) , 1.95 (d, J = 11.4 Hz, 2H), 1.83 (d, J = 12.6 Hz, 2H), 1.75 (dt, J = 18.2, 7.3 Hz, 6H), 1.51 (s, 2H), 1.31 (d, J=7.4Hz, 3H).
MS(ESI):m/z 678[M+H] +. MS(ESI): m/z 678[M+H] + .
实施例51Example 51
2-氨基嘧啶类化合物对野生型EGFR及突变性EGFR激酶的活性抑制实验：2-Aminopyrimidine compounds inhibit the activity of wild-type EGFR and mutant EGFR kinase:
EGFR(WT)为野生型表皮生长因子受体，EGFR(T790M)为带有第790位氨基酸由苏氨酸突变成甲硫氨酸的表皮生长因子受体，EGFR(L858R)为带有第858位氨基酸由亮氨酸突变成精氨酸的表皮生长因子受体，EGFR(L861Q)为带有第861位氨基酸由亮氨酸突变成谷氨酰胺的表皮生长因子受体，EGFR(L858R/T790M)为带有第858位氨基酸由亮氨酸突变成谷氨酰胺，第790位氨基酸由苏氨酸突变成甲硫氨酸双突变的表皮生长因子受体。EGFR(L858R/T790M/C797S)为带有第858位氨基酸由亮氨酸突变成谷氨酰胺，第790位氨基酸由苏氨酸突变成甲硫氨酸，第797位由半胱氨酸突变为丝氨酸的三突变的表皮生长因子受体。EGFR (WT) is the wild-type epidermal growth factor receptor, EGFR (T790M) is the epidermal growth factor receptor with the 790th amino acid mutated from threonine to methionine, EGFR (L858R) is the Epidermal growth factor receptor with 858 amino acid mutation from leucine to arginine, EGFR (L861Q) is an epidermal growth factor receptor with 861 amino acid mutation from leucine to glutamine, EGFR ( L858R/T790M) is an epidermal growth factor receptor with amino acid 858 mutation from leucine to glutamine and amino acid 790 mutation from threonine to methionine double mutation. EGFR (L858R/T790M/C797S) has amino acid 858 mutated from leucine to glutamine, amino acid 790 mutated from threonine to methionine, 797 cysteine Triple mutant epidermal growth factor receptor mutated to serine.
用酶联免疫吸附法(Enzyme-Linked Immunosorbent Assay,ELISA)检测化合物对激酶活性的抑制作用。EGFR WT和EGFR T790M/L858R激酶购自Eurofins公司，EGFR T790M/L858R/C797SR激酶购自BPS Bioscience公司。主要实验步骤如下：酶反应底物Poly(Glu,Tyr) 4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl,pH 7.2-7.4)稀释成20μg/mL，37℃反应12-16h包被酶标板。每孔加入用反应缓冲液(50mM HEPES pH 7.4,50mM MgCl 2,0.5mM MnCl 2,0.2mM Na 3VO 4,1mM DTT)稀释的ATP(终浓度5μM)溶液，加入待测化合物或溶剂对照，然后激酶启动反应，37℃摇床反应1h。T-PBS洗板三次，加入抗体PY99于37℃摇床反应0.5h。T-PBS洗板后，加入辣根过氧化物酶标记的羊抗鼠的IgG，37℃摇床反应0.5h。再次洗板后，加入2mg/mL的OPD显色液，25℃避光反应1-10min。加入2M H 2SO 4终止 反应，用可调波长式微孔板酶标仪SPECTRA MAX 190检测，采用波长为492nm。IC 50值由抑制曲线分析得到。 Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect the inhibitory effect of compounds on kinase activity. EGFR WT and EGFR T790M/L858R kinase were purchased from Eurofins, and EGFR T790M/L858R/C797SR kinase was purchased from BPS Bioscience. The main experimental steps are as follows: Enzyme reaction substrate Poly (Glu, Tyr) 4:1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 μg/mL, 37 ℃ reaction 12- 16h coated microplate. Add ATP (final concentration 5 μM) solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT) to each well, add the test compound or solvent control, Then the kinase started the reaction, and the reaction was carried out at 37°C for 1 hour in a shaker. Wash the plate three times with T-PBS, add antibody PY99 and shake at 37°C for 0.5h. After washing the plate with T-PBS, goat anti-mouse IgG labeled with horseradish peroxidase was added, and the reaction was performed in a shaker at 37°C for 0.5h. After washing the plate again, add 2mg/mL of OPD color developing solution and react at 25℃ for 1-10min in the dark. The reaction was stopped by adding 2M H 2 SO 4 and detected with a tunable wavelength microplate reader SPECTRA MAX 190, using a wavelength of 492 nm. The IC 50 value was obtained from the inhibition curve analysis.
