WO2022184116A1 - New sos1 inhibitor, preparation method therefor and use thereof - Google Patents

New sos1 inhibitor, preparation method therefor and use thereof Download PDF

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WO2022184116A1
WO2022184116A1 PCT/CN2022/078929 CN2022078929W WO2022184116A1 WO 2022184116 A1 WO2022184116 A1 WO 2022184116A1 CN 2022078929 W CN2022078929 W CN 2022078929W WO 2022184116 A1 WO2022184116 A1 WO 2022184116A1
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alkyl
cycloalkyl
pharmaceutically acceptable
membered
acceptable salt
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PCT/CN2022/078929
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French (fr)
Chinese (zh)
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张雁
杨圣伟
庞司林
赵春艳
丁海敏
王峰
唐锋
彭少平
任晋生
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江苏先声药业有限公司
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Priority to CN202280017194.9A priority Critical patent/CN117062818A/en
Publication of WO2022184116A1 publication Critical patent/WO2022184116A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the technical field of medicine, and relates to SOS1 inhibitor compounds or optical isomers, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as SOS1 inhibitors.
  • R 2b is selected from -OR 2c , -N(R 2c ) 2 , -NHR 2c , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)N(R 2c ) 2 , - C(O)NHR 2c , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -S(O) 2 NHR 2c , -NHC(O ) R 2c or -N(C 1-4 alkyl)C(O)R 2c ;
  • R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, said C 1-6 alkyl, C 3-10 cycloalkyl or The 3-10 membered heterocyclyl is optionally substituted with R 2b and/or R 2c .
  • R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, or -C(O)R 2c .
  • R 2d is selected from halogen.
  • R 3 , R 4 are independently selected from H, deuterium, CH 3 or CD 3 .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof,
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of diseases related to SOS1.
  • the SOS1-related disease is selected from cancer.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, paracyclic, bridged or spirocyclic ring or the like. Unless otherwise indicated, the carbocycle is typically a 4- to 10-membered ring.
  • specific examples of the term “C 4 -C 10 cycloalkenyl” include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl Alkenyl etc.
  • C 6-10 aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of carbon atoms (“C 6 aryl”), such as phenyl; or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms (“C 10 aryl”), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • the heterocyclyl group may be bicyclic, including but not limited to: a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as hexahydro pyrrolo[1,2-a]pyrazin-2(1H)-yl ring, Or 6,6 membered bicyclic, such as dihydroisoquinolinyl.
  • the term "3-8 membered heterocyclyl” is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 8 ring atoms.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • Step 5 Synthesis of 6-(1-Methylcyclopropyl)-1,6-naphthyridine-4,7(1H,6H)-dione
  • reaction solution was cooled and poured into ice, then adjusted to pH 8 with saturated sodium bicarbonate, then extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound.
  • Step 3 Synthesis of 4-chloro-6-(1-methylcyclopropyl)-1,6-naphthyridine-2,7(1H,6H)-dione
  • Step 7 Synthesis of 3-(1-Acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one
  • reaction solution was moved to room temperature and stirred for a period of time.
  • a small amount of methanol was added to quench the reaction, then poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous sulfuric acid. Dry over sodium, filter, and concentrate the filtrate under reduced pressure and purify by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
  • Step 2 3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylate Synthesis of tert-butyl acid
  • Step 3 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1, Synthesis of 2-dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester
  • reaction solution was cooled and poured into water, the pH of the system was adjusted to 7-8 with dilute hydrochloric acid (2M), extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. After concentration under pressure, the crude title compound was obtained, which was used in the next reaction without purification.
  • 2M dilute hydrochloric acid
  • Step 7 (R)-6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-(difluoromethyl)-2- Synthesis of Fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one
  • Step 1 (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-di Synthesis of Hydrogen-1,8-Naphthyridine-3-Carboxylic Acid Methyl Esters
  • 1,8-Dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (1.13 g) was dispersed in 10 mL of N,N-dimethylformamide, Dibromohydantoin (3.38 g) was then added to react at room temperature for 8 hours, the reaction solution was concentrated, and the title compound was obtained by column chromatography (gradient elution of petroleum ether/ethyl acetate).
  • Example 10 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
  • reaction solution was cooled, concentrated ammonia water was added, the pH of the system was adjusted to 8-9, then concentrated under reduced pressure, ethyl acetate was added, the insolubles were filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate/methanol gradient wash) removal) to obtain the title compound.
  • Step 8 (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-methyl-1,2,3,6 -Synthesis of -tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridin-7(6H)-one
  • the difference is that the morpholine in step 4 is replaced by N,4-dimethylpiperidine-4-carboxamide, and the title compound is obtained by the same method.
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30256.01) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163), when When the cell growth reached 80-90%, the cells were digested and blown away and seeded in a 96-well plate (Corning, 4515), with 3000 cells per well (180 ⁇ l RPMI1640 complete medium), and then the 96-well plate was placed at 37°C, 5% Incubate overnight in a CO 2 incubator.
  • the percent inhibition of H358 cell proliferation by a compound can be calculated using the following formula:
  • Y is the percentage of inhibition
  • X is the logarithm of the concentration of the compound to be tested
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • slope factor is the slope coefficient of the curve.
  • test results Under the experimental conditions, the examples of the present invention have good proliferation inhibitory activity on H358 cells. The corresponding activity test results of the test compounds are shown in Table 1.
  • Example IC50 (nM) 1 17.3 2 111.3 3 31.2 4 80.2 5 52.5 7 195.3 9 162.2 17 67.0 18 65.7
  • the experimental method is outlined as follows:
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (ThermoFisher, A1049101) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163)
  • RPMI1640 ThermoFisher, A1049101
  • FBS FBS
  • penicillin-streptomycin Gabco, 15140163
  • the coverage rate in the culture vessel reaches 80-90%, the cells are blown off and then planted in a 96-well plate (Corning, 3599), with 50,000 cells per well (90 ⁇ L PPMI1640 complete medium), and placed at 37°C, 5 minutes after standing for 5 minutes. Incubate for 6 h in a %CO 2 incubator, and replace with serum-free RPMI1640 starvation overnight.
  • the percentage inhibition of the p-ERK pathway in H358 cells by the compounds of the present invention can be calculated by the following formula:
  • the IC50 50% inhibitory concentration of the compound was obtained using the following nonlinear fitting formula:

Abstract

An SOS1 inhibitor compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug for treating cancers.

