WO2021185297A1 - Egfr酪氨酸激酶抑制剂及其用途 - Google Patents

Egfr酪氨酸激酶抑制剂及其用途 Download PDF

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WO2021185297A1
WO2021185297A1 PCT/CN2021/081404 CN2021081404W WO2021185297A1 WO 2021185297 A1 WO2021185297 A1 WO 2021185297A1 CN 2021081404 W CN2021081404 W CN 2021081404W WO 2021185297 A1 WO2021185297 A1 WO 2021185297A1
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cancer
alkyl
amino
compound
egfr
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PCT/CN2021/081404
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French (fr)
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陈弘道
胡佳琪
王心悟
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南京药石科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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

Definitions

  • This application belongs to the field of chemistry and medicine, and specifically relates to an EGFR tyrosine kinase inhibitor and its use.
  • Lung cancer is one of the most common malignant tumors in the world. Lung cancer is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma and large cell carcinoma. Compared with SCLC, NSCLC cancer cells grow and divide more slowly, and spread and metastasize relatively late. NSCLC accounts for about 80% of all lung cancers, and the prognosis is poor. About 75% of patients are in the advanced stage when they are discovered.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • epidermal growth factor receptor EGFR
  • NSCLC Oncotarget.2016Jul 5; 7(27): 41691-41702
  • EGFR is a member of the epidermal growth factor receptor (HER) family, which is composed of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.
  • EGFR is a glycoprotein. It is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. It is a tyrosine kinase receptor with a permeable cell membrane and located on the surface of the cell membrane (Clin Cancer Res; 21(3) February 1, 2015, 526-533).
  • EGFR is not only overexpressed, but also has abnormal activation mutations in its tyrosine kinase structure region that do not depend on ligand binding.
  • the most common kinase activity mutations are EGFR (Exon 19 del E746-A750) and EGFR (Exon 21 L858R), the first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) that has been marketed and gefitinib (gefitinib) And erlotinib (erlotinib) has been approved for the treatment of these two mutations, but the first generation of EGFR-TKI developed drug resistance during the treatment process, and the generation of drug resistance was replaced with the threonine at position 790 of EGFR It is related to the secondary mutation of methionine (T790M).
  • the second-generation non-reversible covalent inhibitors such as Afatinib
  • the reasons are It is more active against wild-type EGFR than inhibiting EGFR (delE746-A750/T790M) and EGFR (L858R/T790M) resistant mutants, thus exhibiting dose-dependent toxicity (Biologics, 2014, 8:183-192) , Unable to obtain an effective treatment window. Therefore, the third-generation EGFR-TKIs, such as AZD9291, CO-1686 and HM61713, have been developed.
  • the third-generation EGFR-TKI is a tyrosine kinase inhibitor with specific selectivity. Compared with the first and second generation of EGFR-TKI, the third generation of EGFR-TKI reduces the inhibition of wild-type EGFR, reduces clinical toxic side effects, and can use higher clinical doses to obtain better curative effects . (J Clin Oncol 2014; 32: abstr 8009; J Clin Oncol 2014; 32: abstr 8010).
  • EGFR exon20ins Another EGFR mutation that is abnormally activated and induces cancer is the exon 20 insertion mutation (EGFR exon20ins).
  • EGFR exon20ins Another EGFR mutation that is abnormally activated and induces cancer.
  • EGFR exon20ins Another EGFR mutation that is abnormally activated and induces cancer.
  • EGFR exon20ins Previous studies have shown that this type of mutation accounts for 4%-10% of all EGFR-mutated lung cancers (PLoS ONE 2015 10(7) ):e0133859). At present, there are still no drugs available for treatment in the clinic (Mol Cancer Ther. 2013, 12, 220). Patients with such mutations are not sensitive to the currently marketed EGFR inhibitor drugs.
  • the current standard treatment regimen is cytotoxic chemotherapy with prognostic effect Poor, strong side effects, no targeted drugs are currently available.
  • This application discloses a class of compounds that can be used as EGFR protein kinase inhibitors and their use in the preparation of drugs for the prevention or treatment of EGFR-related diseases.
  • this application provides a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:
  • each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano, alkoxy or
  • R 2 is an aryl, heteroaryl or cycloalkyl group, and the aryl, heteroaryl or cycloalkyl group is optionally substituted with 0-2 R 2 ′;
  • Each R 2 ' is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
  • R 4 is selected from
  • n 1, 2 or 3;
  • Z 1 is C or N
  • Z 2 is an alkylene group or a bond.
  • formula (I) is formula (Ia):
  • Each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano, alkoxy or
  • R 2 is an aryl, heteroaryl or cycloalkyl group, and the aryl, heteroaryl or cycloalkyl group is optionally substituted with 0-2 R 2 ′;
  • Each R 2 ' is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
  • R 4 is selected from
  • n 1, 2 or 3;
  • Z 1 is C or N
  • Z 2 is a methylene group or a bond.
  • formula (I) is formula (Ib):
  • Each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano, alkoxy or
  • R 2 is an aryl, heteroaryl or cycloalkyl group, and the aryl, heteroaryl or cycloalkyl group is optionally substituted with 0-2 R 2 ′;
  • Each R 2 ' is independently selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
  • R 4 is selected from
  • n 1, 2 or 3;
  • Z 1 is C or N.
  • R 2 is phenyl, pyridyl, or cyclohexyl optionally substituted with 0-2 R 2 ′.
  • R 2 is selected from:
  • the compound is selected from the following compounds:
  • the aforementioned compounds can be used to prepare drugs for the prevention or treatment of receptor tyrosine kinase mutations, especially EGFR mutation-related diseases;
  • the EGFR mutation-related diseases are cancers, especially related cancers that have mutations in the exon 20 domain of EGFR ,
  • this application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof; and a pharmaceutically acceptable carrier or excipient Agent.
  • the pharmaceutically acceptable carrier or excipient may include any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents such as hydrates and solvents. If necessary, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like.
  • the aforementioned pharmaceutical composition may also contain one or more other anti-cancer drugs, and the anti-cancer drugs are small molecule drugs, monoclonal antibodies or fusion protein drugs.
  • the compound with EGFR tyrosine kinase inhibitory activity provided in this application has a strong inhibitory ability on EGFR (D770_N771insNPG) insertion mutation kinase activity.
  • the inhibition of the proliferation ability of wild-type EGFR high-expressing mouse primary B cells (BaF3) is low, and at the same time, it can effectively inhibit the proliferation of BaF3 cells with high expression of EGFR exon20 insertion mutation.
  • the selective inhibitory activity of mutant cells relative to wild cells is a more important and critical indicator as a clinical treatment window.
  • the compound provided in the present application can be used in clinical applications at a higher dose without causing obvious toxicity, greatly improving the curative effect, and obtaining a better prognostic effect. And it has a good inhibitory effect on the abnormal proliferation of tumor cells with high expression of common EGFR mutations, EGFR (delE746-A750), and Her2 insertion mutations.
  • isomer includes enantiomeric forms, diastereomeric forms, and geometric (or conformational) isomeric forms of a given structure.
  • this application includes the R and S configurations of each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and enantiomers, diastereomers Isomers and geometric (or conformational) isomer mixtures.
  • Suitable acid addition salts are formed from acids, which form non-toxic salts, such as hydrochloride/chloride.
  • Suitable base salts are formed from bases, which form non-toxic salts such as calcium and sodium salts. It is also possible to form half salts of acids and bases, such as hemisulfate and hemicalcium salts.
  • terapéuticaally effective amount refers to the following amount of the compound of the present application, which (i) treats a specific disease, disorder, or disorder; (ii) reduces, alleviates, or eliminates one or more symptoms of a specific disease, disorder, or disorder Or (iii) to prevent or delay the onset of one or more symptoms of the specific disease, condition or disorder described in this application.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound formulated with it.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group.
  • Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl Group, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-Dimethylbutyl and so on.
  • alkenyl refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, alkenyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • C 2-6 alkenyl includes linear or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • an alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms.
  • C 2-6 alkynyl includes straight or branched chain hydrocarbon alkynyl groups having 2 to 6 carbon atoms as defined above.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms (e.g. 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydro Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) Heteroatoms of m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • the heterocyclic group includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic, and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, which is combined with the parent structure
  • the rings connected together are heterocyclic groups, non-limiting examples of which include:
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl, etc.
