WO2022121967A1 - 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

Info

Publication number
WO2022121967A1
WO2022121967A1 PCT/CN2021/136618 CN2021136618W WO2022121967A1 WO 2022121967 A1 WO2022121967 A1 WO 2022121967A1 CN 2021136618 W CN2021136618 W CN 2021136618W WO 2022121967 A1 WO2022121967 A1 WO 2022121967A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
alkyl
alkoxy
alkynyl
alkenyl
Prior art date
Application number
PCT/CN2021/136618
Other languages
English (en)
French (fr)
Inventor
胡佳琪
姜佩佩
欧阳浩
杨民民
Original Assignee
南京药石科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京药石科技股份有限公司 filed Critical 南京药石科技股份有限公司
Publication of WO2022121967A1 publication Critical patent/WO2022121967A1/zh

Links

Classifications

    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present application belongs to the field of chemical medicine, and in particular relates to an EGFR tyrosine kinase inhibitor and use thereof.
  • 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, cancer cells in NSCLC grow and divide more slowly and spread relatively later. NSCLC accounts for about 80% of all lung cancers and has a poor prognosis, with about 75% of patients in the middle and advanced stages when discovered. Overexpression and mutation of epidermal growth factor receptor (EGFR) have been clearly demonstrated to lead to uncontrolled cell growth, which is associated with the progression of most cancers, especially NSCLC (Oncotarget. 2016 Jul 5;7(27): 41691-41702).
  • EGFR epidermal growth factor receptor
  • EGFR is a member of the epidermal growth factor receptor (HER) family, which consists of EGFR (Erb-Bl), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.
  • EGFR is a glycoprotein, which is a receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. It belongs to a tyrosine kinase type receptor, which penetrates through the cell membrane and is 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 aberrantly activating mutations in its tyrosine kinase domain that are independent of ligand binding.
  • the most common kinase activity mutations are EGFR (Exon 19 del E746-A750) and EGFR (Exon 21 L858R), the first generation of EGFR tyrosine kinase inhibitor (EGFR-TKI) gefitinib and erlotinib (erlotinib) have been approved for the treatment of these two mutations, but the first-generation EGFR-TKI developed resistance during treatment, and the generation of resistance was related to the substitution of threonine at position 790 of EGFR Associated with a secondary mutation of methionine (T790M).
  • the second generation of irreversible covalent inhibitors such as afatinib (Afatinib) is more effective in the treatment of EGFR (delE746-A750) and EGFR (L858R), but is not effective in the drug-resistant T790M mutant, the reason It is more active against wild-type EGFR than the inhibitory EGFR (delE746-A750/T790M) and EGFR (L858R/T790M) resistant mutants, thus showing dose-dependent toxicity (Biologics, 2014, 8:183-192) , an effective therapeutic window cannot be obtained. Therefore, third-generation EGFR-TKIs, such as AZD9291, CO-1686 and HM61713, were developed.
  • the third-generation EGFR-TKIs are specific and selective tyrosine kinase inhibitors. Compared with the first- and second-generation EGFR-TKIs, the third-generation EGFR-TKIs reduce the inhibition of wild-type EGFR, reduce clinical side effects, and can use higher clinical doses to obtain better efficacy (J Clin Oncol 2014;32:abstr 8009; J Clin Oncol 2014;32:abstr 8010).
  • EGFR exon20 ins Another type of EGFR mutation that abnormally activates and induces cancer is exon 20 insertion mutations (EGFR exon20 ins), which have been previously shown to account for 4%-10% of all EGFR-mutant lung cancers (PLoS ONE 2015 10( 7):e0133859).
  • EGFR exon20 ins exon 20 insertion mutations
  • the present application discloses a class of compounds that can be used as EGFR protein kinase inhibitors and their use in the preparation of medicaments for preventing or treating EGFR-related diseases.
  • the application provides a compound of the following general formula (I):
  • Cy is a heterocyclic group or heteroaryl group containing 1-4 heteroatoms and 5-14 ring atoms, and the heterocyclic group or heteroaryl group is optionally substituted by 1-3 R4, and Cy not for
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl, said alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens;
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • X is N or -CR 3 ;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens; and