Description

新型SOS1抑制剂及其制备方法和应用Novel SOS1 inhibitor and preparation method and application thereof
本申请要求以下2件在先申请的优先权，以下在先申请的全文通过引用的方式结合于本申请中：This application claims priority to the following 2 prior applications, the entire contents of which are incorporated herein by reference:
2021年3月5日向中国国家知识产权局提交的，专利申请号为202110246153.4，发明名称为“新型SOS1抑制剂及其制备方法和应用”的在先申请；An earlier application submitted to the State Intellectual Property Office of China on March 5, 2021, with the patent application number 202110246153.4 and the invention titled “New SOS1 Inhibitor and its Preparation Method and Application”;
2021年9月17日向中国国家知识产权局提交的，专利申请号为202111094388.2，发明名称为“新型SOS1抑制剂及其制备方法和应用”的在先申请。Submitted to the State Intellectual Property Office of China on September 17, 2021, the patent application number is 202111094388.2, and the invention is an earlier application entitled "New SOS1 inhibitor and its preparation method and application".
技术领域technical field
本发明属于医药技术领域，涉及SOS1抑制剂化合物或其光学异构体、药学上可接受的盐，含有它们的药物组合物以及作为SOS1抑制剂的用途。The present invention belongs to the technical field of medicine, and relates to SOS1 inhibitor compounds or optical isomers, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as SOS1 inhibitors.
背景技术Background technique
RAS家族蛋白包括KRAS(V-Ki-ras2 Kirsten大鼠肉瘤病毒致癌基因同源物)、NRAS(神经母细胞瘤RAS病毒致癌基因同源物)和HRAS(Harvey鼠肉瘤病毒致癌基因)等，是存在于细胞中处于GTP结合状态或GDP结合状态的小GTP酶(McCormick等人,J.Mol.Med.(Berl).,2016,94(3):253-8；Nimnual等人,Sci.STKE.,2002,2002(145):pe36)。RAS family proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog) and HRAS (Harvey murine sarcoma virus oncogene), etc. Small GTPases present in cells in either a GTP-bound state or a GDP-bound state (McCormick et al, J. Mol. Med. (Berl)., 2016, 94(3): 253-8; Nimnual et al, Sci. STKE ., 2002, 2002(145):pe36).
RAS家族蛋白在人类癌症中起着重要作用。RAS蛋白突变引起的肿瘤占人类所有肿瘤的20-30％，并且被认为是致瘤驱动因素，特别是在肺癌，结直肠癌和胰腺癌中(Malumbres&Barbacid 2002 Nature Reviews Cancer，Pylayeva-Gupta等人，2011 Nature Reviews Cancer)。RAS family proteins play an important role in human cancer. Tumors caused by mutations in RAS proteins account for 20-30% of all tumors in humans and are thought to be tumorigenic drivers, especially in lung, colorectal, and pancreatic cancer (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al., 2011 Nature Reviews Cancer).
SOS1(son of sevenless homolog 1)蛋白是一种在细胞中广泛表达的调控蛋白，作为RAS、RAC蛋白的一类鸟嘌呤核苷酸交换因子，在细胞内RAS、RAC信号转导通路中起着重要的调控作用。SOS1具有两个针对RAS家族蛋白的结合位点：催化位点，所述催化位点结合GDP结合的RAS家族蛋白以促进鸟嘌呤核苷酸交换；变构位点，所述变构位点结合GTP结合的RAS家族蛋白，这导致SOS1的催化GEF功能进一步增加(Freedman等人，Proc.Natl.Acad.Sci.USA.,2006,103(4 5):16692-7；Pierre等人,Biochem.Pharmacol.,2011,82(9):1049-56)。公开数据表明SOS1参与在癌症中的突变KRAS活化和致癌信号传导(Jeng等人,Nat.Commun.,2012,3:1168)。消耗SOS1水平会降低携带KRAS突变的肿瘤细胞的增殖率和存活，而在KRAS野生型细胞系中没有观察到作用。SOS1丧失的影响无法通过引入催化位点突变的SOS1弥补，进一步证明了SOS1GEF活性在KRAS突变癌细胞中的重要作用。SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a kind of guanine nucleotide exchange factor of RAS and RAC proteins, it plays a role in the signal transduction pathway of RAS and RAC in cells. important regulatory role. SOS1 has two binding sites for RAS family proteins: a catalytic site, which binds GDP-bound RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family protein, which leads to a further increase in the catalytic GEF function of SOS1 (Freedman et al., Proc. Natl. Acad. Sci. USA., 2006, 103(45):16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56). Published data suggest that SOS1 is involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depleting SOS1 levels reduced the proliferation rate and survival of KRAS-mutated tumor cells, whereas no effect was observed in KRAS wild-type cell lines. The effects of SOS1 loss could not be compensated by the introduction of catalytic site-mutated SOS1, further demonstrating the important role of SOS1GEF activity in KRAS-mutant cancer cells.
在近几十年中，RAS家族蛋白-SOS1蛋白相互作用已进行了越来越多的研究。已鉴别出小的激活分子，其结合至紧密靠近RAS结合位点的SOS1的亲脂性口袋(Burns等人，Proc.Natl.Acad.Sci.2014,111(9):3401-6)。然而，这些分子的结合似乎导致核苷酸交换增加，从而激活RAS而非使其失活。In recent decades, RAS family protein-SOS1 protein interactions have been increasingly studied. Small activating molecules have been identified that bind to the lipophilic pocket of SOS1 in close proximity to the RAS binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, the binding of these molecules appears to result in increased nucleotide exchange, which activates RAS rather than inactivating it.
虽然现有文献中也报道了一些SOS1小分子抑制剂(如专利文献WO2018/115380A1及WO2018/172250A1)，但仍有大量的患者无法得到满意的临床治疗效果，因此目前仍然需要开发具有活性更好，选择性更好、安全性更佳的SOS1抑制剂。Although some SOS1 small molecule inhibitors have also been reported in the existing literature (such as patent documents WO2018/115380A1 and WO2018/172250A1), there are still a large number of patients who cannot obtain satisfactory clinical therapeutic effects, so there is still a need to develop drugs with better activity. , SOS1 inhibitors with better selectivity and safety.
发明内容SUMMARY OF THE INVENTION
本发明提供式(I)所示化合物及其药学上可接受的盐。这些化合物可以抑制SOS1的活性，从而影响生物学功能。The present invention provides compounds represented by formula (I) and pharmaceutically acceptable salts thereof. These compounds can inhibit the activity of SOS1, thereby affecting biological function.