  • the heteroaryl group includes the heteroaryl group as described above fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, where the alkoxy group is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • cycloalkyloxy refers to -O-cycloalkyl, where cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclic groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, where aryl and alkyl are as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • step 1 Using a method similar to Example 1, the compound 1.2 in step 1 was replaced with (2-(pyridin-2-ylmethoxy)phenyl)boronic acid, and the compound 1.4 in step 2 was replaced with 4-fluoro-2-methoxy -5-Nitroaniline to give the title compound.
  • step 1 Using a method similar to Example 1, the compound 1.2 in step 1 was replaced with (2-(pyridin-2-yloxy)phenyl)boronic acid, and the compound 1.4 in step 2 was replaced with 4-fluoro-2-methoxy- 5-Nitroaniline gives the title compound.
  • step 1 Using a method similar to Example 1, the compound 1.2 in step 1 was replaced with (2-(m-tolyloxy)phenyl)boronic acid, and the compound 1.4 in step 2 was replaced with 4-fluoro-2-methoxy-5-nitro Aniline to give the title compound.
  • step 2 Using a method similar to Example 1, replace the compound 1.2 of step 1 with (2-(pyridin-3-yloxy)phenyl) pinacol borate (prepared by the aforementioned method A), the compound of step 2 1.4 Replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 Using the method similar to Example 1, the compound 1.2 of step 1 was replaced with (2-(cyclohexyloxy)phenyl)boronic acid, and the compound 1.4 of step 2 was replaced with 4-fluoro-2-methoxy-5-nitro Aniline to give the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with (2-(3-(trifluoromethyl)phenoxy)phenyl) pinacol borate (prepared by the aforementioned method A), The compound 1.4 of step 2 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with (5-methyl-2-(m-tolyloxy)phenyl) pinacol borate (prepared by the aforementioned method A), step 2 Substitution of 1.4 of the compound with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace the compound 1.2 of step 1 with (2-(3-ethylphenoxy)phenyl) pinacol borate (prepared by the aforementioned method A), the compound of step 2 1.4 Replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with (2-((5-methylpyridin-3-yloxy)phenyl) pinacol borate (prepared by the aforementioned method A) , The compound 1.4 of step 2 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using the method similar to Example 1, replace the compound 1.2 of step 1 with (3-(m-tolyloxy)pyridin-4-yl)pinacol borate (prepared by the aforementioned method C), the compound of step 2 1.4 Replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with (2-((6-methylpyridin-2-yl)oxy)phenyl) pinacol borate (prepared by the aforementioned method B) ), the compound 1.4 of step 2 is replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 Using a method similar to Example 1, replace compound 1.2 of step 1 with (2-(3,5-dimethylphenoxy)phenyl) pinacol borate (prepared by the aforementioned method A), step The second compound 1.4 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with (2-((4-methylpyridin-2-yl)oxy)phenyl) pinacol borate (prepared by the aforementioned method B) ), the compound 1.4 of step 2 is replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using the method similar to Example 1, replace compound 1.2 of step 1 with 4,4,5,5-tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaboron Alkane (prepared by the aforementioned method A), the compound 1.4 of step 2 is replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)- 1,3,2-dioxaborane (prepared by the aforementioned method A), the compound 1.4 of step 2 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.2 of step 1 with 1-methyl-3-(2-boronic acid pinacol ester phenoxy)-1-hydro-pyrazole (prepared by the aforementioned method A) ), the compound 1.4 of step 2 is replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 replace compound 1.1 of step 1 with 2,4-dichloro-5-fluoropyrimidine, and replace compound 1.2 with (2-(pyridin-2-yloxy)phenyl)boronic acid, step The second compound 1.4 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.1 of step 1 with 2,4-dichloro-5-methoxypyrimidine, and compound 1.2 with (2-(pyridin-2-yloxy)phenyl)boronic acid , The compound 1.4 of step 2 is replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 the compound 1.2 in step 1 was replaced with (2-(pyridin-2-yloxy)phenyl)boronic acid, and the compound 1.4 in step 2 was replaced with 4-fluoro-2-methoxy- 5-Nitroaniline, replace N,N,N'-trimethylethylenediamine in step 3 with (3R)-(+)-3-dimethylaminopyrrolidine to obtain the title compound.
  • step 2 Using a method similar to Example 1, replace compound 1.1 of step 1 with 2,4-dichloro-5-methylpyrimidine, and compound 1.2 with (2-(pyridin-2-yloxy)phenyl)boronic acid, The compound 1.4 of step 2 was replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 Using a method similar to Example 1, the compound 1.2 of step 1 was replaced with 2-(2-boronic acid pinacol ester phenoxy)-benzonitrile (prepared by the aforementioned method A), and the compound 1.4 of step 2 was replaced It is 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • step 1 Using a method similar to Example 1, the compound 1.2 of step 1 was replaced with 2-cyano-3-(2-boronic acid pinacol ester phenoxy)pyridine (prepared by the aforementioned method A), the compound of step 2 1.4 Replaced with 4-fluoro-2-methoxy-5-nitroaniline to obtain the title compound.
  • the EGFR D770_N771insNPG kinase expressed in the baculovirus expression system was purchased from Shanghai Univ Biological Inc.. Contains biotin-labeled peptide substrate TK Substrate-biotin, Eu-labeled specific phosphorylated peptide antibody TK Antibody-Cryptate, HTRF fluorescent receptor reagent Streptavidin-XL665 and 5 ⁇ kinase reaction buffer solution, detection buffer TK Kinase HTRF detection kit (#62TK0PEC) was purchased from Cisbio Bioassays (Codolet, France). Dithiothreitol (DTT), magnesium chloride, manganese chloride, adenosine triphosphate (ATP), dimethyl sulfoxide (DMSO) and HEPES buffers were obtained from Sigma at the highest level of purity available.
  • DTT dithiothreitol
  • magnesium chloride magnesium chloride
  • manganese chloride adenosine triphosphat
  • the phosphorylation reaction buffer is composed of 1M HEPES (pH 7.0), 5mM MgCl 2 , 1mM MnCl 2 , and 1mM DTT is added to the buffer immediately before the start of the experiment.
  • the obtained gradient dilution solution is further diluted with a phosphorylation reaction buffer solution to obtain a working solution of the test compound dissolved in a reaction buffer solution containing 5% DMSO.
  • the final concentrations of kinase, peptide substrate, ATP and DMSO The concentrations were 0.01ng/ul, 200nM, 4 ⁇ M and 1%.
  • the reaction was performed at room temperature for 60 minutes in the dark.
  • the final concentration of Streptavidin-XL665 in the WT EGFR kinase reaction system is 15.61 nM, and the final concentration of Streptavidin-XL665 in the EGFR D770_N771insNPG kinase reaction system is 31.25 nM.
  • the antibody is diluted according to the final concentration provided by the supplier.
  • Use Tecan( Switzerland) Multi-function microplate reader Spark reads the plate and detects two sets of homogeneous time-resolved fluorescence intensity.
  • the excitation wavelength is 320nm and the emission wavelength is 665nm and 620nm, respectively.
  • the experimental results show that the compound of the present application can effectively inhibit the EGFR D770_N771insNPG kinase activity, and the IC 50 of Example 2 is less than 1 nM.
  • H358, A431, HCC827 cells were purchased from the Chinese Academy of Sciences Cell Bank (Shanghai), BaF3 EGFR WT, BaF3 EGFR D770_N771insSVD, BaF3 EGFR V769_D770insASV, BaF3 ERBB2A775_G776insYVMA cells were purchased from Beijing Kangyuan Bochuang, MDA-MB-231, SK-BR-3 , BT474 was purchased from Nanjing Kebai Biological Technology Co., Ltd.
  • MEM medium MEM medium, RPMI1640 medium, penicillin-streptomycin double antibody, 0.5% trypsin (10X) and epidermal growth factor EGF were purchased from ThermoFisher (Waltham, MA, USA). Certified fetal bovine serum (FBS) was purchased from Biological Industries (Israel). Corning 96 and 384-well cell culture plates were purchased from CORNING (USA). Cell-Titer Purchased from Promega Corporation (Madison, WI, USA).