表1中所列为化合物编号(与上述实施例中的化合物编号对应)以及化合物对各激酶抑制活性的检测结果。Table 1 lists the compound numbers (corresponding to the compound numbers in the above examples) and the detection results of the compounds' inhibitory activity on each kinase.
表1化合物对激酶的抑制活性结果Table 1 Results of inhibitory activity of compounds on kinase
Figure PCTCN2019124686-appb-000077
Figure PCTCN2019124686-appb-000077
Figure PCTCN2019124686-appb-000078
Figure PCTCN2019124686-appb-000078
从表1可知，本发明的2-氨基嘧啶类化合物，对EGFR三突变蛋白酶产生抑制作用，从而可以抑制多种肿瘤细胞的生长。本发明的化合物尤其能够有效抑制EGFR蛋白激酶耐药突变体(如EGFR T790M和EGFR T790M/C797S)的活性，能够选择性作用于EGFR L858R/T790M以及EGFR L858R/T790M/C797S肺癌细胞，可以克服现有第三代选择性EGFR T790M小分子抑制剂Osimertinib(AZD9291)，Olmutinib(HM6171)，Rociletinib(CO-1686)等诱发的非小细胞肺癌等肿瘤病人的临床耐药。 It can be seen from Table 1 that the 2-aminopyrimidine compounds of the present invention have an inhibitory effect on the EGFR triple mutant protease, thereby inhibiting the growth of various tumor cells. The compound of the present invention can effectively inhibit the activity of EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR T790M/C797S ), can selectively act on EGFR L858R/T790M and EGFR L858R/T790M/C797S lung cancer cells, and can overcome the existing There are third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) induced clinical drug resistance in non-small cell lung cancer and other tumor patients.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-mentioned embodiments can be arbitrarily combined. To simplify the description, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, All should be considered within the scope of this description.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因 此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned examples only express several embodiments of the present invention, and their descriptions are more specific and detailed, but they should not be construed as limiting the patent scope of the invention. It should be noted that, for a person of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all fall within the protection scope of the present invention. Therefore, the protection scope of the invention patent shall be subject to the appended claims.

Claims (24)

  1. 具有式I所示结构的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：A 2-aminopyrimidine compound having the structure shown in Formula I or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof:
    Figure PCTCN2019124686-appb-100001
    Figure PCTCN2019124686-appb-100001
    式中：In the formula:
    A、B、C分别独立地选自：N或C-R 2a； A, B, C are independently selected from: N or CR 2a ;
    各R 1、R 2、R 2a分别独立地选自：H、卤素、氰基、硝基、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷氧基、或者取代或未取代的C 3～C 6环烷氧基； Each R 1 , R 2 , and R 2a is independently selected from the group consisting of H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkane Group, substituted or unsubstituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy;
    R 3选自：取代或未取代的吡唑基、-(CH 2) mNR 5R 6、-(CH 2) mOCR 4R 5R 6或者-(CH 2) mCR 4R 5R 6；其中，m选自：0、1、2、3或4； R 3 is selected from: substituted or unsubstituted pyrazolyl, -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 or -(CH 2 ) m CR 4 R 5 R 6 ; Where m is selected from: 0, 1, 2, 3, or 4;
    R 4选自：氢或C 1～C 3烷基； R 4 is selected from: hydrogen or C 1 ～C 3 alkyl;