本发明提供了一种式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000001
Figure PCTCN2022078929-appb-000001
其中，环B选自wherein Ring B is selected from
Figure PCTCN2022078929-appb-000002
Figure PCTCN2022078929-appb-000002
R 1选自H、卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6氘代烷基、-O-C 1-6烷基或C 3-6环烷基； R 1 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl;
R 2选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 4-10环烯基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 4-10环烯基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代； R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 3- 10-membered heterocyclyl or 5-10-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 ring alkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b and/or R 2c ;
R 2b选自-OR 2c、-N(R 2c) 2、-NHR 2c、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)N(R 2c) 2、-C(O)NHR 2c、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-S(O) 2NHR 2c、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c； R 2b is selected from -OR 2c , -N(R 2c ) 2 , -NHR 2c , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)N(R 2c ) 2 , - C(O)NHR 2c , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -S(O) 2 NHR 2c , -NHC(O ) R 2c or -N(C 1-4 alkyl)C(O)R 2c ;
R 2c独立地选自C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2d取代； R 2c is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d ;
R 2d选自卤素、羟基、氰基、氨基、-C(O)R 2f、-C(O)N(R 2f) 2、-C(O)OR 2f、-S(O) 2R 2f、-S(O) 2N(R 2f) 2、-N(C 1-4烷基)R 2f、-NHC(O)R 2f、-N(C 1-4烷基)C(O)R 2f、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2f取代； R 2d is selected from halogen, hydroxyl, cyano, amino, -C(O)R 2f , -C(O)N(R 2f ) 2 , -C(O)OR 2f , -S(O) 2 R 2f , -S(O) 2 N(R 2f ) 2 , -N(C 1-4 alkyl)R 2f , -NHC(O)R 2f , -N(C 1-4 alkyl)C(O)R 2f , C 3-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, C 6-10 aryl, 3 -10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2f ;
R 2f独立地选自H或C 1-6烷基； R 2f is independently selected from H or C 1-6 alkyl;
R 3、R 4独立地选自H、氘、C 1-3氘代烷基、C 1-6烷基或C 1-6卤代烷基； R 3 and R 4 are independently selected from H, deuterium, C 1-3 deuterated alkyl, C 1-6 alkyl or C 1-6 haloalkyl;
R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、-C(O)R 5b、-C(O)N(R 5b) 2、-C(O)OR 5b、
Figure PCTCN2022078929-appb-000003
3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代； R 5 is independently selected from SF 5 , nitro, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 ring Alkyl, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 , -C(O)R 5b , - C(O)N(R 5b ) 2 , -C(O)OR 5b ,
Figure PCTCN2022078929-appb-000003
3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -OC 3-6 cycloalkyl group, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a ;
R 5a独立地选自卤素、羟基、氰基或氨基； R 5a is independently selected from halogen, hydroxy, cyano or amino;
R 5b独立地选自H或C 1-6烷基； R 5b is independently selected from H or C 1-6 alkyl;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
R 6选自H、卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 6a取代； R 6 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O- (3-8-membered heterocyclic group), 3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group , -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted by R 6a ;
R 6a选自卤素、羟基、氰基或氨基； R 6a is selected from halogen, hydroxy, cyano or amino;
R 7选自H、卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 7a取代； R 7 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O- (3-8-membered heterocyclic group), 3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group , -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted by R 7a ;
R 7a选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6卤代烷基； R 7a is selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 haloalkyl;
环A选自C 6-10芳基、5-10元杂环基或5-10元杂芳基。 Ring A is selected from C 6-10 aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl.
在一些实施方案中，R 1选自H、卤素、C 1-6烷基或C 1-6氘代烷基。 In some embodiments, R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 deuterated alkyl.
在一些实施方案中，R 1选自H、C 1-6烷基或C 1-6氘代烷基。 In some embodiments, R 1 is selected from H, C 1-6 alkyl, or C 1-6 deuterated alkyl.
在一些实施方案中，R 1选自H、卤素、C 1-3烷基或C 1-3氘代烷基。 In some embodiments, R 1 is selected from H, halogen, C 1-3 alkyl, or C 1-3 deuterated alkyl.
在一些实施方案中，R 1选自H、C 1-3烷基或C 1-3氘代烷基。 In some embodiments, R 1 is selected from H, C 1-3 alkyl, or C 1-3 deuterated alkyl.
在一些实施方案中，R 1选自H、卤素、CH 3或CD 3。 In some embodiments, R1 is selected from H, halogen, CH3 or CD3 .
在一些实施方案中，R 1选自H、CH 3或CD 3。 In some embodiments, R 1 is selected from H, CH 3 or CD 3 .
在一些实施方案中，R 2选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered Heterocyclyl or 5-10-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, The 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2b and/or R 2c .
在一些实施方案中，R 2选自C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with R 2b and/or R 2c .
在一些实施方案中，R 2选自C 1-6烷基、C 3-10环烷基或3-10元杂环基，所述C 1-6烷基、C 3- 10环烷基或3-10元杂环基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, said C 1-6 alkyl, C 3-10 cycloalkyl or The 3-10 membered heterocyclyl is optionally substituted with R 2b and/or R 2c .
在一些实施方案中，R 2选自C 3-10环烷基或3-10元杂环基，所述C 3-10环烷基或3-10元杂环基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, the C 3-10 cycloalkyl or 3-10 membered heterocyclyl optionally being replaced by R 2b and / or R 2c substituted.
在一些实施方案中，R 2选自C 3-6环烷基或4-9元杂环基，所述C 3-6环烷基或4-9元杂环基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 3-6 cycloalkyl or 4-9 membered heterocyclyl, the C 3-6 cycloalkyl or 4-9 membered heterocyclyl optionally being replaced by R 2b and / or R 2c substituted.
在一些实施方案中，R 2选自C 3-6环烷基或4-7元杂环基，所述C 3-6环烷基或4-7元杂环基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from C 3-6 cycloalkyl or 4-7 membered heterocyclyl, the C 3-6 cycloalkyl or 4-7 membered heterocyclyl optionally being replaced by R 2b and / or R 2c substituted.
在一些实施方案中，R 2选自环丙基、氧杂环丁基、吗啉基、
Figure PCTCN2022078929-appb-000004
哌啶基或四氢吡咯基，所述环丙基、氧杂环丁基、吗啉基、
Figure PCTCN2022078929-appb-000005
哌啶基或四氢吡咯基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from cyclopropyl, oxetanyl, morpholinyl,
Figure PCTCN2022078929-appb-000004
piperidinyl or tetrahydropyrrolyl, the cyclopropyl, oxetanyl, morpholinyl,
Figure PCTCN2022078929-appb-000005
Piperidinyl or tetrahydropyrrolyl is optionally substituted with R 2b and/or R 2c .
在一些实施方案中，R 2选自环丙基、氧杂环丁基、吗啉基或
Figure PCTCN2022078929-appb-000006
所述环丙基、氧杂环丁基、吗啉基或
Figure PCTCN2022078929-appb-000007
任选地被R 2b和/或R 2c取代。 In some embodiments, R is selected from cyclopropyl, oxetanyl , morpholinyl or
Figure PCTCN2022078929-appb-000006
The cyclopropyl, oxetanyl, morpholinyl or
Figure PCTCN2022078929-appb-000007
optionally substituted with R 2b and/or R 2c .