  • A775_G776insYVMA exponentially growing cells were inoculated in RPMI1640 medium containing 10% bovine serum and 1% penicillin-streptomycin dual antibody, and BaF3 EGFR WT exponentially growing cells were inoculated into 10% bovine serum, 1% penicillin-streptomycin dual antibody Antibody and 50ng/mL EGF RPMI1640 medium, HCC827, BaF3 ERBB2
  • A775_G776insYVMA density is 75,000 cells/mL
  • H358 density is 100,000 cells/mL
  • BaF3 V769_D770insASV density is 50,000 cells/mL
  • BaF3 EGFR WT The density is 125000 cells/mL, 384-well plate, 20 ⁇ L per well, and placed in a 37°C, 5% CO 2 incubator overnight.
  • the compound was diluted in DMSO to 12 points, 3-fold serial dilutions, starting from 2mM.
  • 20 ⁇ L of the compound solution in the culture medium was added to each cell-plated well of the 384 plate according to a gradient. After adding the compound solution, the 384-well plate was placed in a 37°C, 5% CO 2 incubator and incubated for 3 days.
  • Promega (Madison, WI, USA)'s CellTiter-Glo detection kit was used to determine cell viability by quantifying the ATP present in cell culture.
  • Ref-1 was prepared according to the preparation method described in WO2015195228A1, and the structure is as follows:
  • Table 3 shows the inhibitory results of some compounds prepared according to the foregoing examples on the proliferation of HCC 827 and H358WT cells.
  • Table 4 shows the inhibitory results of some compounds prepared according to the foregoing examples on the proliferation of MDA-MB-231, SK-BR-3 and BT474 cells.

Abstract

本申请提供一种式(I)化合物、其立体异构体或其药学上可接受的盐，以及其用于制备预防或治疗EGFR突变引起的相关疾病药物的用途。

Description

EGFR酪氨酸激酶抑制剂及其用途 技术领域
本申请属于化学医药领域，具体涉及一种EGFR酪氨酸激酶抑制剂及其用途。
背景技术
肺癌是世界上最常见的恶性肿瘤之一，肺癌分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)，其中NSCLC包括鳞状细胞癌(鳞癌)、腺癌和大细胞癌。与SCLC相比，NSCLC的癌细胞生长分裂较慢，扩散转移相对较晚。NSCLC约占所有肺癌的80％，预后不良，约75％的患者发现的时候已处于中晚期。而表皮生长因子受体(EGFR)的过度表达和突变已被明确证实将导致不可控的细胞生长，与大部分癌症疾病的进程有关，尤其是NSCLC(Oncotarget.2016 Jul 5；7(27):41691-41702)。
EGFR是表皮生长因子受体(HER)家族成员之一，该家族由EGFR(Erb-Bl)、Erb-B2(HER-2/neu)、Erb-B3和Erb-B4组成。EGFR是一种糖蛋白，是表皮生长因子(EGF)细胞增殖和信号传导的受体，属于酪氨酸激酶型受体，细胞膜贯通，位于细胞膜表面(Clin Cancer Res；21(3)February 1,2015,526-533)。
在NSCLC病人中，EGFR不仅有过度表达，而且还在它的酪氨酸激酶结构区域有不依赖于配体结合的激酶活性异常激活突变。其中最常见的激酶活性突变是EGFR(Exon 19 del E746-A750)和EGFR(Exon 21 L858R)，第一代已经上市的EGFR酪氨酸激酶抑制剂(EGFR-TKI)吉非替尼(gefitinib)和厄洛替尼(erlotinib)已经被批准用于治疗这两种突变，但第一代EGFR-TKI在治疗过程中产生耐药性，耐药性的产生与EGFR 790号位的苏氨酸置换为蛋氨酸(T790M)发生的二次突变相关。第二代的非可逆共价抑制剂，如阿法替尼(Afatinib)对治疗EGFR(delE746-A750)和EGFR(L858R)效果更好，但对耐药性T790M突变体效果不佳，其原因是对野生型EGFR比抑制EGFR(delE746-A750/T790M)和EGFR(L858R/T790M)耐药性突变体活性更高，从而表现出了剂量依赖性毒性(Biologics,2014,8:183-192)，无法获得有效的治疗窗口。因此研究出第三代EGFR-TKI，比如AZD9291、CO-1686和HM61713。第三代EGFR-TKI是具有特异选择性的酪氨酸激酶抑制剂。相较于第一代和第二代EGFR-TKI，第三代的EGFR-TKI降低了对野生型的EGFR的抑制，减少临床上的毒副作用，可以使用更高的临床剂量获得较好的疗效。(J Clin Oncol 2014；32:abstr 8009；J Clin Oncol 2014；32:abstr 8010)。
另外一种异常激活进而诱导癌症发生的EGFR突变是外显子20插入突变(EGFR exon20ins)，先前的研究表明这类突变占所有的EGFR突变肺癌的4％-10％(PLoS ONE 2015 10(7):e0133859)。目前在临床上仍然没有药物能用于治疗(Mol Cancer Ther.2013,12,220)，这类突变病人对现有上市的EGFR抑制剂药物都不敏感，目前标准治疗方案为细胞毒类化疗，预后效果差，副作用强，目前尚无靶向药物可用。靶向EGFR exon20插入突变的候选药物Poziotinib 和Ref-1已经进入临床研究，但它们对野生型EGFR抑制能力非常强，因此会带来较大的毒副作用，比如皮肤毒性等。严重限制了临床剂量的提高和临床药效。另外，还有最近刚刚进入临床的化合物CLN-081和DZ9008，虽然在体外活性上表明降低了对野生型的毒性，但它们的临床效果还没有进一步证实。综上，具有更高活性和低毒性的化合物仍有待开发。
发明内容
本申请公开了一类可作为EGFR蛋白激酶抑制剂的化合物以及其在制备预防或治疗EGFR相关疾病药物中的用途。
一方面，本申请提供式(I)化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2021081404-appb-000001
其中，每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
Figure PCTCN2021081404-appb-000002
R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基
R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
R 4选自
Figure PCTCN2021081404-appb-000003
n为1、2或3；
Z 1为C或N；并且
Z 2为亚烷基或键。
在一些实施方案中，式(Ⅰ)是式(Ⅰa)：
Figure PCTCN2021081404-appb-000004
每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
Figure PCTCN2021081404-appb-000005
R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
R 4选自
Figure PCTCN2021081404-appb-000006
n为1、2或3；
Z 1为C或N；并且
Z 2为亚甲基或键。
在另一些实施方案中，式(Ⅰ)是式(Ⅰb)：
Figure PCTCN2021081404-appb-000007
每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
Figure PCTCN2021081404-appb-000008
R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基 或烷氧基；
R 4选自
Figure PCTCN2021081404-appb-000009
n为1、2或3；并且
Z 1为C或N。
在另一些实施方案中，R 2为可选地被0-2个R 2’取代的苯基、吡啶基或环己基。
在另一些实施方案中，R 2选自：
Figure PCTCN2021081404-appb-000010
在另一些实施方案中，所述化合物选自如下化合物：
Figure PCTCN2021081404-appb-000011
Figure PCTCN2021081404-appb-000012
Figure PCTCN2021081404-appb-000013
Figure PCTCN2021081404-appb-000014
前述化合物可用于制备预防或治疗受体酪氨酸激酶突变，尤其是EGFR突变相关疾病药物；所述EGFR突变相关疾病为癌症，尤其是在EGFR的外显子20结构域中发生突变的相关癌症，如非小细胞肺癌，乳腺癌，脑癌，卵巢癌，胰腺癌，子宫癌，宫颈癌，皮肤癌，前列腺癌，膀胱癌，肝癌，胃肠组织癌，食道癌，甲状腺癌，白血病，淋巴瘤以及多发性骨髓瘤等。
另一方面，本申请还提供了一种药物组合物，其包含治疗有效量的式(I)的化合物或其药学上可接受的盐、异构体；和药学上可接受的载体或赋形剂。药学上可接受的载体或赋形剂可包含任何常规药物载体或赋形剂。合适的药物载体包括惰性稀释剂或填充剂、水以及各种有机溶剂诸如水合物和溶剂。如果需要，药物组合物可含有另外的成分，诸如调味剂、粘合剂、赋形剂等。
前述药物组合物还可包含其它一种或多种抗癌药物，所述抗癌药物为小分子药物、单克隆抗体或融合蛋白药物。
本申请所提供的具有EGFR酪氨酸激酶抑制活性的化合物，对EGFR(D770_N771insNPG)插入突变激酶活性具有很强的抑制能力。对野生型EGFR高表达小鼠原B细胞(BaF3)增殖能力的抑制较低，与此同时，能有效的抑制EGFR exon20插入突变高表达的BaF3细胞增殖。相比于单一的突变EGFR高表达肿瘤细胞增殖抑制活性，突变细胞相对于野生细胞抑制活性的选择性是作为临床治疗窗口更为重要和关键的指标。因此本申请所提供的化合物在临床应用中能够使用更高的剂量而不带来明显的毒性，大大提高疗效，获得更好的预后效果。并且对常见的EGFR突变，EGFR(delE746-A750)，Her2插入突变高表达肿瘤细胞的异常增殖都有良好的抑制效果。
术语：