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens.
  • the compound represented by the general formula (I) is a compound represented by the general formula (Ia):
  • ring A is a saturated or unsaturated ring containing 0-2 heteroatoms and 5-6 ring atoms, and said ring A is optionally substituted by 1-3 R 4 ;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl, said alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens;
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • X is N or -CR 3 ;
  • R 3 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens; and
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, cyano, nitro, amino, hydroxyl , hydroxyalkyl, alkoxy, alkylacyl optionally substituted with 1-3 halogens.
  • Cy is selected from:
  • the compound represented by general formula (I) is selected from:
  • the compound represented by general formula (I) is selected from:
  • the compounds of the present application are:
  • the present application also provides the use of the aforementioned compound for preparing a medicament for preventing or treating related diseases caused by mutations in receptor tyrosine kinases.
  • the receptor tyrosine kinase is mutated to an EGFR mutation.
  • the associated disease caused by the EGFR mutation is cancer.
  • the cancer is non-small cell lung cancer, breast cancer, brain cancer, ovarian cancer, pancreatic cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, bladder cancer, liver cancer, gastrointestinal tissue cancer, Esophageal cancer, thyroid cancer, leukemia, lymphoma, or multiple myeloma.
  • the related disease caused by the EGFR mutation is a related cancer caused by a mutation in the exon 20 domain of EGFR.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition further comprises one or more other anticancer drugs, which are small molecule drugs, monoclonal antibodies or fusion protein drugs.
  • isomer includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure.
  • this application includes the R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers as well as enantiomers, diastereomers for each asymmetric center 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. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed.
  • terapéuticaally effective amount refers to an amount of a compound of the present application that (i) treats a particular disease, condition or disorder; (ii) alleviates, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder or (iii) preventing or delaying the onset of one or more symptoms of the specified disease, condition or disorder described herein.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • 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 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 base, 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, etc.
  • alkenyl refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
  • an alkenyl group has 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 straight or branched chain 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 and the like.
  • alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms.
  • C2-6alkynyl includes straight or branched chain hydrocarbon alkynyl groups as defined above having 2 to 6 carbon atoms.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein 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 group containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms Carbon atoms (eg 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
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system.
  • a spiro atom may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl, More preferably 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 an all-carbon polycyclic group of 5 to 20 members 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 more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being 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; and most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. 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 monospiroheterocyclyl group.
  • fused heterocyclyl 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, and one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided 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 groups.
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common
  • the pi-electron system of the yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • the heterocyclic group includes the above-mentioned heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure
  • the rings linked together are heterocyclyl, non-limiting examples of which include:
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl and the like.
  • the heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • hydroxyalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy 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, wherein cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • the reaction solution was cooled to room temperature, water (150 mL) and EA (200 mL) were added, filtered, the filtrate was separated, the aqueous phase was extracted with EA (200 mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried.
  • the crude product was purified by column chromatography to give compound 1.3 (7.20 g, 16.57 mmol) in 73.45% yield.
  • reaction solution was cooled to room temperature, poured into saturated sodium bicarbonate solution (100 mL), added with EA (100 mL ⁇ 2) for extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried. Purification by column chromatography gave compound 1.5 (4.70 g, 10.867 mmol) with a yield of 63.4%.
  • BaF3 EGFR D770_N771insSVD and BaF3 EGFR V769_D770insASV cells were purchased from Beijing Kangyuan Bochuang Biotechnology Co., Ltd., and A431 (human skin squamous cell carcinoma cells) EGFR wild-type cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. DMEM medium, RPMI1640 medium, penicillin-streptomycin dual antibody, 0.5% trypsin (10X) were purchased from ThermoFisher (Waltham, MA, USA). Certified fetal bovine serum (FBS) was purchased from Biological Industries (Israel). Corning 96-well cell culture plates and Corning 384-well cell culture plates were purchased from CORNING (USA). Cell-Titer Purchased from Promega Corporation (Madison, WI, USA).
  • Table 1 shows the results of inhibiting the proliferation of A431 EGFR WT, BaF3 EGFR D770_N771insSVD, and BaF3 EGFR V769_D770insASV cells by representative compounds of the present application.
  • the human liver microsomes (HLM) used in the experiment were purchased from Corning (Cat No. 452117), and the coenzyme NADPH was purchased from Shanghai Yuanye Biotechnology (Cat No. S10103).
  • the tested CYP isoform-specific substrates, phenacetin, diclofenac sodium, and dextromethorphan were purchased from Sigma; S-mephenytoin and midazolam were purchased from TRC.
  • the positive reference compounds of each subtype of CYP enzymes ⁇ -Naphthoflavone and Quinidine were purchased from Sigma; (+)-N-3-benzynirvanol and Ketoconazole were purchased from TRC, and Sulfaphenazole was purchased from Shanghai Bide.
  • the conventional reagents DMSO, methanol, and magnesium chloride used in other experiments were purchased from J&K, Merck, and Shanghai Runjie, respectively.
  • Serial dilution stock solutions of compounds to be tested in 1:1 DMSO and methanol were prepared: selected concentrations were: 5 mM, 1.5 mM, 0.5 mM, 0.15 mM, 0.05 mM, 0.015 mM, 0.005 mM.
  • PB phosphate buffer
  • Each CYP subenzyme-specific inhibitor DMSO storage stock solution was prepared. Before the test, it was diluted 100 times with MeOH, and the working solutions were prepared. 300 ⁇ M, Ketoconazole 300 ⁇ M.
  • IC50 values of inhibitors When the highest concentration inhibited activity less than 50%, IC50 was recorded as >50 ⁇ M.
  • Table 2 shows the results of the cytochrome P450 (CYP450) enzyme inhibition test results of the compound of Example 1 of the present application and the positive control TAS6417.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供了一种通式(I)所示的化合物、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 exon20 ins)，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，具有良好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。
第一方面，本申请提供了一种如下通式(I)所示的化合物：
Figure PCTCN2021136618-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐，
其中，Cy为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基，所述杂环基或杂芳基可选地被1-3个R 4取代，且Cy不为
Figure PCTCN2021136618-appb-000002
R 1选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；
R 2为氢或C 1-C 6烷基；
X为N或-C-R 3；
R 3选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；以及
R 4选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羰基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代。
在一些实施方案中，所述通式(I)所示的化合物为通式(Ia)所示的化合物：
Figure PCTCN2021136618-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐，
其中，环A为含有0-2个杂原子、5-6个环原子的饱和或不饱和环，所述环A可选地被1-3个R 4取代；
R 1选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；
R 2为氢或C 1-C 6烷基；
X为N或-C-R 3；
R 3选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；以及