在一些实施方案中，R 2选自环丙基、吗啉基、哌啶基或四氢吡咯基，所述环丙基、吗啉基、哌啶基或四氢吡咯基任选地被R 2b和/或R 2c取代。 In some embodiments, R 2 is selected from cyclopropyl, morpholinyl, piperidinyl, or tetrahydropyrrolyl, which is optionally replaced by R 2b and/or R 2c substituted.
在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)N(R 2c) 2、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c。在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c或-C(O)NHR 2c。 In some embodiments, R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)N(R 2c ) 2 , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -NHC(O)R 2c or -N(C 1-4 alkyl)C (O)R 2c . In some embodiments, R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, -C(O)R 2c or -C(O)NHR 2c .
在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基或-C(O)R 2c。 In some embodiments, R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, or -C(O)R 2c .
在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基或氨基。 In some embodiments, R 2b is selected from -OR 2c , -N(R 2c ) 2 , halo, hydroxy, cyano, or amino.
在一些实施方案中，R 2b选自-OR 2c、-C(O)R 2c或-C(O)NHR 2c。 In some embodiments, R 2b is selected from -OR 2c , -C(O)R 2c or -C(O)NHR 2c .
在一些实施方案中，R 2b选自-OR 2c或-C(O)R 2c。 In some embodiments, R 2b is selected from -OR 2c or -C(O)R 2c .
在一些实施方案中，R 2b选自-OCH 3、-C(O)CH 3或-C(O)NHCH 3。 In some embodiments, R 2b is selected from -OCH 3 , -C(O)CH 3 or -C(O)NHCH 3 .
在一些实施方案中，R 2b选自-OCH 3或-C(O)CH 3。 In some embodiments, R 2b is selected from -OCH 3 or -C(O)CH 3 .
在一些实施方案中，R 2c独立地选自C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2d取代。 In some embodiments, R 2c is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, The C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with R 2d .
在一些实施方案中，R 2c独立地选自C 1-6烷基、3-10元杂环基或5-10元杂芳基，所述C 1- 6烷基、3-10元杂环基或5-10元杂芳基任选地被R 2d取代。 In some embodiments, R 2c is independently selected from C 1-6 alkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said C 1-6 alkyl, 3-10 membered heterocycle or 5-10 membered heteroaryl optionally substituted with R 2d .
在一些实施方案中，R 2c独立地选自C 1-6烷基、4-9元杂环基或5-6元杂芳基，所述C 1-6烷基、4-9元杂环基或5-6元杂芳基任选地被R 2d取代。 In some embodiments, R 2c is independently selected from C 1-6 alkyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl, the C 1-6 alkyl, 4-9 membered heterocycle or 5-6 membered heteroaryl optionally substituted with R 2d .
在一些实施方案中，R 2c独立地选自C 1-6烷基或4-9元杂环基，所述C 1-6烷基或4-9元杂环基任选地被R 2d取代。在一些实施方案中，R 2c独立地选自C 1-6烷基或氧杂环丁基，所述C 1- 6烷基或氧杂环丁基任选地被R 2d取代。 In some embodiments, R 2c is independently selected from C 1-6 alkyl or 4-9 membered heterocyclyl optionally substituted with R 2d . In some embodiments, R 2c is independently selected from C 1-6 alkyl or oxetanyl optionally substituted with R 2d .
在一些实施方案中，R 2c为甲基、CH 2F、CHF 2、CF 3或氧杂环丁基。 In some embodiments, R 2c is methyl, CH 2 F, CHF 2 , CF 3 or oxetanyl.
在一些实施方案中，R 2c独立地选自C 1-6烷基，所述C 1-6烷基任选地被R 2d取代。在一些实施方案中，R 2c为甲基、CH 2F、CHF 2或CF 3。 In some embodiments, R 2c is independently selected from C 1-6 alkyl optionally substituted with R 2d . In some embodiments, R 2c is methyl, CH 2 F, CHF 2 or CF 3 .
在一些实施方案中，R 2d选自卤素、羟基、氰基、氨基、-C(O)R 2f、-C(O)N(R 2f) 2、-C(O)OR 2f、-S(O) 2R 2f、-S(O) 2N(R 2f) 2、-N(C 1-4烷基)R 2f、-NHC(O)R 2f或-N(C 1-4烷基)C(O)R 2f。 In some embodiments, R 2d is selected from halogen, hydroxy, cyano, amino, -C(O)R 2f , -C(O)N(R 2f ) 2 , -C(O)OR 2f , -S( O) 2 R 2f , -S(O) 2 N(R 2f ) 2 , -N(C 1-4 alkyl)R 2f , -NHC(O)R 2f or -N(C 1-4 alkyl) C(O)R 2f .
在一些实施方案中，R 2d选自卤素。 In some embodiments, R 2d is selected from halogen.
在一些实施方案中，R 2d选自F。 In some embodiments, R 2d is selected from F.
在一些实施方案中，R 3、R 4独立地选自H、氘、C 1-3氘代烷基或C 1-6烷基。 In some embodiments, R 3 , R 4 are independently selected from H, deuterium, C 1-3 deuterated alkyl, or C 1-6 alkyl.
在一些实施方案中，R 3、R 4独立地选自H、氘、CH 3或CD 3。 In some embodiments, R 3 , R 4 are independently selected from H, deuterium, CH 3 or CD 3 .
在一些实施方案中，R 3选自H或氘，R 4选自CH 3或CD 3。 In some embodiments, R3 is selected from H or deuterium, and R4 is selected from CH3 or CD3 .
在一些实施方案中，R 5独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、-C(O)R 5b、-C(O)N(R 5b) 2、-C(O)OR 5b、
Figure PCTCN2022078929-appb-000008
3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cyclo Alkyl, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 , -C(O)R 5b , - C(O)N(R 5b ) 2 , -C(O)OR 5b ,
Figure PCTCN2022078929-appb-000008
3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -OC 3-6 cycloalkyl group, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
Figure PCTCN2022078929-appb-000009
3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from SF 5 , nitro, halo, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
Figure PCTCN2022078929-appb-000009
3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -S(O) 2 -C 1 -4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、- O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
Figure PCTCN2022078929-appb-000010
3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
Figure PCTCN2022078929-appb-000010
3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -S(O) 2 -C 1 -4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
Figure PCTCN2022078929-appb-000011
或3-8元杂环基，所述C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或3-8元杂环基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from SF 5 , nitro, halo, hydroxy, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
Figure PCTCN2022078929-appb-000011
or 3-8 membered heterocyclyl, the C 1-6 alkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl or 3-8 membered heterocyclyl is optionally Substituted by R 5a .