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如，本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指，诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成，其形成无毒盐，例如盐酸盐/氯化物。合适的碱盐由碱形成，其形成无毒盐，例如钙盐和钠盐。还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量，其(i)治疗具体的疾病、病症或障碍；(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状；或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烯基”指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中，烯基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如，术语“C 2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键)，包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
术语“炔基”指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中，炔基基团具有2至20、2至10、2至6、或3至6个碳原子。例如，“C 2-6炔基”包括具有2至6个碳原子的如上定义的直链或支链烃链炔基基团。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子(例如3、4、5或6个碳原子)，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以 含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双 环、三环或四环，更优选为双环或三环。
所述杂环基包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021081404-appb-000015
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
所述杂芳基包括如上所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021081404-appb-000016
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
具体实施方式
本申请所涉及部分中间体可参考如下通用方法制得：方法A：
Figure PCTCN2021081404-appb-000017
方法B：
Figure PCTCN2021081404-appb-000018
方法C：
Figure PCTCN2021081404-appb-000019
实施例1 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(2-苯氧基苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000020
步骤一：
Figure PCTCN2021081404-appb-000021
将化合物1.1(1g，6.71mmol，1eq.)，化合物1.2(1g，4.67mmol，0.69eq.)，四三苯基膦钯(775.28mg，670.91μmol，0.1eq.)，碳酸钾(2.78g，20.14mmol，3eq.)溶于二氧六环(20mL)和水(4mL)中，氮气置换三次，升温至75℃，反应5小时。将反应液中加入EA(50mL)萃取，分出有机相，无水硫酸镁干燥，旋干，柱层析(正庚烷：乙酸乙酯＝10：1)，得浅黄色油状物(1.20g，收率：63.23％)。
步骤二：
Figure PCTCN2021081404-appb-000022
将化合物1.3(1.20g，4.24mmol，1eq.)，化合物1.4(993.92mg，6.37mmol，1.5eq.)，碳酸铯(4.15g，12.73mmol，3eq.)，xphos(404.68mg，848.88umol，0.2eq.)，Pd 2(dba) 3(388.67mg，424.44umol，0.1eq.)，二氧六环(20mL)，氮气置换3次，升温至110℃，反应3小时。反应液加入二氯甲烷(30mL)，过滤，滤液旋干，柱层析，得到棕黄色固体(1.50g，收率：87.83％)。
步骤三：
Figure PCTCN2021081404-appb-000023
将化合物1.5(1.50g，3.73mmol，1eq.)，N,N,N'-三甲基乙二胺(1.14g，11.18mmo l，3eq.)溶于ACN(30mL)，升温至80℃，反应12小时。将反应液旋干，柱层析(DC M:MeOH＝30:1+5％氨水)，得到棕色胶状固体(600mg，收率：33.22％)。
步骤四：
Figure PCTCN2021081404-appb-000024
将化合物1.6(400mg，825.51umol，1eq.)，Fe(461.01mg，8.26mmol，10eq.)溶于EtOH(10mL)和饱和NH 4Cl水溶液(5mL)，升温至80℃，搅拌4h，将反应液降至 室温，加入二氯甲烷(100mL)，过滤，滤液用二氯甲烷萃取，有机相合并，无水硫酸镁干燥，过滤，旋干。得黑色胶状物400mg，粗品直接进行一下步反应。
步骤五：
Figure PCTCN2021081404-appb-000025
氮气保护下，将化合物1.7(400mg，879.96umol，1eq.)，N，N-二乙基乙胺(178.09mg，1.76mmol，2eq.)溶于DCM(10mL)，降温至-10℃，加入化合物1.8(79.64mg，879.96umol，1eq.)，搅拌30分钟。反应液柱层析(DCM:MeOH＝25:1)，得到棕色固体(68mg，收率：15.19％)。 1H NMR(400MHz,DMSO-d6)(ppm):9.80(brs,1H),9.62(s,1H),8.63(s,1H),8.43(d,1H),8.19-8.21(d,1H),7.50-7.54(m,2H),7,31-7.40(m,3H),7.20-7.23(d,1H),7.10-7.14(t,1H),7.0-7.03(m,3H),6.30-6.35(dd,1H),5.77-5.78(d,1H),2.60-3.33(m,6H),2.59(s,3H)。LC-MS(m/z):510.19[M+H] +。
实施例2 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-苯氧基苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000026
使用实施例1相似的方法，将步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):9.85(brs,1H),8.90(s,1H),8.42-8.43(d,1H),8.20-8.30(m,1H),8.09(s,1H),7.49-7.54(m,1H),7.29-7.40(m,4H),7.11-7.14(t,1H),6.98-7.02(m,4H),6.30-6.35(dd,1H),5.76-5.79(d,1H),3.88(s,3H),3.0-3.29(m,2H),2.64(m,6H)。LC-MS(m/z):538.86[M+H] +。
实施例3 N-(5-((4-(2-(苄氧基)苯基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)苯基酰胺
Figure PCTCN2021081404-appb-000027
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(苄氧基)苯基)硼酸，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.21(s,1H),9.55(s,1H),8.76(s,1H),8.42-8.43(d,1H),8.10-8.11(d,1H),7.44-7.50(m,4H),7.33-7.44(m,4H),7.22-7.27(t,2H),7.10-7.12(t,1H),6.37-6.40(d,1H),6.31-6.32(d,1H),5.78-5.81(dd,1H),5.26(d,2H),2.80-2.82(t,2H),2.65(s,3H),2.21-2.26(m,2H),2.20(s,6H)。LC-MS(m/z):524.09[M+H] +。
实施例4 N-(5-((4-(2-(苄氧基)苯基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000028
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(苄氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DM SO-d6)(ppm):10.12(s,1H),9.07(s,1H),8.40-8.42(d,1H),8.19-8.21(d,1H),8.03(s,1H),7.33-7.48(m,7H),7.24-7.26(d,1H),7.08-7,10(t,1H),7.0(s,1H),6.37-6.39(d,1H),6.30-6.31(d,1H),5.75-5.78(dd,1H),5.26(s,2H),3.86(s,3H),2.85-2.88(t,2H),2.70(s,3H),2.21-2.29(m,2H),2.20(s,6H)。LC-MS(m/z):554.06[M+H] +。
实施例5 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(吡啶-2-基甲氧基)苯基)嘧啶-2-基)氨基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000029
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(吡啶-2-基甲氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MH z,DMSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.59-8.60(m,1H),8.44-8.45(d,1H),8.15-8.25(d,1H),8.05(s,1H),7.82-7.84(t,1H),7.50-7.53(m,3H),7.42-7.47(m,1H),7.20-7.24(d,1H),7.09-7.11(t,1H),7.01(s,1H),6.20-6.39(m,2H),5.75-5.78(d,1H),5.33(s,2H),3.86(s,3H),2.85-2.88(t,2H),2.70(s,3H),2.28-2.30(t,2H),2.20(s,6H)。LC-MS(m/z):554.98[M+H] +。
实施例6 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(2-(吡啶-2-基甲氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000030
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(吡啶-2-基甲氧基)苯基)硼酸，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.21(s,1H),9.56(s,1H),8.76-8.77(d,1H),8.59-8.60(m,1H),8.45-8.47(d,1H),8.08-8.10(dd,1H),7.82-7.83(t,1H),7.43-7.52(m,4H),7.35(m,1H),7.22-7.24(d,2H),7.11-7.13(t,1H),6.31-6.44(m,2H),5.78-5.80(dd,1H),5.33(s,2H),2.79-2.82(t,2H),2.65(s,3H),2.19-2.25(m,8H)。LC-MS(m/z):524.98[M+H] +。
实施例7 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(对甲苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000031