R 4选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羰基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代。
在另一些实施方案中，Cy选自：
Figure PCTCN2021136618-appb-000004
Figure PCTCN2021136618-appb-000005
在另一些实施方案中，通式(I)所示的化合物选自：
Figure PCTCN2021136618-appb-000006
Figure PCTCN2021136618-appb-000007
在另一些实施方案中，通式(I)所示的化合物选自：
Figure PCTCN2021136618-appb-000008
Figure PCTCN2021136618-appb-000009
在另一些实施方案中，本申请的化合物为：
Figure PCTCN2021136618-appb-000010
第二方面，本申请还提供了前述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。
在一些实施方案中，所述受体酪氨酸激酶突变为EGFR突变。
在另一些实施方案中，所述EGFR突变引起的相关疾病为癌症。
在另一些实施方案中，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。
在另一些实施方案中，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。
第三方面，本申请还提供一种药物组合物，其包含治疗有效量的前述的化合物以及药学上可接受的载体或赋形剂。
在一些实施方案中，所述药物组合物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。
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)，其中烷基如上述定义。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 PCTCN2021136618-appb-000011
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 PCTCN2021136618-appb-000012
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
实施例1：(S)-N-(4-氨基-5-(6,7-二氢-5H-环戊[b]吡啶-3-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000013
步骤一：
Figure PCTCN2021136618-appb-000014
将化合物1.1(10.00g，83.918mmol，1eq.)、偶联频哪醇硼酸酯(23.441g，92.310mmol，1.1eq.))、[Ir(COD)OMe] 2(556.263mg，839.184μmol，0.01eq.)和3,4,7,8-四甲基-1,10-菲罗啉(396.617mg，1.678mmol，0.02eq.)加入到含THF(150mL)的250mL单口瓶中，N 2置换三次后，在N 2保护下，80℃反应16小时。反应液直接旋干。粗品经柱层析纯化，得到化合物1.2(12.50g，50.995mmol)，收率：60.77％。
步骤二：
Figure PCTCN2021136618-appb-000015
将(S)-(1-(4-氨基-5-碘-7H-吡咯[2,3-d]嘧啶-7-基)戊-4-烯-2-基)氨基羧酸叔丁酯(10.00g，22.559mmol，1eq.))和化合物1.2(8.295g，33.839mmol，1.50eq.)溶于1,4-二氧六环(100mL)置于250mL单口瓶中，加入碳酸钠(7.173g，67.677mmol，3eq.)，Pd(dppf)Cl 2(825.326mg，1.128mmol，0.05eq.)和水(20mL)，氮气置换三次，反应体系在氮气保护下，100℃搅拌16小时。反应液冷却至室温，加水(150mL)和EA(200mL)，过滤，滤液分液，水相加入EA(200mL)萃取，合并有机相，无水硫酸镁干燥，过滤，滤液旋干。粗品经柱层析纯化，得到化合物1.3(7.20g，16.57mmol)，收率为73.45％。
步骤三：
Figure PCTCN2021136618-appb-000016
将化合物1.3(7.50g，17.26mmol，1eq.)溶于THF(100mL)置于100mL四口瓶中，0～10℃下分批加入NBS(3.686g，20.712mmol，1.2eq.)，反应体系在20℃下搅拌1小时。TLC显示反应完全后，将反应液慢慢倒入10％亚硫酸钠溶液(100mL)中，加入EA(100mL×2)萃取，有机相用3％的碳酸氢钠溶液(100mL)洗，无水硫酸镁干燥，过滤，滤液旋干。得到化合物1.4(8.80g，17.140mmol)，收率为99.3％。直接将化合物1.4用于下一步反应。
步骤四：
Figure PCTCN2021136618-appb-000017
将化合物1.4(8.80g，17.140mmol,1eq.)溶于THF(100mL)置于250mL单口瓶中，加入NaOH(2.742g，68.559mmol，4M，17.140mL，4eq.)和Pd(PPh 3) 4(2.971g，2.571mmol，0.15eq.)，氮气置换三次，反应体系在80℃下搅拌16小时。反应液降至室温，倒入到饱和碳酸氢钠溶液(100mL)中，加入EA(100mL×2)萃取，合并有机相，用无水硫酸镁干燥，过滤，滤液旋干。经柱层析纯化得到化合物1.5(4.70g，10.867mmol)，收率为63.4％。
步骤五：
Figure PCTCN2021136618-appb-000018
将化合物1.5(0.29g，670.49μmol，1eq.)溶于EtOH(50mL)中，随后加入HCl(5mL， 5M)，90℃下回流16小时。反应液中加入10mL NaOH(4M)水溶液，二氯甲烷萃取三次，有机相用饱和食盐水洗涤两次，直接浓缩得到化合物1.6(0.17g，511.43μmol，收率为76.3％。
步骤六：
Figure PCTCN2021136618-appb-000019
在50mL茄型瓶中，将化合物1.6(0.17g，511.43μmol，1eq.)和DIPEA(99.15mg，767.14μmol，1.5eq.)溶于H 2O(10mL)和MeCN(10mL)中，冰盐浴降温，缓慢滴入丙烯酰氯(46.29mg，511.43μmol，1eq.)的乙腈溶液，滴完后，冰盐浴反应20分钟。反应液中加入1mL的氨水，搅拌两分钟后，二氯甲烷萃取三遍，有机相用饱和食盐水洗涤两次，直接浓缩，经柱层析纯化得到标题化合物(50.02mg，129.5μmol)，收率为25.3％。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.44(m,1H),8.33(m,1H),8.12(s,1H),7.65(m,1H),6.22(m,2H),5.80(m,1H),5.65(m,1H),4.78(m,1H),4.22(m,2H),2.99(m,4H),2.21(m,2H),1.58(s,3H)；LC-MS(m/z):387.19[M+H] +。
实施例2：(S)-N-(4-氨基-6-甲基-5-(5,6,7,8-四氢喹啉-3-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000020
使用实施例1相似的方法，将步骤一的化合物1.1替换为5,6,7,8-四氢喹啉，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.40(m，2H)，8.15(s，1H)，7.55(m，1H)，6.20(m，2H)，5.80-5.60(m，4H)，4.68(m，1H)，4.20(m，2H)，2.85(m，4H),1.86(m，4H),1.82(m，4H),1.59(s，3H)；LC-MS(m/z):401.20[M+H] +。
实施例3：(S)-N-(4-氨基-6-甲基-5-(1H-吡咯[2,3-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000021
使用实施例1相似的方法，将步骤二的化合物1.2替换为7-氮杂吲哚-5-硼酸，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)11.83(s,1H),8.45(s,1H),8.26(s,1H),8.11(m,1H),7.98(m,1H),7.58(m,1H)；6.52(m,1H),6.32-6.02(m,2H),5.76(m,1H),5.61(m,1H)；4.77(m,1H),4.18(m,2H),1.52(s,3H)；LC-MS(m/z):386.17[M+H] +。
实施例4：(S)-N-(4-氨基-6-甲基-5-(1-甲基-1H-吡咯[2,3-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000022
使用实施例1相似的方法，将步骤二的化合物1.2替换为1-甲基7-氮杂吲哚-5-频哪醇硼酸酯，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.49(m,1H),8.32(m,1H),8.18(s,1H),8.06(m,1H),7.68(m,2H),6.55(m,1H),6.40-5.50(m,6H),4.78(m,1H),4.25(m,2H),3.90(s,3H),1.52(s,3H)；LC-MS(m/z):400.18[M+H] +。
实施例5:(S)-N-(4-氨基-5-(咪唑并[1,2-a]吡啶-7-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000023
使用实施例1相似的方法，将步骤二的化合物1.2替换为咪唑并[1,2-a]吡啶-7-频哪醇硼酸 酯，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.62(s,,1H),8.47(s,1H),8.09(d,2H),7.65(d,2H),6.98(m,1H),6.50-5.50(m,6H),4.78(m,1H),4.20(m,2H),1.69(s,3H)；LC-MS(m/z):386.17[M+H] +。