    R 5和R 6分别独立地选自：氢、取代或未取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N或C一同形成取代或未取代的含有杂原子的单环、稠环、螺环或桥环； R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or R 5 , R 6 and the N or C to which they are attached together form a substituted or unsubstituted heteroatom-containing Single ring, condensed ring, spiro ring or bridge ring;
    L选自：CH 2、NH或O； L is selected from: CH 2 , NH or O;
    n选自：0、1、2或3；n is selected from: 0, 1, 2 or 3;
    G选自：未取代或R 10取代的具有8-10个环原子的稠环烷基、稠脂杂环基、稠芳环基或稠芳杂环基； G is selected from: unsubstituted or R 10 substituted fused cycloalkyl group having 8-10 ring atoms, fused aliphatic heterocyclic group, fused aromatic ring group or fused aromatic heterocyclic group;
    R 10分别独立地选自H、卤素、氧代、硫代、氮代、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷基、取代或未取代的C 1～C 6烷氧基、取代或未取代的C 3～C 6环烷氧基或者S(O 2)R 7；R 7选自：H、C 1-C 6烷基或者C 3-C 6环烷基； R 10 is independently selected from H, halogen, oxo, thio, nitro, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted Substituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkoxy or S(O 2 )R 7 ; R 7 is selected from: H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
    其中，当G选自C 1～C 6烷基取代或未被取代的
    Figure PCTCN2019124686-appb-100002
    时，R 2a不为C 1～C 6烷氧基。     Where, when G is selected from C 1 ～C 6 alkyl substituted or unsubstituted
    Figure PCTCN2019124686-appb-100002
    In this case, R 2a is not C 1 to C 6 alkoxy.
  2. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，所述2-氨基嘧啶类化合物为：The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, wherein the 2-aminopyrimidine compound is:
    Figure PCTCN2019124686-appb-100003
    Figure PCTCN2019124686-appb-100003
  3. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    G选自：G is selected from:
    Figure PCTCN2019124686-appb-100004
    Figure PCTCN2019124686-appb-100005
    其中，X 1、X 2分别独立地选自：CH、C或N；X 3、X 4、X 5、X 6、X 7、X 8、X 9、X 10分别独立地选自：CH 2、CH、C、C＝O、C＝S、C＝NR 10、CR 10、N、NH、NR 10、NS(O 2)R 7、S、S(O)、S(O 2)或O。
    Figure PCTCN2019124686-appb-100004
    Figure PCTCN2019124686-appb-100005
    Wherein, X 1 and X 2 are independently selected from: CH, C or N; X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from: CH 2 , CH, C, C=O, C=S, C=NR 10 , CR 10 , N, NH, NR 10 , NS(O 2 )R 7 , S, S(O), S(O 2 ) or O .
  4. 根据权利要求3所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 3, characterized in that
    G选自以下基团：G is selected from the following groups:
    未被取代或被1-5个R 10取代的萘基、未被取代或被1-5个R 10取代的吲哚基、未被取代或被1-5个R 10取代的吲唑基、未被取代或被1-5个R 10取代的苯并噻吩基、未被取代或被1-5个R 10取代的苯并呋喃基、未被取代或被1-5个R 10取代的1,1-二氧代苯并噻吩基、未被取代或被1-5个R 10取代的1,2-苯并恶唑基、未被取代或被1-5个R 10取代的苯并咪唑基、未被取代或被1-5个R 10取代的吡啶并吡咯基、未被取代或被1-5个R 10取代的咪唑并吡啶基、未被取代或被1-5个R 10取代的吡唑并吡啶基、未被取代或被1-5个R 10取代的噻吩并吡咯基、或者未被取代或被1-5个R 10取代的噻吩并吡唑基。 Unsubstituted or substituted with 1-5 R 10 naphthyl, unsubstituted or substituted with 1-5 R 10 indolyl, unsubstituted or substituted with 1-5 R 10 indazolyl, Unsubstituted or substituted with 1-5 R 10 benzothienyl, unsubstituted or substituted with 1-5 R 10 benzofuranyl, unsubstituted or substituted with 1-5 R 10 1 , l-dioxo-benzothienyl, unsubstituted or substituted with 1-5 R 10 group is 1,2-oxazolyl, unsubstituted or substituted with 1-5 R 10 benzimidazole Group, unsubstituted or substituted by 1-5 R 10 pyridopyrrolyl, unsubstituted or substituted by 1-5 R 10 imidazopyridyl, unsubstituted or substituted by 1-5 R 10 Pyrazolopyridinyl, thienopyrrolyl unsubstituted or substituted with 1-5 R 10 , or thienopyrazolyl unsubstituted or substituted with 1-5 R 10 .