在一些实施方案中，R 5独立地选自卤素、羟基、氰基、氨基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
Figure PCTCN2022078929-appb-000012
或3-8元杂环基，所述C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或3-8元杂环基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
Figure PCTCN2022078929-appb-000012
or 3-8 membered heterocyclyl, the C 1-6 alkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl or 3-8 membered heterocyclyl is optionally Substituted by R 5a .
在一些实施方案中，R 5独立地选自SF 5、硝基、氰基、卤素、C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2或
Figure PCTCN2022078929-appb-000013
所述C 1-6烷基或-S(O) 2-C 1-4烷基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from SF 5 , nitro, cyano, halogen, C 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)( R 5b ) 2 or
Figure PCTCN2022078929-appb-000013
Said C 1-6 alkyl or -S(O) 2 -C 1-4 alkyl is optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自SF 5、硝基、氰基、卤素、C 1-6烷基，所述C 1-6烷基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from SF 5 , nitro, cyano, halogen, C 1-6 alkyl optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自卤素、C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2或
Figure PCTCN2022078929-appb-000014
所述C 1-6烷基或-S(O) 2-C 1-4烷基任选地被R 5a取代。 In some embodiments, R 5 is independently selected from halogen, C 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 or
Figure PCTCN2022078929-appb-000014
Said C 1-6 alkyl or -S(O) 2 -C 1-4 alkyl is optionally substituted with R 5a .
在一些实施方案中，R 5独立地选自硝基、氰基、F、CH 3、-S(O) 2-CH 3或-P(O)(CH 3) 2，所述CH 3或-S(O) 2-CH 3任选地被R 5a取代。 In some embodiments, R 5 is independently selected from nitro, cyano, F, CH 3 , -S(O) 2 -CH 3 or -P(O)(CH 3 ) 2 , said CH 3 or - S(O) 2 - CH3 is optionally substituted with R5a .
在一些实施方案中，R 5独立地选自F、CH 3、-S(O) 2-CH 3或-P(O)(CH 3) 2，所述CH 3或-S(O) 2-CH 3任选地被R 5a取代。 In some embodiments, R 5 is independently selected from F, CH 3 , -S(O) 2 -CH 3 or -P(O)(CH 3 ) 2 , said CH 3 or -S(O) 2 - CH3 is optionally substituted with R5a .
在一些实施方案中，R 5a独立地选自卤素或羟基。 In some embodiments, R 5a is independently selected from halo or hydroxy.
在一些实施方案中，R 5a独立地选自卤素。 In some embodiments, R 5a is independently selected from halogen.
在一些实施方案中，R 5a独立地选自F。 In some embodiments, R 5a is independently selected from F.
在一些实施方案中，R 6选自H或卤素。 In some embodiments, R 6 is selected from H or halogen.
在一些实施方案中，R 6选自H。 In some embodiments, R 6 is selected from H.
在一些实施方案中，R 7选自H、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 7a取代。 In some embodiments, R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3- 8-membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl, the C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl are optionally substituted with R 7a .
在一些实施方案中，R 7选自H、C 1-6烷基、C 3-6环烷基、4-7元杂环基或5-6元杂芳基，所述C 1-6烷基、C 3-6环烷基、4-7元杂环基或5-6元杂芳基任选地被R 7a取代。 In some embodiments, R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, the C 1-6 alkane group, C 3-6 cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 7a .
在一些实施方案中，R 7选自H、C 1-6烷基或4-7元杂环基，所述C 1-6烷基或4-7元杂环基任选地被R 7a取代。 In some embodiments, R 7 is selected from H, C 1-6 alkyl or 4-7 membered heterocyclyl optionally substituted with R 7a .
在一些实施方案中，R 7选自H、C 1-3烷基或四氢吡啶基，所述C 1-3烷基或四氢吡啶基任选地被R 7a取代。 In some embodiments, R 7 is selected from H, C 1-3 alkyl or tetrahydropyridyl optionally substituted with R 7a .
在一些实施方案中，R 7选自H或C 1-3烷基。 In some embodiments, R 7 is selected from H or C 1-3 alkyl.
在一些实施方案中，R 7选自H或CH 3。 In some embodiments, R7 is selected from H or CH3 .
在一些实施方案中，R 7选自H。 In some embodiments, R7 is selected from H.
在一些实施方案中，R 7a选自C 1-6烷基。 In some embodiments, R 7a is selected from C 1-6 alkyl.
在一些实施方案中，R 7a选自CH 3。 In some embodiments, R 7a is selected from CH 3 .
在一些实施方案中，n选自0、1或2。In some embodiments, n is selected from 0, 1 or 2.
在一些实施方案中，环A选自C 6-10芳基、9-10元杂环基或9-10元杂芳基。 In some embodiments, Ring A is selected from C6-10 aryl, 9-10 membered heterocyclyl, or 9-10 membered heteroaryl.
在一些实施方案中，环A选自C 6-10芳基或9-10元杂环基。 In some embodiments, Ring A is selected from C 6-10 aryl or 9-10 membered heterocyclyl.
在一些实施方案中，环A选自
Figure PCTCN2022078929-appb-000015
Figure PCTCN2022078929-appb-000016
In some embodiments, Ring A is selected from
Figure PCTCN2022078929-appb-000015
Figure PCTCN2022078929-appb-000016
在一些实施方案中，环A选自
Figure PCTCN2022078929-appb-000017
In some embodiments, Ring A is selected from
Figure PCTCN2022078929-appb-000017
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(I-1)所示化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000018
Figure PCTCN2022078929-appb-000018
其中，
Figure PCTCN2022078929-appb-000019
选自N-CH＝C-C＝CH或C＝CH-N-C＝CH；环A、R 1、R 2、R 3、R 4、R 5、R 6、n如上文的定义。 in,
Figure PCTCN2022078929-appb-000019
Selected from N-CH=CC=CH or C=CH-NC=CH; Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n are as defined above.
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(IIa)所示化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIa) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000020
Figure PCTCN2022078929-appb-000020
其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、R 7、n如上文的定义。 wherein Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined above.
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(II)所示化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000021
Figure PCTCN2022078929-appb-000021
其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、n如上文的定义。 wherein Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n are as defined above.
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(III)所示化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000022
Figure PCTCN2022078929-appb-000022
其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、n如上文的定义。 wherein Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n are as defined above.
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(IV)所示化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000023
Figure PCTCN2022078929-appb-000023
其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、R 7、n如上文的定义。 wherein Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined above.
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022078929-appb-000024
Figure PCTCN2022078929-appb-000024
Figure PCTCN2022078929-appb-000025
Figure PCTCN2022078929-appb-000025
Figure PCTCN2022078929-appb-000026
Figure PCTCN2022078929-appb-000026
进一步，本发明还提供了一种药物组合物，所述药物组合物包含式(I)所示化合物或其药学上可接受的盐，以及药学上可接受的辅料。Further, the present invention also provides a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
进一步，本发明涉及的式(I)所示化合物或其药学上可接受的盐，或其药物组合物在制备预防或者治疗与SOS1相关疾病的药物中的用途。Further, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating diseases related to SOS1.