实施例6：(S)-N-(4-氨基-5-(咪唑并[1,2-a]吡啶-6-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000024
使用实施例1相似的方法，将步骤二的化合物1.2替换为咪唑并[1,2-a]吡啶-6-硼酸，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.70(d,1H),8.48(m,1H),8.13(s,1H),8.03(d,1H),7.74(s,1H),7.70(d,1H),7.38(m,1H),6.40-5.90(m,4H),5.82(m,1H),5.62(m,1H),4.78(m,1H),4.19(m,2H),1.64(s,3H)；LC-MS(m/z):386.17[M+H] +。
实施例7：(S)-N-(4-氨基-6-甲基-5-(噻吩[2,3-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000025
步骤一：
Figure PCTCN2021136618-appb-000026
在250mL的茄型瓶中，将5-溴噻吩[2,3-b]吡啶(1.38g，6.45mmol，1eq.)、偶联频哪醇硼酸酯(2.46g，9.67mmol，1.5eq.)、醋酸钾(4.51g,19.34mmol,3.0eq.)和Pd(dppf) 2Cl 2(471.66mg，644.61μmol，0.1eq.)加入到1,4-二氧六环(100mL)中，N 2置换三次后，在N 2保护下，80℃反应16小时。反应液直接浓缩，进行下一步反应。
后续步骤使用实施例1相似的方法，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.61(s,1H),8.55-8.20(m,2H),8.14(s,1H),7.99(s,1H),7.52(s,1H),6.20(m,2H),6.00-5.50(m,3H),4.78(s,1H),4.20(m,2H),1.51(s,3H)；LC-MS(m/z):403.13[M+H] +。
实施例8：(S)-N-(4-氨基-5-(呋喃[2,3-b]吡啶-5-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000027
使用实施例7相似的方法，将步骤一的起始物料替换为5-溴呋喃并[2,3-b]吡啶,得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.45(m,1H),8.34(m,1H),8.20(s,1H),8.12(m,3H),7.07(s,1H),6.22(m,2H),5.78(m,1H),5.64(m,1H),4.79(s,1H),4.20(m,2H),1.50(s,3H)；LC-MS(m/z):387.15[M+H] +。
实施例9：(S)-N-(4-氨基-6-甲基-5-(2-甲基-1H-吡咯[2,3-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000028
使用实施例1相似的方法，将步骤二的化合物1.2替换为2-甲基7-氮杂吲哚-5-频哪醇硼酸酯，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)11.83(s,1H),8.45(s,1H),8.26(s,1H),8.11(m,1H),7.98(m,1H),7.58(m,1H)；6.52(m,1H),6.32-6.02(m,2H),5.76(m,1H),5.61(m,1H)；4.77(m,1H),4.18(m,2H),1.52(s,3H)；LC-MS(m/z):400.18[M+H] +。
实施例10：(S)-N-(4-氨基-6-甲基-5-(3-甲基-1H-吡咯[2,3-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000029
使用实施例1相似的方法，将步骤二的化合物1.2替换为3-甲基7-氮杂吲哚-5-频哪醇硼酸酯，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)11.49(s,1H),8.46(s,1H),8.34-8.07(m,2H),7.95(d,1H),7.34(m,1H),6.25(d,2H),5.90-5.50(m,2H),4.79(s,1H),4.24(m,2H),2.28(s,3H),1.53(s,3H),LC-MS(m/z):400.18[M+H] +。
实施例11:(S)-N-(4-氨基-5-(7,7-二氟-6,7-二氢-5H-环戊[b]吡啶-3-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000030
使用实施例1相似的方法，将步骤一的化合物1.1替换为7,7-二氟环戊烷并[b]吡啶，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.65(s,1H),8.43(d,1H),8.14(s,1H),7.91(m,1H)6.19(m,2H),5.85(m,3H),5.69(m,1H),4.80(m,1H),4.20(m,2H),3.04(m,2H),2.7(m,2H)1.54(s,3H)；LC-MS(m/z):423.17[M+H] +。
7,7-二氟环戊烷并[b]吡啶的合成如下，
Figure PCTCN2021136618-appb-000031
将5,6-二氢-7H-环戊[b]吡啶-7-酮(10.00g，75.10mmol，1eq.)加入到DCM(200mL)中，用冰水浴冷却至0℃，滴加DAST(36.32g，225.31mmol，3.0eq.)，加完在室温下反应24小时。反应液直接缓慢倒入饱和碳酸氢钠水溶液中淬灭，经硅藻土过滤除去，滤饼用DCM洗涤，滤液分液，有机相用饱和氯化钠洗一次，分液干燥，过滤，滤液旋干，经柱层析得到7,7-二氟环戊烷并[b]吡啶(5.60g)，总收率为48.06％。
实施例12:(S)-N-(4-氨基-6-甲基-5-(2-甲基嘧啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙 烯酰胺
Figure PCTCN2021136618-appb-000032
使用实施例1相似的方法，将步骤二的化合物1.2替换为2-甲基嘧啶-4-硼酸，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.73(s,2H),8.58(s,1H),8.13(s,1H),6.46-65.95(m,4H),5.80(s,1S),5.62(m,1H),4.78(s,1H),4.19(m,2H),2.70(s,3H),1.57(s,3H)；LC-MS(m/z):361.17[M+H] +。
实施例13：(S)-N-(4-氨基-5-(5,6-二甲基吡啶-3-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚氮-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000033
使用实施例7相似的方法，将步骤一的起始物料替换为2,3-二甲-5-溴吡啶，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.46(s,1H),8.45(s,1H),8.15(s,1H),7.66(m,2H),6.22(m,2H),5.81(s,1H),5.62(m,1H),4.78(broad,1H),4.22(m,2H),2.52(s,3H),2.23(s,3H),1.58(s,3H)；LC-MS(m/z):375.19[M+H] +。
实施例14:(S)-N-(4-氨基-5-(5-环丙基吡啶-3-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000034
使用实施例7相似的方法，将步骤一的起始物料替换为3-环丙基-5-溴吡啶，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.44(m,3H),8.13(s,1H),7.51(m,1H),6.19(m,2H),5.95-5.50(m,2H),4.79(s,1H),4.18(m,2H),2.04(m,1H),1.56(s,3H),1.11(s,m,2H),0.81(m,2H)；LC-MS(m/z):387.19[M+H] +。
实施例15：(S)-N-(4-氨基-6-甲基-5-(喹啉-6-基)-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000035
使用实施例7相似的方法，将步骤一的起始物料替换为6-溴喹啉，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)8.98(s,1H),8.45(m,2H),8.11(m,3H),7.83(m,1H),7.62(m,1H),6.23(m,2H),5.81(s,1H),5.63(m,1H),4.81(s,1H),4.22(m,2H),3.30(s,2H),1.55(s,3H)；LC-MS(m/z):397.18[M+H] +。
实施例16:(S)-N-(4-氨基-6-甲基-5-(2-氧吲哚啉-5-基)-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000036
使用实施例7相似的方法，将步骤一的起始物料替换为5-溴吲哚啉-2-酮，得到标题化合物。
1H NMR(400MHz，DMSO-d 6)δ(ppm)10.55(s,1H),8.44(s,1H),8.12(s,1H),7.24(m,2H),6.91(m,1H),6.22(m,2H),5.76(s,1H),5.62(m,1H),4.77(s,1H),4.20(m,2H),3.55(s,2H),3.30(s,2H)1.62(s,3H)；LC-MS(m/z):401.12[M+H] +。
实施例17:(S)-N-(4-氨基-5-(咪唑[1,2-b]哒嗪-7-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000037