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(对甲苯氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.31-8.33(d,1H),8.09(s,1H),7.46-7.48(t,1H),7.34-7.35(d,1H),7.28-7.30(t,1H),7.17-7.19(d,2H),7.01(s,1H),6.90-7.0(m,3H),6.31-6.50(m,2 H),5.76-5.79(dd,1H),3.86(s,3H),2.86-2.88(t,2H),2.86(s,3H),2.20-2.30(m,10H)。LC-MS(m/z):554.06[M+H] +。
实施例8 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(吡啶-2-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000032
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(吡啶-2-基氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MH z,DMSO-d6)(ppm):10.13(s,1H),9.05(s,1H),7.83-8,40(m,5H),6.90-7,37(m,5H),7.38-7.80(m,2H),6.35(m,2H),5.78(m,1H),3.84-3.87(m,3H),2.70-2.86(m,5H),2.10-2.22(m,7H)。LC-MS(m/z):541.30[M+H] +。
实施例9 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(间甲苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000033
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(间甲苯氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.30-8.40(m,1H),8.09(s,1H),7.48-7.50(m,1H),7.23-7.34(m,3H),6.93-7.01(m,4H),6.85(s,1H),6.78-6.80(d,1H),6.25-6.45(m,2H),5.76-5.79(d,1H),3.86(s,1H),2.86-2.90(t,2H),2.71(s,3H),2.27-2.30(m,5H),2.20(s,6H)。LC-MS(m/z):553.92[M+H] +。
实施例10 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4-甲基-2-苯氧基苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000034
使用实施例1相似的方法，将步骤一的化合物1.2替换为(4-甲基-2-苯氧基苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.14(s,1H),9.06(s,1H),8.38-8.39(d,1H),8.26-8.28(d,1H),8.05(s,1H),7.31-7.39(m,3H),7.09-7.14(m.2H),6.98-7.01(m,3H),6.83(s,1H),6.35-6.40(m,2H),5.76-5.79(dd,1H),3.85(s,3H),2.86-2.88(t,2H),2.71(s,3H),2.28-2.32(m,5H),2.21(s,6H)。LC-MS(m/z):553.94[M+H] +。
实施例11 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-2-苯氧基苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000035
使用实施例1相似的方法，将步骤一的化合物1.2替换为(3-甲基-2-苯氧基苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):9.67(brs,1H),8.75(brs,1H),8.34-8.35(d,1H),8.03(s,2H),7.50-7.52(m,1H),7.34-7.36(t,1H),7.21-7.26(m,3H),6.92-6.96(m,3H),6.69-6.71(m,2H),6.30-6.34(m,2H),5.77-5.80(m,1H),3.85(s,3H),2.55-2.80(m,7H),2.13(s,3H)。LC-MS(m/z):553.98[M+H] +。
实施例12 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(吡啶-3-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000036
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(吡啶-3-基氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.11(brs,1H),9.76(brs,1H),8.82(s,1H),8.33-8.44(m,3H),8.23-8.24(m,1H),8.09(s,1H),7.53-7.57(m,1H),7.29-7.39(m,4H),7.08-7.10(d,1H),6.96(s,2H),6.30-6.34(m,1H),5.74-5.77(m,1H),3.88(s,3H),3.10-3.33(m,3H),2.55-2.68(m,8H)。LC-MS(m/z):541.04[M+H] +。
实施例13 N-(5-((4-(2-(环己氧基)苯基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000037
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(环己氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,D MSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.44-8.45(d,1H),8.15-8.25(d,1H),8.00(s,1H),7.42-7.48(m,2H),7.17-7.19(d,1H),7.01-7.05(m,2H),6.25-6.45(m,2H),5.75-5.78(dd,1H),4.45-4.60(m,1H),3.86(s,3H),2.85-2.88(m,2H),2.70(s,3H),2.21-2.30(m,8H),1.90-1.91(m,2H),1.65-1.66(m,2H),1.50-1.54(m,4H),1.34-1.40(m,4H)。LC-MS(m/z):545.99[M+H] +。
实施例14 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(3-甲氧基苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000038
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(3-甲氧基苯氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MH z,DMSO-d6)(ppm):10.13(s,1H),9.06(s,1H),8.42-8.43(d,1H),8.30-8.40(d,1H),8.09(s,1H),7.49-7.51(m,1H),7.32-7.33(m,2H),7.24-7.27(t,1H),7.01-7.04(m,2H),6.69-6.71(m,1H),6.59-6.60(m,1H),6.49-6.52(m,1H),6.32-6.40(m,2H),5.76-5.79(d,1H),3.85(s,3H),3.73(s,3H),2.86-2.88(t,2H),2.71(s,3H),2,29(m,2H),2.21(s,6H)。LC-MS(m/z):569.91[M+H] +。
实施例15 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(3-(三氟甲基)苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000039
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(3-(三氟甲基)苯氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.10(s,1H),9.04(s,1H),8.41-8.43(d,1H),8.32-8.34(d,1H),8.07(s,1H),7.51-7.61(m,2H),7.46-7.48(m,1H),7.36-7,41(m,2H),7.29-7.30(d,1H),7.23-7.26(m,1H),7.11-7.13(dd,1H),7.00(s,1H),6.28-6.50(m,2H),5.76-5.79(d,1H),3.84(s,3H),2.86-2.87(t,2H),2.70(s,3H),2.30(m,2H),2.21(s,6H)。LC-MS(m/z):608.04[M+H] +。
实施例16 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(5-甲基-2-(间甲苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000040
使用实施例1相似的方法，将步骤一的化合物1.2替换为(5-甲基-2-(间甲苯氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.15(s,1H),9.07(s,1H),8.39-8.40(d,1H),8.06-8.09(m,2H),7.28-7.31(m,2H),7.19-7.23(t,1H),7.02(s,1H),6.89-6.92(m,2H),6.78(s,1H),6.71-6.74(m,1H),6.27-6.41(m,1H),6.22-6.23(d,1H),5.75-5.78(m,1H),3.85(s,1H),2.85-2.88(t,2H),2.71(s,3H),2.31(s,3H),2.26-2.30(m,6H),2.21(s,6H)。LC-MS(m/z):568.27[M+H] +。
实施例17 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(2-(3-异丙基苯氧基)苯基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000041
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(3-异丙基苯氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):9.95(brs,1H),8.95(brs,1H),8.42-8.43(d,1H),8.20-8.30(m,1H),8.09(s,1H),7.47-7.55(m,1H),7.34-7.35(d,1H),7.26-7.30(m,3H),6.94-7.03(m,4H),6.76-6.78(m,1H),6.28-6.29(d,1H),5.75-5.78(m,1H),3.87(s,3H),3.04(m,3H),2.85-2.88(m2H),2.65(s,3H),1.16-1.18(d,6H)。LC-MS(m/z):582.24[M+H] +。
实施例18 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(2-(3-乙基苯氧基)苯基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000042