  5. 根据权利要求4所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 4, characterized in that
    G选自以下基团：G is selected from the following groups:
    Figure PCTCN2019124686-appb-100006
    Figure PCTCN2019124686-appb-100006
    Figure PCTCN2019124686-appb-100007
    Figure PCTCN2019124686-appb-100007
  6. 根据权利要求5所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 5, characterized in that
    G选自以下基团：
    Figure PCTCN2019124686-appb-100008
    Figure PCTCN2019124686-appb-100009
    G is selected from the following groups:
    Figure PCTCN2019124686-appb-100008
    Figure PCTCN2019124686-appb-100009
    R 10选自C 1～C 6烷基或C 3～C 6环烷基；R 7选自：H、C 1～C 6烷基、C 3～C 6环烷基。 R 10 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R 7 is selected from: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl.
  7. 根据权利要求1-6任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    R 3选自：R 8取代的吡唑基、-(CH 2) mNR 5R 6、-(CH 2) mOCR 4R 5R 6、-(CH 2) mCR 4R 5R 6；其中，m选自：0、1、2、3或4； R 3 is selected from: pyrazolyl substituted with R 8 , -(CH 2 ) m NR 5 R 6 , -(CH 2 ) m OCR 4 R 5 R 6 , -(CH 2 ) m CR 4 R 5 R 6 ; Where m is selected from: 0, 1, 2, 3 or 4;
    R 4选自：氢或C 1～C 3烷基； R 4 is selected from: hydrogen or C 1 ～C 3 alkyl;
    R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N或C一同形成R 8取代的含1、2或3个杂原子的3～8元单环，或者R 5、R 6和与其相连的N或C一同形成R 8取代的含1、2或3个杂原子的8～12元稠环、螺环或桥环，杂原子选自：O、N或者S； R 5 and R 6 are independently selected from: hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 together with N or C connected thereto form R 8 substituted 1, 2 or 3 3 to 8 membered monocyclic rings of hetero atoms, or R 5 and R 6 together with N or C connected to them form an 8 to 12 membered fused ring, spiro ring or R 8 substituted with 1, 2 or 3 heteroatoms Bridge ring, hetero atom selected from: O, N or S;
    各R 8分别独立地选自：H、R 9取代或未取代的4～8元杂环基、卤素、羟基、氨基、C 1～C 3烷基、-C(＝O)NHR 9取代的C 1～C 3烷基、羟基取代的C 1～C 3烷基、C 3～C 6环烷基取代的C 1～C 3烷基、C 3～C 8杂环基取代的C 1～C 3烷基、C 1～C 3烷氧基、-NHR 9、-N(R 9) 2或者-C(＝O)R 9；R 9为C 1～C 3烷基。 Each R 8 is independently selected from: H, R 9 substituted or unsubstituted 4-8 membered heterocyclic group, halogen, hydroxy, amino, C 1 -C 3 alkyl, -C(=O)NHR 9 substituted C 1 ～C 3 alkyl, hydroxy substituted C 1 ～C 3 alkyl, C 3 ～C 6 cycloalkyl substituted C 1 ～C 3 alkyl, C 3 ～C 8 heterocyclic group substituted C 1 ～ C 3 alkyl, C 1 -C 3 alkoxy, -NHR 9 , -N(R 9 ) 2 or -C(=O)R 9 ; R 9 is C 1 -C 3 alkyl.
  8. 根据权利要求7所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 7, characterized in that
    R 3选自：-NR 5R 6； R 3 is selected from: -NR 5 R 6 ;
    R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基，或者R 5、R 6和与其相连的N一同形成R 8取代的含1或2个杂原子的6元单环，杂原子选自：O、N或S。 R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl substituted with R 8 , or R 5 , R 6 and N to which they are connected together form R 8 substituted 1 or 2 heteroatoms 6-membered single ring, heteroatom selected from: O, N or S.