使用实施例7相似的方法，将步骤一的起始物料替换为7-氯咪唑并[1,2-b]哒嗪，得到标题化合物。
1H NMR(400MHz,CDCl 3)δ(ppm)8.44～8.54(m,1H),8.10～8.28(m,3H),7.90(s,1H),7.22～6.75(brs,1H),6.38～6.42(m,1H),6.18(brs,1H),6.01(s,1H),5.68～5.77(m,2H),5.11(s,1H),4.66～4.69(m,1H),4.13～4.66(m,1H),1.76(s,3H)；LC-MS(m/z):387.68[M+H] +。
实施例18:(S)-N-(4-氨基-6-甲基-5-(2-甲基-2H-吡唑并[3,4-b]吡啶-5-基)-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000038
使用实施例7相似的方法，将步骤一的起始物料替换为5-溴-1-甲基吡唑并[3,4-b]吡啶，得到标题化合物。
1H NMR(400MHz，CDCl 3)δ(ppm)8.65-8.73(m,1H),8.08-8.36(m,3H),6.37-6.41(m,1H),6.16-6.20(m,1H),5.89-5.92(m,1H),5.67-5.70(m,1H),5.08-5.20(m,2H),4.66(s,2H),4.25(s,3H),1.59(s,3H)；LC-MS(m/z):401.42[M+H] +。
实施例19:(S)-N-(4-氨基-6-甲基-5-(6-甲基-6,7-二氢-5H-吡咯[3,4-b]吡啶-3-基)-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000039
使用实施例7相似的方法，将步骤一的起始物料替换为3-溴-6-甲基-5,7-二氢吡咯[3,4-b] 吡啶，得到标题化合物。
1H NMR(400MHz,CDCl 3)δ(ppm)8.46-8.6(d,1H),8.21(s,2H),7.89-7.90(t,1H),7.59-7.73(d,1H),6.41-6.42(d,1H),6.17-6.21(m,1H),5.94-5.97(t,1H),5.66-5.69(t,1H),5.08(s,1H),4.67-4.74(m,1H),4.26-4.31(m,3H),4.00(m,1H),2.83-2.89(d,3H),1.62(s,3H)；LC-MS(m/z):402.46[M+H] +。
实施例20:(S)-N-(4-氨基-5-(2-环丙基-1H-吡咯[2,3-b]吡啶-5-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000040
使用实施例7相似的方法，将步骤一的起始物料替换为5-溴-2-环丙基-1H-吡咯[2,3-b]吡啶，得到标题化合物。
1H NMR(400MHz,DMSO-d 6)δ(ppm)11.65(s,1H),8.44～8.45(m,1H),8.10～8.13(m,2H),7.76～7.83(m,1H),6.13～6.29(m,3H),5.75(brs,1H),5.62～5.64(m,1H),4.78(brs,1H),4.10～4.24(m,2H),2.05～2.19(m,1H),1.53(s,3H),1.00～1.04(m,2H),0.88～0.91(m,2H)；LC-MS(m/z):426.08[M+H] +。
实施例21:(S)-N-(4-氨基-5-(咪唑[1,2-a]嘧啶-6-基)-6-甲基-8,9-二氢嘧啶[5,4-b]吲哚嗪-8-基)丙烯酰胺
Figure PCTCN2021136618-appb-000041
使用实施例7相似的方法，将步骤一的起始物料替换为6-溴代咪唑[1,2-a]嘧啶，得到标题化合物。
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.95,9.07(s,1H),8.47～8.52(m,2H),8.12,8.19(s,1H),7.89～7.92(m,1H),7.77(s,1H),6.13～6.35(m,4H),5.83～5.84(m,1H),5.61～5.62(m,1H),4.79(brs,1H),4.20～4.25(m,2H),1.62(s,3H)；LC-MS(m/z):387.01[M+H] +。
实验例1细胞增殖抑制实验
BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV细胞购买于北京康源博创生物科技有限公司，A431(人皮肤鳞癌细胞)EGFR野生型细胞购买于南京科佰生物科技有限公司。DMEM培养基、RPMI1640培养基、青霉素-链霉素双抗、0.5％的胰酶(10X)购自ThermoFisher(Waltham，MA，USA)。经认证的胎牛血清(FBS)购买于Biological Industries(Israel)。Corning96孔细胞培养板和Corning384孔细胞培养板购买于CORNING(USA)。Cell-Titer
Figure PCTCN2021136618-appb-000042
购买于Promega Corporation(Madison，WI，USA)。
为了评估化合物对A431和BaF3 EGFR D770_N771iinsSVD、BaF3 EGFR V769_D770insASV细胞增殖的抑制能力，将A431指数增长的细胞接种于含15％牛血清和1％青霉素-链霉素双抗的DMEM培养基，BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV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，A431密度为100000个细胞/mL，BaF3 EGFR D770_N771insSVD、BaF3 V769_D770insASV密度为50000个细胞/mL，384孔板，每孔20μL，并放置在37℃，5％CO 2的培养箱中过夜培养。将化合物在DMSO中稀释12个浓度梯度、3倍梯度稀释，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，DMSO的最终浓度为0.5％)。将培养基中的20μL化合物溶液按照浓度梯度加到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。室温孵育20分钟后使用TECAN公司的SPARK多功能酶标仪在化学发光的程序下进行检测。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)。
实验中所使用的阳性对照物TAS6417以市售方式获得结构如下：
Figure PCTCN2021136618-appb-000043
本申请代表性化合物对于A431 EGFR WT、BaF3 EGFR D770_N771insSVD、BaF3 EGFR V769_D770insASV细胞增殖抑制的结果见表1。
表1
Figure PCTCN2021136618-appb-000044
Figure PCTCN2021136618-appb-000045
结果显示，本申请代表性化合物对于A431 EGFR WT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1化合物的选择性和临床治疗空间优于阳性对照物 TAS6417。
实验例2细胞色素P450(CYP450)酶抑制实验
为评估本申请所合成化合物对在大多数药物肝脏代谢过程中起主要作用的CYP450酶的抑制能力，进而为评估化合物可能存在的体内药物药物相互作用风险提供有效体外数据，本实验通过鸡尾酒法测试了本申请所含化合物对CYP酶主要亚型(1A2，2C9，2C19，2D6，3A4)的抑制作用。
实验所用人肝微粒体(HLM)购自Corning(Cat No.452117),辅酶因子NADPH购自上海源叶生物科技(Cat No.S10103)。实验所测CYP亚型特异性底物，非那西丁，双氯芬酸钠，右美沙芬购自Sigma；S-mephenytoin以及咪达唑仑购自TRC。各亚型CYP酶阳性参比化合物α-Naphthoflavone和Quinidine购自Sigma；(+)-N-3-benzylnirvanol以及Ketoconazole购自TRC，Sulfaphenazole购自上海毕得。其余实验所用常规试剂DMSO，甲醇，和氯化镁分别购自J&K，Merck，以及上海润捷。
配制待测试化合物在1:1的DMSO和甲醇中的梯度稀释母液：所选浓度为：5mM、1.5mM、0.5mM、0.15mM、0.05mM、0.015mM、0.005mM。
配置各CYP亚酶特异性底物在甲醇中的存储母液，测试前使用磷酸盐缓冲液(PB)稀释，配置工作溶液，浓度分别为：非那西丁100μM，双氯芬酸钠50μM，S-mephenytoin 300μM，右美沙芬50μM，咪达唑仑20μM。
配置各CYP亚酶特异性抑制剂DMSO存储母液，测试前使用MeOH进行100倍稀释，配置工作溶液，浓度分别为：α-Naphthoflavone 300μM，Sulfaphenazole 300μM，(+)-N-3-benzylnirvanol 100μM，Quinidine 300μM，Ketoconazole 300μM。
在微孔测试板试验孔中加入相应的底物溶液20μL，空白孔中加入20μL PB，各孔中加入HLM工作液的158μL(0.253mg/mL),再在各孔中加入相应的测试化合物或阳性参比抑制剂工作溶液2μL，其他孔中加入2μL缓冲溶液，在37℃水浴中预孵育约10分钟，然后加入预先配置的NADPH(10mM)溶液20μL，继续在37℃水浴中混合，孵育10分钟进行反应后，加入400μL冷的终止液(200ng/mL甲苯酰胺和拉贝他洛的乙腈溶液)终止反应，4000rpm离心20分钟，沉淀蛋白质，取200μL上清移至100μL水中(HPLC)，摇匀10分钟，进行LC/MS/MS分析。
测试各亚型CYP酶底物代谢产物的相对生成量，计算剩余酶活，并通过使用Prism 7(La Jolla，15CA)在S形剂量反应曲线中拟合剩余酶活相对于抑制剂浓度来获得抑制剂的IC 50数值。最高浓度抑制活性小于50％时，IC 50记做>50μM。
本申请实施例1化合物与阳性对照物TAS6417的细胞色素P450(CYP450)酶抑制实验结果见表2。
表2
Figure PCTCN2021136618-appb-000046
Figure PCTCN2021136618-appb-000047