进一步，本发明涉及的式(I)化合物所示或其药学上可接受的盐，或其药物组合物在预防或者治疗与SOS1相关疾病中的用途。Further, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of diseases related to SOS1.
进一步，本发明涉及预防或者治疗SOS1相关疾病的式(I)化合物或其药学上可接受的盐，或其药物组合物。Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating SOS1-related diseases.
本发明还涉及治疗SOS1相关疾病的方法，该方法包括给以患者治疗上有效剂量的本发明所述的式(I)化合物或其药学上可接受的盐，或其药物组合物。The present invention also relates to a method for treating SOS1-related diseases, the method comprising administering to a patient a therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
进一步，所述SOS1相关疾病选自癌症。Further, the SOS1-related disease is selected from cancer.
另一方面，本发明提供式(I)化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗癌症药物中的用途。In another aspect, the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating cancer.
另一方面，本发明提供式(I)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗癌症中的用途。In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer.
另一方面，本发明提供预防或者治疗癌症的式(I)化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating cancer.
另一方面，本发明提供预防或治疗癌症的方法，包括对给以患者治疗上给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present invention provides a method of preventing or treating cancer comprising therapeutically administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
术语定义和说明Definition and Explanation of Terms
除非另有说明，本发明说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本发明说明书记载的范围内。Unless otherwise stated, definitions of groups and terms set forth in the present specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in the tables, definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present invention.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。The compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。 除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮，如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
本文中
Figure PCTCN2022078929-appb-000027
表示连接位点。 in this article
Figure PCTCN2022078929-appb-000027
Indicates the attachment site.
术语“C 1-6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等。术语“C 1-3烷基”应理解为表示具有1、2、3个碳原子的直链或支链饱和一价烃基。 The term "C 1-6 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl and the like. The term "C 1-3 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3 carbon atoms.
术语“卤素”指氟、氯、溴或碘，优选为氟、氯或溴。The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
术语“C 3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～10个碳原子。环烷基的例子如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。根据本发明，所述双环烃环包括桥环、螺环或并环结构。术语“C 3- 8环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～8个原子。术语“C 3-6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个原子。 The term "C 3-10 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin ring. According to the present invention, the bicyclic hydrocarbon ring includes a bridged ring, a spirocyclic ring or a paracyclic ring structure. The term "C3-8cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms. The term "C 3-6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms.
术语“环烯基”是指不完全饱和的且以单环、并环、桥环或螺环等形式存在的非芳族碳环。除非另有指示，该碳环通常为4至10元环。例如，术语“C 4-C 10环烯基”的具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。 The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, paracyclic, bridged or spirocyclic ring or the like. Unless otherwise indicated, the carbocycle is typically a 4- to 10-membered ring. For example, specific examples of the term "C 4 -C 10 cycloalkenyl" include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl Alkenyl etc.
术语“C 6-10芳基”应理解为具有6、7、8、9、10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。 The term "C 6-10 aryl" is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of carbon atoms ("C 6 aryl"), such as phenyl; or a ring of 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring of 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.
术语“3-10元杂环基”应理解为具有3-10个环原子的饱和的或部分不饱和(整体上不是具有芳香性的杂芳族)的一价单环或双环。所述双环包括桥环、螺环、稠环。所述杂环基中的“杂”包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2。特别地，所述杂环基可以是单环的，包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、2,5-二氢-1H-吡咯基、4,5-二氢噁唑基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、1,1-二氧硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基、4H-[1,3,4]噻二嗪基、4H-[1,4]噻嗪基；或7元环，如二氮杂环庚烷基。所述杂环基可以是双环的，包括但不限于：5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环、
Figure PCTCN2022078929-appb-000028
Figure PCTCN2022078929-appb-000029
或者6,6元双环，如二氢异喹啉基。术语“3-8元杂环基”应理解为具有3-8个环原子的饱和的或部分不饱和的一价单环或双环。术语“3-6元杂环基”应理解为具有3-6个环原子的饱和的或部分不饱和的一价单环或双环。本申请中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。 The term "3-10 membered heterocyclyl" is to be understood as a saturated or partially unsaturated (not heteroaromatic as a whole) monovalent monocyclic or bicyclic ring having 3 to 10 ring atoms. The bicyclic rings include bridged rings, spiro rings, and fused rings. "Hetero" in the heterocyclyl group includes, but is not limited to, independently selected from N, O, S, C(=O), C(=S), S(=O), S(O) 2 . In particular, the heterocyclyl group may be monocyclic, including but not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxane pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydrooxazolyl; or a 6-membered ring such as tetra Hydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl, 4H-[1,3,4]thiadiazinyl, 4H-[1,4]thiazinyl; or a 7-membered ring such as diazepanyl. The heterocyclyl group may be bicyclic, including but not limited to: a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as hexahydro pyrrolo[1,2-a]pyrazin-2(1H)-yl ring,
Figure PCTCN2022078929-appb-000028
Figure PCTCN2022078929-appb-000029
Or 6,6 membered bicyclic, such as dihydroisoquinolinyl. The term "3-8 membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 8 ring atoms. The term "3-6 membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 6 ring atoms. Although some bicyclic heterocyclic groups in this application partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups are still non-aromatic in their entirety.
术语“5-10元杂芳基”应理解为包括这样的具有芳香性的一价单环、双环或三环芳族环系，特别是5或6或9或10个环原子。所述杂芳基中的“杂”包括但不限于独立地选自N、O、S。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-10 membered heteroaryl" is understood to include such monovalent mono-, bi- or tricyclic aromatic ring systems having aromaticity, in particular 5 or 6 or 9 or 10 ring atoms. "Hetero" in the heteroaryl group includes, but is not limited to, independently selected from N, O, S. In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naphthyridinyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)抑制疾病或疾病状态，即遏制其发展；(i) inhibiting the disease or disease state, i.e. arresting its development;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of the disease or disease state, even if the disease or disease state resolves.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本发明公开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the invention to be used for the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，淀粉类，纤维素及其衍生物等在药物制剂中常用到的辅料。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的 生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The words "comprise", "comprise" or "comprise" and their English variants such as comprises or comprising are to be understood in an open, non-exclusive sense, ie, "including but not limited to".
本发明还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本发明化合物。可结合到本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The invention also includes isotopically-labeled compounds of the invention which are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
某些同位素标记的本发明化合物(例如用 3H及 14C标记)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本发明化合物。 Certain isotopically-labeled compounds of the invention (eg, labeled with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability. Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the invention can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本发明化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze drying methods, and the like.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants or flavoring agents.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.01 mg/kg to 200 mg/kg body weight, in single or divided doses.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents suitable for the chemical changes of the present invention and their required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on the basis of the existing embodiments.