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(3-乙基苯氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.30-8.34(m,1H),8.06(s,1H),7.48-7.52(t,1H),7.25-7.35(m,3H),6.97-7.01(m,3H),6.89(s,1H),6.77-6.80(dd,1H),6.32-6.38(m,2H),5.76-5.79(m,1H),3.86(s,3H),2.86-2.88(m,2H),2.70(s,3H),2.55-2.61(m,2H),2.30(m,2H),2.21(s,6H),1.13-1.16(t,3H)。LC-MS(m/z):567.86[M+H] +。
实施例19 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-(4-(2-((5-甲基吡啶-3-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000043
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-((5-甲基吡啶-3-基氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):9.67(s,1H),8.77(s,1H),8.43-8.44(d,1H),8.10-8.22(m,3H),7.52-7.56(t,1H),7.24-7.37(m,3H),7.05-7.08(d,1H),6.96(s,1H),6.82(m,1H),6.31-6.35(d,1H),5.77-5.75(d,1H),3.88(s,3H),3.10-3.30(m,2H),2.60-2.73(m,5H),2.26(s,6H)。LC-MS(m/z):554.64[M+H] +。
实施例20 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((4-(间甲苯氧基)吡啶-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000044
使用实施例1相似的方法，将步骤一的化合物1.2替换为(3-(间甲苯氧基)吡啶-4-基)频那醇硼酸酯(以前述方法C制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.02(s,1H),9.10(s,1H),8.83(s,1H),8.48-8.49(dd,2H),8.31(s,1H),7.36-7.41(m,2H),6.95-7.14(m,4H),6.74-6.76(d,1H),6.49(s,1H),6.23-6.28(m,1H),5.72-5.77(m,1H),3.85(s,3H),2.95(t,2H),2.68(s,3H),2.21-2.34(m,10H)。LC-MS(m/z):554.91[M+H] +。
实施例21 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-((6-甲基吡啶-2-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000045
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-((6-甲基吡啶-2-基)氧基)苯基)频那醇硼酸酯(以前述方法B制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.04(s,1H),8.36-8.37(d,1H),8.26-8.28(d,1H),8.04(s,1H),7.69-7.73(t,1H),7.51-7.55(t,1H),7.34-7.37(t,1H),7.14-7.19(m,2H),6.95-7.0(m,2H),6.79-6.81(d,1H),6.28-6.44(m,2H),5.76-5.78(d,1H),3.85(s,3H),2.87(m,2H),2.70(s,3H),2.20-2.30(m,11H)。LC-MS(m/z):555.35[M+H] +。
实施例22 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(2-(3,5-二甲基苯氧基)苯基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000046
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(3,5-二甲基苯氧基)苯基)频那醇硼酸酯(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.42-8.43(d,1H),8.33-8.35(d,1H),8.09(s,1H),7.47-7.51(m,1H),7.27-7.34(m,2H),6.96-7.01(m,2H),6.77(s,1H),6.63(s,2H),6.37-6.44(m,1H),6.27-6.32(m,1H),5.76-5.78(m,1H),3.86(s,3H),2.87(m,2H),2.70(s,3H),2.20-2.30(m,14H)。LC-MS(m/z):568.34[M+H] +。
实施例23 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-((4-甲基吡啶-2-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000047
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-((4-甲基吡啶-2-基)氧基)苯基)频那醇硼酸酯(以前述方法B制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。 1H NMR(400MHz,DMSO-d6)(ppm):10.01(s,1H),9.73(s,1H),8.82(s,1H),8.36-8.38(d,1H),8.18-8.20(m,1H),8.05(s,1H),7.91-7.93(d,1H),7.51-7.55(m,1H),7.33-7.37(t,1H),7.14-7.18(t,2H),6.92-6.96(m,4H),6.30-6.35(m,1H),5.75-5.78(d,1H),3.88(s,3H),3.24(m,2H),2.71(m,5H),2.61(s,3H),2.32(s,3H)。LC-MS(m/z):555.22[M+H] +。
实施例24 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-苯氧基苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000048
使用实施例1相似的方法，将步骤一的化合物1.2替换为4,4,5,5-四甲基-2-(3-苯氧基苯基)-1,3,2-二氧杂硼烷(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.11(s,1H),9.02(s,1H),8.50(d,1H),8.18(s,1H),8.11(d,1H),7.88(s,1H),7.52(t,1H),7.40(m,3H),7.15(m,2H),7.03(m,2H),6.99(s,1H),6.39(m,1H),6.25(m,1H),5.72(m,1H),3.83(s,3H),2.87(m,2H),2.70(s,3H),2.30(m,2H),2.20(s,6H).LC-MS(m/z):540[M+H] +。
实施例25 N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(4-(三氟甲基)苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000049
使用实施例1相似的方法，将步骤一的化合物1.2替换为4,4,5,5-四甲基-2-(2-(4-(4-(三氟甲基)苯氧基)苯基)-1,3,2-二氧杂硼烷(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,CDCl3-d)(ppm):9.63(s,1H),9.37(s,1H),8.51(s,1H),8.41(m,1H),7.67(s,1H),7.55(m,2H),7.45(m,2H),7.03(m,3H),6.69(s,1H),6.54(m,1H),5.78(m,1H),3.89(s,3H),3.32(m,2H),3.10(m,2H),2.81(m,9H),1.90(s,1H),1.60(s,1H).LC-MS(m/z):608[M+H] +。
实施例26 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-(((6-甲基吡啶-3-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000050
使用实施例1相似的方法，将步骤一的化合物1.2替换为2-甲基-5-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)吡啶(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.08(s,1H),9.02(s,1H),8.44(d,1H,J＝5.16Hz),8.29(d,1H,J＝7.36Hz),8.25(d,1H,J＝2.68H z),8.11(s,1H),7.50(m,1H),7.32(m,3H),7.24(m,1H),7.00(m,2H),6.46(s,1H),6.30(m,1H),5.77(m,1H),3.85(s,3H),2.92(s,2H),2.69(s,3H),2.43(m,5H),2.27(s,6H).LC-MS(m/z):555[M+H] +。
实施例27 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-(4-(三氟甲基)苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000051
使用实施例1相似的方法，将步骤一的化合物1.2替换为4,4,5,5-四甲基-2--(3-(4-(三氟甲基)苯氧基)苯基)-1,3,2-二氧杂硼烷(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.10(s,1H),9.06(s,1H),8.52(d,1H),8.23(d,1H),8.18(s,1H),8.03(s,1H),7.74(d,2H),7.59(t,1H),7.46(d,1H),7.30(m,1H),7.16(m,2H),6.99(s,1H),6.36(m,1H),6.18-6.23(m,1H),5.68-5.71(m,1H),3.83(s,3H),2.87(m,2H),2.69(s,3H),2.30(m,2H),2.20(s,6H)。L C-MS(m/z):608[M+H] +。
实施例28 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-((6-甲基吡啶-3-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000052
使用实施例1相似的方法，将步骤一的化合物1.2替换为2-甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)吡啶(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.1(s,1H),9.05(s,1H),8.51(d,1H),8.28(s,1H),8.17(s,1H),8.12(d,1H),7.91(s,1H),7.52(m,1H),7.41(m,2H),7.29(m,1H),7.16(m,1H),7.00(s,1H),6.37(m,1H),6.21-6.25(m,1H),5.71(m,1H),3.83(s,3H),2.87(m,2H),2.71(s,3H),2.47(s,3H),2.28(m,2H),2.19(s,6H).LC-MS(m/z):555[M+H] +。
实施例29 N-(2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4-(4-(三氟甲基)苯氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000053