Claims (13)

  1. 一种如下通式(I)所示的化合物：
    Figure PCTCN2021136618-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐，
    其中，Cy为含有1-4个杂原子、5-14个环原子的杂环基或杂芳基，所述杂环基或杂芳基可选地被1-3个R 4取代，且Cy不为
    Figure PCTCN2021136618-appb-100002
    R 1选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；
    R 2为氢或C 1-C 6烷基；
    X为N或-C-R 3；
    R 3选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；以及
    R 4选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羰基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(Ia)所示的化合物：
    Figure PCTCN2021136618-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐，
    其中，环A为含有0-2个杂原子、5-6个环原子的饱和或不饱和环，所述环A可选地被1-3个R 4取代；
    R 1选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；
    R 2为氢或C 1-C 6烷基；
    X为N或-C-R 3；
    R 3选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代；以及
    R 4选自氢、C 1-C 6烷基、C 3-C 6环烷基、C 2-C 6烯基、C 2-C 6炔基、卤素、氰基、硝基、氨基、羟基、羟烷基、烷氧基、烷基酰基，所述烷基、烯基、炔基、羰基、羟烷基、烷氧基、烷基酰基可选地被1-3个卤素取代。
  3. 根据权利要求1所述的通式(I)所示的化合物，其中Cy选自：
    Figure PCTCN2021136618-appb-100004
    Figure PCTCN2021136618-appb-100005
  4. 根据权利要求1所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2021136618-appb-100006
    Figure PCTCN2021136618-appb-100007
  5. 根据权利要求1所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2021136618-appb-100008
    Figure PCTCN2021136618-appb-100009
  6. 根据权利要求1所述的通式(I)所示的化合物，其结构为：
    Figure PCTCN2021136618-appb-100010
  7. 一种根据权利要求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7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。
PCT/CN2021/136618 2020-12-09 2021-12-09 Egfr酪氨酸激酶抑制剂及其用途 WO2022121967A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011446082 2020-12-09
CN202011446082.4 2020-12-09