具体实施方式Detailed ways
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 - 6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10 −6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); “IC 50 ” refers to the half inhibitory concentration, which refers to the half of the maximum inhibitory effect. concentration.
缩略词：Abbreviations:
TEA：三乙胺；TsCl：对甲苯磺酰氯；CH 3CN或ACN：乙腈；Xantphos：4,5-双二苯基膦 -9,9-二甲基氧杂蒽；palladium(p-cinnamyl)chloride dimer:氯化钯(π-肉桂基)二聚物；dioxane：二氧六环；BocNH 2：氨基甲酸叔丁酯；DMSO：二甲基亚砜；DIEA或DIPEA：N,N-二异丙基乙胺；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；THF：四氢呋喃；DMF：N,N-二甲基甲酰胺；DMF-DMA：N,N-二甲基甲酰胺二甲基缩醛；DBDMH：1,3-二溴-5,5-二甲基海因；KHMDS：双(三甲基硅烷基)氨基钾；Pd(OAc) 2：醋酸钯；BINAP：1,1'-联萘-2,2'-双二苯膦；toluene：甲苯；Pd(PPh 3) 2Cl 2：双(三苯基膦)二氯化钯；pyridine：吡啶；SmI 2:二碘化钐；Brettphos Pd G3:[(2-二-环己基膦基-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯基)-2-(2'-氨基-1,1'-联苯基)]甲磺酸钯(II)；NaOBu-t：叔丁醇钠；Brettphos：2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯；DCM:二氯甲烷；TFA：三氟乙酸；Ac 2O：乙酸酐；DBU：1,8-二氮杂二环[5.4.0]十一碳-7-烯；PyAOP：(7-氮杂苯并***-1-氧)三吡咯磷六氟磷酸盐；18-冠-6或18-crown-6：1,4,7,10,13,16-六氧杂环十八烷；AcOH：乙酸；X-phos：2-二环己基膦-2',4',6'-三异丙基联苯；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(PPh 3)Cl 2：双三苯基膦二氯化钯；BINAP:1,1'-联萘-2,2'-双二苯膦；NBS：N-溴代丁二酰亚胺；NCS：N-氯代丁二酰亚胺。 TEA: triethylamine; TsCl: p-toluenesulfonyl chloride; CH3CN or ACN: acetonitrile; Xantphos: 4,5-bisdiphenylphosphino-9,9-dimethylxanthene; palladium (p-cinnamyl) chloride dimer: palladium chloride (π-cinnamyl) dimer; dioxane: dioxane; BocNH 2 : tert-butyl carbamate; DMSO: dimethyl sulfoxide; DIEA or DIPEA: N,N-diiso Propylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; THF: tetrahydrofuran; DMF: N,N- Dimethylformamide; DMF-DMA: N,N-dimethylformamide dimethyl acetal; DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; KHMDS: bis(trimethyl) silyl) potassium amide; Pd(OAc) 2 : palladium acetate; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; toluene: toluene; Pd(PPh 3 ) 2 Cl 2 : bismuth (triphenylphosphine) palladium dichloride; pyridine: pyridine; SmI 2 : samarium diiodide; Brettphos Pd G3: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2'- 4'-6'-Triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; NaOBu-t : sodium tert-butoxide; Brettphos: 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl; DCM: Dichloromethane; TFA: trifluoroacetic acid; Ac 2 O: acetic anhydride; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; PyAOP: (7-azabenzone Triazol-1-oxo)tripyrrophos hexafluorophosphate; 18-crown-6 or 18-crown-6: 1,4,7,10,13,16-hexaoxacyclooctadecane; AcOH:acetic acid ; X-phos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd(PPh 3 )Cl 2 : bistriphenylphosphine palladium dichloride; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; NBS: N-bromosuccinimide; NCS: N- Chlorosuccinimide.
实施例1：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮Example 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1, 6-Naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000030
Figure PCTCN2022078929-appb-000030
步骤1：1-(1-甲基环丙基)-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-羧酸甲酯的合成Step 1: Synthesis of methyl 1-(1-methylcyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate
Figure PCTCN2022078929-appb-000031
Figure PCTCN2022078929-appb-000031
参考专利CN111372932A中P127页中间体E-4a的制备方法，不同的是将E-4a制备过程中的C-1a替换为1-甲基环丙胺盐酸盐，制得4-羟基-1-(1-甲基环丙基)-6-氧代吡啶-3-羧酸甲酯。With reference to the preparation method of intermediate E-4a on page P127 in patent CN111372932A, the difference is that C-1a in the preparation process of E-4a is replaced with 1-methylcyclopropylamine hydrochloride to obtain 4-hydroxy-1-( 1-Methylcyclopropyl)-6-oxopyridine-3-carboxylic acid methyl ester.