  9. 根据权利要求8所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 8, characterized in that
    R 3选自：
    Figure PCTCN2019124686-appb-100010
    R 8取代的
    Figure PCTCN2019124686-appb-100011
    R 8取代的
    Figure PCTCN2019124686-appb-100012
    R 8取代的
    Figure PCTCN2019124686-appb-100013
    或者R 8取代的
    Figure PCTCN2019124686-appb-100014
    R 5和R 6分别独立地选自：氢、R 8取代的C 1～C 6烷基。     R 3 is selected from:
    Figure PCTCN2019124686-appb-100010
    R 8 replaced
    Figure PCTCN2019124686-appb-100011
    R 8 replaced
    Figure PCTCN2019124686-appb-100012
    R 8 replaced
    Figure PCTCN2019124686-appb-100013
    Or substituted by R 8
    Figure PCTCN2019124686-appb-100014
    R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl substituted with R 8 .
  10. 根据权利要求9所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 9, characterized in that
    R 8选自：H、卤素、羟基、氨基、C 1～C 3烷基、-C(＝O)R 9、羟基取代的C 1～C 3烷基、C 1～C 3烷氧基、-NHR 9、-N(R 9) 2、
    Figure PCTCN2019124686-appb-100015
    R 9为C 1～C 3烷基。     R 8 is selected from: H, halogen, hydroxy, amino, C 1 -C 3 alkyl, -C(=O)R 9 , hydroxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NHR 9 , -N(R 9 ) 2 ,
    Figure PCTCN2019124686-appb-100015
    R 9 is C 1 to C 3 alkyl.
  11. 根据权利要求9所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 3选自： The 2-aminopyrimidine compound according to claim 9 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, wherein R 3 is selected from:
    Figure PCTCN2019124686-appb-100016
    Figure PCTCN2019124686-appb-100016
    Figure PCTCN2019124686-appb-100017
    Figure PCTCN2019124686-appb-100018
    或者
    Figure PCTCN2019124686-appb-100019
    Figure PCTCN2019124686-appb-100017
    Figure PCTCN2019124686-appb-100018
    or
    Figure PCTCN2019124686-appb-100019
  12. 根据权利要求1-6任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    R 1、R 2和R 2a分别独立地选自：H、卤素、氰基、硝基、C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基、C 3～C 6环烷氧基、卤素取代的C 1～C 6烷基或卤素取代的C 1～C 6烷氧基。 R 1 , R 2 and R 2a are independently selected from: H, halogen, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, halogen-substituted C 1 -C 6 alkyl or halogen-substituted C 1 -C 6 alkoxy.
  13. 根据权利要求12所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 1选自：H、卤素、甲基、氰基、三氟甲基、二氟甲基、甲氧基、环丙基或三氟甲氧基； The 2-aminopyrimidine compound according to claim 12 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, wherein R 1 is selected from the group consisting of: H, halogen, methyl, cyanide Group, trifluoromethyl, difluoromethyl, methoxy, cyclopropyl or trifluoromethoxy;
    R 2和R 2a分别独立地选自：H、氟、氯、溴、甲基、乙基、三氟甲基、二氟甲基、三氟甲氧基、环丙基、异丙基、正丙基、甲氧基、异丙氧基或环戊基氧基。 R 2 and R 2a are independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, cyclopropyl, isopropyl, n- Propyl, methoxy, isopropoxy or cyclopentyloxy.
  14. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    G选自
    Figure PCTCN2019124686-appb-100020
    Figure PCTCN2019124686-appb-100021
    Figure PCTCN2019124686-appb-100022
    时，R 2a选自：H、卤素、氰基、硝基、卤素取代或未取代的C 1～C 6烷基、卤素取代或未取代的C 3～C 6环烷基、卤素取代或未取代的C 1～C 6烷氧基、或者卤素取代或未取代的C 3～C 6环烷氧基；     G is selected from
    Figure PCTCN2019124686-appb-100020
    Figure PCTCN2019124686-appb-100021
    Figure PCTCN2019124686-appb-100022
    When R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl, halogen-substituted or unsubstituted Substituted C 1 ～C 6 alkoxy, or halogen substituted or unsubstituted C 3 ～C 6 cycloalkoxy;
    G选自
    Figure PCTCN2019124686-appb-100023
    时，R 2a选自：H、卤素、氰基、硝基、卤素取代或未取代的C 1～C 6烷基、或者卤素取代或未取代的C 3～C 6环烷基。     G is selected from
    Figure PCTCN2019124686-appb-100023
    In this case, R 2a is selected from: H, halogen, cyano, nitro, halogen-substituted or unsubstituted C 1 -C 6 alkyl, or halogen-substituted or unsubstituted C 3 -C 6 cycloalkyl.