Publications (1)

Publication Number Publication Date
WO2022121967A1 true WO2022121967A1 (zh) 2022-06-16

Family

ID=81974242

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/136618 WO2022121967A1 (zh) 2020-12-09 2021-12-09 Egfr酪氨酸激酶抑制剂及其用途

Country Status (1)

Country Link
WO (1) WO2022121967A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104136438A (zh) * 2012-02-23 2014-11-05 大鹏药品工业株式会社 喹啉基吡咯并嘧啶基稠环化合物或其盐
CN105683195A (zh) * 2013-08-22 2016-06-15 大鹏药品工业株式会社 新的喹啉取代的化合物
CN110191711A (zh) * 2016-10-31 2019-08-30 大鹏药品工业株式会社 外显子20插入突变型egfr的选择性抑制剂
CN111465397A (zh) * 2017-09-01 2020-07-28 大鹏药品工业株式会社 外显子18和/或外显子21突变型egfr的选择性抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104136438A (zh) * 2012-02-23 2014-11-05 大鹏药品工业株式会社 喹啉基吡咯并嘧啶基稠环化合物或其盐
CN105683195A (zh) * 2013-08-22 2016-06-15 大鹏药品工业株式会社 新的喹啉取代的化合物
CN110191711A (zh) * 2016-10-31 2019-08-30 大鹏药品工业株式会社 外显子20插入突变型egfr的选择性抑制剂
CN111465397A (zh) * 2017-09-01 2020-07-28 大鹏药品工业株式会社 外显子18和/或外显子21突变型egfr的选择性抑制剂

Similar Documents

Publication Publication Date Title
JP7079303B2 (ja) Ｒｅｔキナーゼ阻害剤としての置換ピラゾロ［１，５－ａ］ピリジン化合物
US11661423B2 (en) Heterocyclic compounds as RET kinase inhibitors
EP2931722B1 (en) Substituted 1h-pyrrolo [2,3-b]pyridine and 1h-pyrazolo [3, 4-b]pyridine derivatives as salt inducible kinase 2 (sik2) inhibitors
RU2742115C2 (ru) Гетероциклические соединения в качестве ингибиторов киназы RET
RU2747260C2 (ru) Ингибитор рфрф4, способ его получения и его фармацевтическое применение
RU2326882C2 (ru) Пиримидиновые соединения, обладающие антипролиферативной активностью (ii)
DK2716633T3 (en) QUINAZOLINE DERIVATIVE AS A TYROSIN-KINASE INHIBITOR, PROCEDURE FOR PREPARING IT AND USING THEREOF
IL261107B2 (en) A novel compressed pyrimidine compound or a salt thereof
WO2021175270A1 (zh) 新型hpk1抑制剂及其制备方法和应用
WO2022135432A1 (zh) 作为egfr抑制剂的大环杂环类化合物及其应用
KR20110052708A (ko) 2-알킬-6-시클로아미노-3-（피리딘-4-일）이미다조〔1,2-ｉｂ〕피리다진 유도체, 그의 제조법 및 그의 치료 용도
CN113527299B (zh) 一类含氮稠环类化合物、制备方法和用途
WO2015058661A1 (zh) Bcr-abl激酶抑制剂及其应用
WO2019029629A1 (en) SUBSTITUTED PYRAZOLOPYRIMIDINES FOR USE AS KINASE INHIBITORS
JP2021503479A (ja) 置換ヘテロアリール化合物及び使用方法
KR20210049096A (ko) 암을 치료하기에 유용한 ErbB 조절자로서의 4-치환된 피롤로[2,3-b]피리딘
WO2021249319A1 (zh) 三环化合物、药物组合物及其应用
MXPA06008571A (es) Derivados de pirrolo-pirimidina utiles para el tratamiento de enfermedades proliferativas.
WO2022121967A1 (zh) Egfr酪氨酸激酶抑制剂及其用途
CN103596953A (zh) 吡啶并萘啶类P13K和mTOR双重抑制剂及其制备与应用
WO2022179584A1 (zh) 新型ezh2抑制剂及其用途
WO2022197898A1 (en) Cyclic compounds and methods of using same
EP4293029A1 (en) Azaheteroaryl compound, preparation method therefor, and application thereof
CN117120447A (zh) 环状化合物和其使用方法
CN117800976A (zh) 一类含氮杂环类化合物、制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21902672

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21902672

Country of ref document: EP

Kind code of ref document: A1