使用实施例1相似的方法，将步骤一的化合物1.2替换为4,4,5,5-四甲基-2-(4-(4-(三氟甲基)苯氧基)苯基)-1,3,2-二氧杂硼烷(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.29(s,1H),9.74(s,1H),8.98(s,1H),8.52(d,1H),8.40(d,1H),8.07(s,1H),7.81(d,1H),7.44(d,1H),7.30(s,1H),7.28(s,1H),7.20(s,1H),7.17(s,1H),7.09(m,1H),6.96(s,1H),6.16-6.21(m,1H),5.62-5.65(m,1H),3.91(s,3H),3.26(m,4H),2.73(s,6H),2.60(m,4H)。LC-MS(m/z):608[M+H] +。
实施例30 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4-((6-甲基吡啶-3-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000054
使用实施例1相似的方法，将步骤一的化合物1.2替换为2-甲基-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷2-基)苯氧基)吡啶(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.16(s,1H),9.23(s,1H),8.49(d,1H),8.41(s,1H),8.38(s,1H),8.35(d,1H),8.03(s,1H),7.51(m,1H),7.40(d,1H),7.35(d,1H),7.07(s,1H),7.05(s,1H),7.01(s,1H),6.35-6.42(m,1H),6.13-6.18(m,1H),5.68-5.71(m,1H),3.87(s,3H),3.35(s,3H),2.86(m,2H),2.70(s,3H),2.27(m,2H),2.19(s,6H)。LC-MS(m/z):555[M+H] +。
实施例31 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-((1-甲基-1H-吡唑-3-基)氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000055
使用实施例1相似的方法，将步骤一的化合物1.2替换为1-甲基-3-(2-硼酸频哪醇酯基苯氧基)-1-氢-吡唑(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.14(s,1H),9.08(s,1H),8.45-8.47(d,1H),8.20-8.30(d,1H),8.10(s,1H),7.63-7.64(d,1H),7.45-7.47(m,1H),7.34-7.35(d,1H),7.26-7.28(t,1H),7/08-7.10(dd,1H),7.01(s,1H),6.40-6.50(m,1H),6.32-6.40(dd,1H),5.85(s,1H),5.75-5.78(m,1H),3.86(s,3H),3.73(s,3H),2.85-2.88(t,2H),2.71(s,3H),2.27-2.30(t,2H),2.20(s,6H).LC-MS(m/z):544.16[M+H] +。
实施例32 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((5-氟-4-(2-(吡啶-2-基氧基)苯基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000056
使用实施例1相似的方法，将步骤一的化合物1.1替换为2,4-二氯-5-氟嘧啶，化合物1.2替换为(2-(吡啶-2-基氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.09(s,1H),8.79(s,1H),8.43(s,1H),8.21(s,1H),8.06-8.07(d,1H),7.78-7.82(m,2H),7.57-7.60(m,1H),7.36-7.40(m,1H),7.26-7.28(d,1H),7.06-7.09(m,1H),6.96-6.98(m,2H),6.25-6.43(m,2H),5.75-5.78(d,1H),3.81(s,3H),2.86(m,2H),2.69(s,3H),2.21-2.30(m,8H)。LC-MS(m/z):556.52[M+H] +。
实施例33 N-(2-(((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((5-甲氧基-4-(2-(吡啶-2-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000057
使用实施例1相似的方法，将步骤一的化合物1.1替换为2,4-二氯-5-甲氧基嘧啶，化合物1.2替换为(2-(吡啶-2-基氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.14(s,1H),9.08(s,1H),8.25(s,1H),8.08-8.09(d,1H),7.76-7.78(t,1H),7.64-7.68(m,2H),7.49-7.53(m,1H),7.32-7.33(m,1H),7.23-7.25(d,1H),7.04-7.07(m,1H),6.95(s,1H),6.86-6.88(d,1H),6.35-6.39(m,1H),6.23-6.27(dd,1H),5.73-5.76(m,1H),3.83(s,3H),3.52(s,3H),2.85-2.88(t,2H),2.67(s,3H),2.27-2.30(t,2H),2.20(s,6H)。LC-M S(m/z):570.65[M+H] +。
实施例34(R)-N-(2-(3-(二甲基氨基)吡咯烷-1-基)-4-甲氧基-5-((4-(2-(吡啶-2-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000058
使用实施例1相似的方法，将步骤一的化合物1.2替换为(2-(吡啶-2-基氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，将步骤三的N,N,N'-三甲基乙二胺替换为(3R)-(+)-3-二甲氨基吡咯烷，得到标题化合物。 1H NMR(400MHz,MEOH-d6)(ppm):8.73(s,1H),8.29-8.30(d,1H),8.15-8.17(m,1H),8.05-8.06(m,1H),7.75-7.79(t,3H),7.53-7.57(t,1H),7.17-7.22(m,2H),7.04-7.07(m,1H),6.92-6.94(,1H),6.71(s,1H),6.56-6.63(m,1H),6.40-6.44(d,1H),5.71-5.83(m,1H),3.94(s,3H),3.20-3.42(m,6H),2.63(s,6H),2.32-2.35(m,1H),2.04-2.07(m,1H)。LC-MS(m/z):552.63[M+H] +。
实施例35 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((5-甲基-4-(2-(吡啶-2-基氧基)苯基)嘧啶-2-基)氨基)苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000059
使用实施例1相似的方法，将步骤一的化合物1.1替换为2,4-二氯-5-甲基嘧啶，化合物1.2替换为(2-(吡啶-2-基氧基)苯基)硼酸，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.03(s,1H),8.82(s,1H),8.23(s,1H),8.05-8.06(d,1H),7.83(s,1H),7.71-7.75(t,1H),7.49-7.55(m,2H),7.31-7.35(m,1H),7.20-7.22(d,1H),7.02-7.05(m,1H),6.95(s,1H),6.87-6.89(d,1H),6.38-6.40(m,1H),6.23-6.27(dd,1H),5.73-5.76(m,1H),3.81(s,3H),2.85-2.88(t,2H),2.67(s,3H),2.27-2.30(t,2H),2.20(s,6H),2.02(s,3H)。LC-MS(m/z):554.65[M+H] +。
实施例36 N-(5-((4-(2-(2-氰基苯氧基)苯基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000060
使用实施例1相似的方法，将步骤一的化合物1.2替换为2-(2-硼酸频哪醇酯基苯氧基)-苯甲腈(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):9.77(s,1H),8.80(s,1H),8.45-8.46(d,1H),8.24-8.26(d,1H),8.06(s,1H),7.88-7.90(d,1H),7.59-7.63(m,2H),7.43-7.46(m,1H),7.22-7.27(m,3H),6.96(s,1H),6.84-6.87(d,1H),6.30-6.35(d,1H),5.76-5.78(d,1H),3.88(s,3H),3.37(m,4H),3.22(m,2H),2.61-2.68(m,8H)。LC-MS(m/z):564.46[M+H] +。
实施例37 N-(5-((4-(2-((2-氰基吡啶-3-基)氧基)苯基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
Figure PCTCN2021081404-appb-000061
使用实施例1相似的方法，将步骤一的化合物1.2替换为2-氰基-3-(2-硼酸频哪醇酯基苯氧基)吡啶(以前述方法A制备得到)，步骤二的化合物1.4替换为4-氟-2-甲氧基-5-硝基苯胺，得到标题化合物。1H NMR(400MHz,DMSO-d6)(ppm):10.11(s,1H),9.00(s,1H),8.44-8.47(m,2H),8.28-8.30(d,1H),7.99(s,1H),7.61-7.65(m,2H),7.46-7.50(t,1H),7.36-7.39(m,2H),7.32-7.34(d,1H),6.99(s,1H),6.36-6.39(m,1H),6.30-6.31(m,1H),5.75-5.78(m,1H),3.84(s,3H),2.84-2.87(t,2H),2.69(s,3H),2.27-2.30(t,2H),2.20(s,6H)。LC-MS(m/z):565.63[M+H] +。
实验例1 EGFR D770_N771insNPG激酶活性抑制测定
在杆状病毒表达系统中表达的EGFR D770_N771insNPG激酶购自上海优宁维(univ Biological Inc.)。含有生物素标记的多肽底物TK Substrate-biotin、Eu标记的特异性磷酸化多肽抗体TK Antibody-Cryptate，HTRF荧光受体试剂Streptavidin-XL665和5×激酶反应缓冲溶液、检测缓冲液Detection buffer的TK激酶HTRF检测试剂盒(#62TK0PEC)购自Cisbio Bioassays(Codolet,France)。二硫苏糖醇(DTT)、氯化镁、氯化锰、三磷酸腺苷(ATP)、 二甲基亚砜(DMSO)和HEPES缓冲液以可获得的最高纯度水平从Sigma获得。