  15. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    G为
    Figure PCTCN2019124686-appb-100024
    G is
    Figure PCTCN2019124686-appb-100024
    R 1选自：H、卤素、C 1～C 6烷基或卤素取代的C 1～C 6烷基； R 1 is selected from: H, halogen, C 1 -C 6 alkyl or halogen substituted C 1 -C 6 alkyl;
    R 2选自：H、卤素、C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基或C 3～C 6环烷氧基； R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy;
    R 2a分别独立地选自：H、卤素、氰基、硝基、取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、取代或未取代的C 1～C 6烷氧基、或者取代或未取代的C 3～C 6环烷氧基。 R 2a is independently selected from: H, halogen, cyano, nitro, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy.
  16. 根据权利要求15所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to claim 15, characterized in that
    A、B、C选自C-H；A, B, C are selected from C-H;
    R 3选自
    Figure PCTCN2019124686-appb-100025
    R 3 is selected from
    Figure PCTCN2019124686-appb-100025
  17. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, characterized in that
    G选自
    Figure PCTCN2019124686-appb-100026
    G is selected from
    Figure PCTCN2019124686-appb-100026
    R 1选自H、卤素或者卤素取代的C 1～C 6烷基； R 1 is selected from H, halogen or halogen substituted C 1 ～C 6 alkyl;
    A、B、C选自C-H；A, B, C are selected from C-H;
    R 2选自：H、卤素、C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 3～C 6环烷基、C 1～C 6烷氧基或C 3～C 6环烷氧基。 R 2 is selected from: H, halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy.
  18. 根据权利要求1所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，所述2-氨基嘧啶类化合物选自：The 2-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer or prodrug molecule thereof, wherein the 2-aminopyrimidine compound is selected from:
    Figure PCTCN2019124686-appb-100027
    Figure PCTCN2019124686-appb-100027
    Figure PCTCN2019124686-appb-100028
    Figure PCTCN2019124686-appb-100028
    Figure PCTCN2019124686-appb-100029
    Figure PCTCN2019124686-appb-100029
  19. 权利要求1-18任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立 体异构体或者其前药分子在制备突变型EGFR抑制剂中的应用。Use of the 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule according to any one of claims 1-18 in the preparation of mutant EGFR inhibitors.
  20. 权利要求1-18任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备防治肿瘤的药物中的应用。Use of the 2-aminopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, in the preparation of a medicament for preventing and treating tumors.
  21. 根据权利要求20所述的应用，其特征在于，所述肿瘤为EGFR基因突变的恶性肿瘤。The use according to claim 20, characterized in that the tumor is a malignant tumor with EGFR gene mutation.
  22. 根据权利要求21所述的应用，其特征在于，所述肿瘤为EGFR L858R/T790M/C797S突变的恶性肿瘤。 The use according to claim 21, characterized in that the tumor is a malignant tumor with EGFR L858R/T790M/C797S mutation.
  23. 根据权利要求20所述的应用，其特征在于，所述肿瘤为：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌或胶质瘤。The use according to claim 20, wherein the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial Cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumor, colon cancer, rectal cancer or glioma.
  24. 一种药物组合物，其特征在于，包括活性成分以及药学上可接受的载体，所述活性成分包括有权利要求1-18任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。A pharmaceutical composition characterized by comprising an active ingredient and a pharmaceutically acceptable carrier, the active ingredient comprising the 2-aminopyrimidine compound of any one of claims 1-18 or a pharmaceutically acceptable thereof Salt or its stereoisomer or its prodrug molecule.
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