EGFR激酶活性抑制测定的一般方法：磷酸化反应缓冲液由1M HEPES(pH 7.0)、5mM MgCl 2、1mM MnCl 2组成，实验开始前在该缓冲液中即时加入1mM DTT。配置待测化合物DMSO存储母液，并根据实验所需，采用DMSO进行三倍浓度梯度稀释。所得梯度稀释溶液进一步采用磷酸化反应缓冲溶液进行稀释，获得待测化合物溶于含有5％DMSO的反应缓冲液的工作溶液。将2μL化合物工作溶液溶液和稀释于反应缓冲液的4μL EGFR激酶溶液添加到白色低体积384孔微量滴定板中，再加入溶于反应缓冲液中的4μL ATP和生物素标记的多肽底物的混合溶液，开始磷酸化反应。在WT EGFR实验中，WT激酶、多肽底物、ATP和DMSO的最终浓度分别为0.01ng/ul、500nM、4μM和1％，在EGFR D770_N771insNPG实验中，激酶、多肽底物、ATP和DMSO的最终浓度分别为0.01ng/ul、200nM、4μM和1％。避光条件下反应在室温下执行60分钟。分别加入稀释于检测缓冲液中的TK Antibody-Cryptate抗体和Streptavidin-XL665各5μL，室温孵育60分钟。WT EGFR激酶反应体系中Streptavidin-XL665终浓度为15.61nM，EGFR D770_N771insNPG激酶反应体系中Streptavidin-XL665终浓度为31.25nM，抗体按照供应商提供的最终浓度稀释。使用Tecan(
Figure PCTCN2021081404-appb-000062
Switzerland)多功能酶标仪Spark进行读板，检测两组均相时间分辨荧光强度，其中激发波长为320nm，发射波长分别为665nm和620nm。使用Prism 7(La Jolla,15CA)对665nm/620nm荧光强度比值相对于抑制剂浓度进行做图，采用S形剂量依赖曲线模型对所得抑制曲线记性你和，获得抑制剂的IC 50值。根据前述实施例制备的部分化合物的EGFR D770_N771insNPG激酶抑制活性IC 50测定结果见表1。
表1
化合物 IC 50(nM)
实施例2 0.68
实施例7 1.52
实施例8 3.06
实施例9 11.32
实验结果显示本申请化合物能有效的抑制EGFR D770_N771insNPG激酶活性，其中实施例2的IC 50小于1nM。
实验例2细胞增殖抑制实验
H358、A431、HCC827细胞购自中国科学院细胞库(上海)，BaF3 EGFR WT、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV、BaF3 ERBB2A775_G776insYVMA细胞购自北京康源博创，MDA-MB-231、SK-BR-3、BT474购自南京科佰生物科技有限公司。MEM培养基、RPMI1640培养基、青霉素-链霉素双抗、0.5％的胰酶(10X)和表皮细胞生长因子EGF购自ThermoFisher(Waltham,MA,USA)。经认证的胎牛血清(FBS)购自Biological Industries(Israel)。康宁96和384孔细胞培养板购自CORNING(USA)。Cell-Titer
Figure PCTCN2021081404-appb-000063
购自Promega Corporation(Madison,WI,USA)。
为了评估合成化合物对肺癌细胞H358、A431、HCC827和BaF3 EGFR WT、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV、BaF3 ERBB2 A775_G776insYVMA细胞增殖的抑制能力，H358、A431、HCC827、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV、BaF3 ERBB2 A775_G776insYVMA指数增长的细胞接种于含10％牛血清和1％青霉素-链霉素双抗的RPMI1640培养基，BaF3 EGFR WT指数增长的细胞接种于含10％牛血清、1％青霉素-链霉素双抗和50ng/mL EGF的RPMI1640培养基，HCC827、BaF3 ERBB2 A775_G776insYVMA密度为75000个细胞/mL，H358密度为100000个细胞/mL，BaF3 EGFR D770_N771insSVD、BaF3 V769_D770insASV密度为50000个细胞/mL，BaF3 EGFR WT密度为125000个细胞/mL,384孔板，每孔20μL，并放置在37℃，5％CO 2的培养箱中过夜。将化合物在DMSO中稀释至12个点、3倍梯度稀释液，从2mM开始。将化合物储备板的1μL DMSO溶液添加到99μL细胞培养基(测定中化合物的最终最高浓度为10μM，并且DMSO的最终浓度为0.5％)。将培养基中的20μL化合物溶液按照梯度加到384板的每个铺细胞的孔中。在加入化合物溶液后，将384孔板放置于37℃，5％CO 2培养箱中孵育3天。采用Promega(Madison,WI,USA)的CellTiter-Glo检测试剂盒，通过定量细胞培养中存在的ATP，测定细胞活力。20分钟的孵育后使用TECAN公司的SPARK多功能酶标仪在化学发光的程序下进行读数。在Prism 7(LaJolla,CA)中使用S形剂量反应模型(可变斜率，四个参数)确定化合物使细胞成活率抑制50％的浓度(IC 50值)。
实验中所使用的药性对照物Poziotinib、Osimertinib、Pyrotinib、TAS6417、Neratinib均以市售方式获得，Ref-1根据WO2015195228A1记载的制备方法制得，结构如下：
Figure PCTCN2021081404-appb-000064
根据前述实施例制备的部分化合物对于BaF3 EGFR WT、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV细胞增殖抑制的结果见表2。
表2
Figure PCTCN2021081404-appb-000065
结果显示，本申请的化合物对于WT EGFR和EGFR Exon20插入中最为广泛的两种突变D770_N771insSVD和V769_D770insASV高表达的BaF3细胞增殖抑制活性之间相比具有良好的选择性，如其中实施例12，BaF3 EGFR WT/BaF3 EGFR D770_N771insSVD和BaF3 EGFR WT/BaF3 EGFR V769_D770insASV的值分别为2.15和2.38，显示本申请化合物良好的选择性和临床治疗空间。
根据前述实施例制备的部分化合物对于HCC 827、H358WT细胞增殖抑制的结果见表3。
表3
Figure PCTCN2021081404-appb-000066
结果显示本申请部分化合物对表达野生型EGFR的H358 NSCLC细胞增殖抑制要远低于Poziotinib。
根据前述实施例制备的部分化合物对于MDA-MB-231、SK-BR-3及BT474细胞增殖抑制的结果见表4。
表4
Figure PCTCN2021081404-appb-000067
结果显示本申请部分化合物对乳腺癌细胞株SK-BR-3和BT474的活性与临床上使用的Pyrotinib和Neratinib类似，但要比同类型的EGFR抑制剂TAS6417在乳腺癌细胞上的活性更好，为这一系列化合物针对HER2靶点以及在乳腺癌治疗上的应用提供了可能。
根据前述实施例制备的部分化合物对于A431 WT、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV细胞增殖抑制的结果见表5。
表5
Figure PCTCN2021081404-appb-000068
Figure PCTCN2021081404-appb-000069

Claims (13)

  1. 式(I)化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2021081404-appb-100001
    其中，每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
    Figure PCTCN2021081404-appb-100002
    R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
    每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基；
    R 3选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
    R 4选自
    Figure PCTCN2021081404-appb-100003
    n为1、2或3；
    Z 1为C或N；并且
    Z 2为亚烷基或键。
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中式(Ⅰ)是式(Ⅰa)：
    Figure PCTCN2021081404-appb-100004
    每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
    Figure PCTCN2021081404-appb-100005
    R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
    每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
    R 4选自
    Figure PCTCN2021081404-appb-100006
    n为1、2或3；
    Z 1为C或N；并且
    Z 2为亚甲基或键。
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中式(Ⅰ)是式(Ⅰb)：
    Figure PCTCN2021081404-appb-100007
    每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
    Figure PCTCN2021081404-appb-100008
    R 2为芳基、杂芳基或环烷基，所述芳基、杂芳基或环烷基可选地被0-2个R 2’取代；
    每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
    R 4选自
    Figure PCTCN2021081404-appb-100009
    n为1、2或3；并且
    Z 1为C或N。
  4. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中：
    每个R 1独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基、烷氧基或
    Figure PCTCN2021081404-appb-100010
    R 2为可选地被0-2个R 2’取代的苯基、吡啶基或环己基；
    每个R 2’独立地选自氢、C 1-C 6烷基、卤代C 1-C 6烷基、卤素、羟基、硝基、氨基、氰基或烷氧基；
    n为1、2或3；
    Z 1为C或N；并且
    Z 2为亚甲基或键。
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中R 2选自：
    Figure PCTCN2021081404-appb-100011
  6. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其选自如下化合物：
    Figure PCTCN2021081404-appb-100012
    Figure PCTCN2021081404-appb-100013
    Figure PCTCN2021081404-appb-100014
    Figure PCTCN2021081404-appb-100015
  7. 权利要求1-6任一项所述的化合物用于制备预防或治疗受体酪氨酸激酶突变引起的相关疾病药物的用途。
  8. 根据权利要求7所述的用途，其中所述受体酪氨酸激酶突变为EGFR突变。
  9. 根据权利要求8所述的用途，其中所述EGFR突变引起的相关疾病为癌症。
  10. 根据权利要求9所述的用途，其中所述癌症为非小细胞肺癌，乳腺癌，脑癌，卵巢癌，胰腺癌，子宫癌，宫颈癌，皮肤癌，前列腺癌，膀胱癌，肝癌，胃肠组织癌，食道癌，甲状腺癌，白血病，淋巴瘤或多发性骨髓瘤。
  11. 根据权利要求8所述的用途，其中所述EGFR突变引起的相关疾病为在EGFR的外显子20结构域中发生突变引起的相关癌症。
  12. 一种药物组合物，其包含治疗有效量的权利要求1-6任一项所述的化合物以及药学上可接受的载体或赋形剂。
  13. 根据权利要求12所述的药物组合物，其还包含其它一种或多种抗癌药物，所述抗癌药物为小分子药物、单克隆抗体或融合蛋白药物。
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