将4-羟基-1-(1-甲基环丙基)-6-氧代吡啶-3-羧酸甲酯(1.88g)溶于乙腈(20mL)中，加入三乙胺(1.28g)，随后加入对甲苯磺酰氯(1.61g)，室温下搅拌反应2小时后反应完毕。将反应液倒入水中，用乙酸乙酯萃取，合并有机层，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化得标题化合物。Methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxopyridine-3-carboxylate (1.88g) was dissolved in acetonitrile (20mL), triethylamine (1.28g) was added, Then, p-toluenesulfonyl chloride (1.61 g) was added, and the reaction was completed after stirring at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
步骤2：4-((叔丁氧羰基)氨基)-1-(1-甲基环丙基)-6-氧代-1,6-二氢吡啶-3-羧酸甲酯的合成Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate
Figure PCTCN2022078929-appb-000032
Figure PCTCN2022078929-appb-000032
将1-(1-甲基环丙基)-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-羧酸甲酯(500mg)，氨基甲酸叔丁酯(310mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(76.7mg)，氯化钯(π-肉桂基)二聚物(34.3 mg)和磷酸钾(562mg)加入到反应瓶中，然后加入二氧六环(6mL)，氩气保护下加热至100℃搅拌10小时后反应完毕。将反应液冷却，过滤，滤液减压浓缩后经柱层析纯化得标题化合物。Methyl 1-(1-methylcyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate (500 mg), tert-butyl carbamate ester (310 mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (76.7 mg), palladium chloride (π-cinnamyl) dimer (34.3 mg) and potassium phosphate ( 562 mg) was added to the reaction flask, then dioxane (6 mL) was added, heated to 100° C. under argon protection and stirred for 10 hours after the reaction was completed. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
步骤3：(5-(甲氧基(甲基)氨甲酰基)-1-(1-甲基环丙基)-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯的合成Step 3: (5-(Methoxy(methyl)carbamoyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamic acid Synthesis of tert-butyl ester
Figure PCTCN2022078929-appb-000033
Figure PCTCN2022078929-appb-000033
将4-((叔丁氧羰基)氨基)-1-(1-甲基环丙基)-6-氧代-1,6-二氢吡啶-3-羧酸甲酯(217mg)加入到反应瓶中，用混合溶剂二甲基亚砜(4.00mL)和乙腈(2.00mL)溶解，加入氢氧化钠溶液(539mg,20％w/w)，室温反应1小时，加入N,N-二异丙基乙胺(174.0mg)，甲氧基甲基胺盐酸盐(69.0mg)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.27g)，反应液在室温下反应2小时。将反应倒入水中，乙酸乙酯萃取，合并有机层，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化得标题化合物。Methyl 4-((tert-butoxycarbonyl)amino)-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (217 mg) was added to the reaction In the bottle, dissolve with mixed solvent dimethyl sulfoxide (4.00mL) and acetonitrile (2.00mL), add sodium hydroxide solution (539mg, 20%w/w), react at room temperature for 1 hour, add N,N-diiso Propylethylamine (174.0 mg), methoxymethylamine hydrochloride (69.0 mg) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (1.27 g), and the reaction solution was reacted at room temperature for 2 hours. The reaction was poured into water, extracted with ethyl acetate, the organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
步骤4：(5-乙酰基-1-(1-甲基环丙基)-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯的合成Step 4: Synthesis of tert-butyl (5-acetyl-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate
Figure PCTCN2022078929-appb-000034
Figure PCTCN2022078929-appb-000034
将(5-(甲氧基(甲基)氨甲酰基)-1-(1-甲基环丙基)-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯(230mg)加入到反应瓶中，用无水四氢呋喃溶解(6mL)，氩气保护下冰浴中冷却至0℃，缓慢加入甲基溴化镁(0.85mL)，缓慢升至室温反应6小时。用饱和氯化铵水溶液将反应淬灭，然后用乙酸乙酯萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化得标题化合物。(5-(Methoxy(methyl)carbamoyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamic acid tert-butyl The ester (230 mg) was added to the reaction flask, dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0°C in an ice bath under argon protection, slowly added with methylmagnesium bromide (0.85 mL), slowly raised to room temperature and reacted for 6 hours . The reaction was quenched with saturated aqueous ammonium chloride solution, then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
步骤5：6-(1-甲基环丙基)-1,6-萘啶-4,7(1H，6H)-二酮的合成Step 5: Synthesis of 6-(1-Methylcyclopropyl)-1,6-naphthyridine-4,7(1H,6H)-dione
Figure PCTCN2022078929-appb-000035
Figure PCTCN2022078929-appb-000035
将(5-乙酰基-1-(1-甲基环丙基)-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯(87mg)加入到反应瓶中，加入N,N-二甲基甲酰胺二甲基缩醛(1.5mL)，然后升温至110℃反应1小时。将反应液浓缩，然后用四氢呋喃溶解(4mL)，加入稀盐酸(1.38mL,2M)，所得反应液在40℃条件下反应过夜。将反应液冷却后用浓氨水调节pH至8-9，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化得标题化合物。tert-butyl (5-acetyl-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate (87 mg) was added to the reaction flask, N,N-dimethylformamide dimethyl acetal (1.5 mL) was added, and the temperature was raised to 110° C. to react for 1 hour. The reaction solution was concentrated, then dissolved in tetrahydrofuran (4 mL), diluted hydrochloric acid (1.38 mL, 2M) was added, and the resulting reaction solution was reacted at 40° C. overnight. After cooling the reaction solution, the pH was adjusted to 8-9 with concentrated ammonia water, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.
步骤6：4-氯-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Step 6: Synthesis of 4-chloro-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000036
Figure PCTCN2022078929-appb-000036
将6-(1-甲基环丙基)-1,6-萘啶-4,7(1H，6H)-二酮(46.7mg)用乙腈(2.1mL)溶解，加入三氯氧磷(66.2mg)和N,N-二异丙基乙胺(58.6mg)，然后升温至70℃反应1小时。将反应液冷却后倒入冰中，然后用饱和碳酸氢钠调节pH至8，然后用乙酸乙酯萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物。6-(1-Methylcyclopropyl)-1,6-naphthyridine-4,7(1H,6H)-dione (46.7 mg) was dissolved in acetonitrile (2.1 mL), and phosphorus oxychloride (66.2 mL) was added. mg) and N,N-diisopropylethylamine (58.6 mg), then the temperature was raised to 70° C. to react for 1 hour. The reaction solution was cooled and poured into ice, then adjusted to pH 8 with saturated sodium bicarbonate, then extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound.
步骤7：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Step 7: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6 -Synthesis of Naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000037
Figure PCTCN2022078929-appb-000037
将4-氯-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮(50mg)，(1R)-1-[3-(二氟甲基)-2-氟苯基]乙胺盐酸盐(48.1mg)用无水二甲基亚砜(2mL)溶解，加入N,N-二异丙基乙胺(82.6mg)，所得反应液在惰性气体保护下升温至80℃反应过夜。将反应液冷却，过滤，滤液浓缩后柱层析纯化得到标题化合物。4-Chloro-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one (50 mg), (1R)-1-[3-(difluoromethyl)- 2-Fluorophenyl]ethylamine hydrochloride (48.1 mg) was dissolved in anhydrous dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (82.6 mg) was added, and the resulting reaction solution was heated under an inert atmosphere. The temperature was raised to 80°C under protection and the reaction was carried out overnight. The reaction solution was cooled, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.
DMSO-d6 δ H 9.24(s,1H),8.02(d,J＝5.3Hz,1H),7.85(d,J＝6.5Hz,1H),7.61(t,J＝7.3Hz,1H),7.54(t,J＝6.8Hz,1H),7.39-7.12(m,2H),6.24(s,1H),5.56(d,J＝5.4Hz,1H),5.07-4.97(m,1H),1.63(d,J＝6.8Hz,3H),1.56(s,3H),1.24-1.06(m,4H). DMSO-d6 δ H 9.24(s, 1H), 8.02(d, J=5.3Hz, 1H), 7.85(d, J=6.5Hz, 1H), 7.61(t, J=7.3Hz, 1H), 7.54( t, J＝6.8Hz, 1H), 7.39-7.12(m, 2H), 6.24(s, 1H), 5.56(d, J＝5.4Hz, 1H), 5.07-4.97(m, 1H), 1.63(d , J=6.8Hz, 3H), 1.56(s, 3H), 1.24-1.06(m, 4H).
LC/MS(m/z,MH +):388.1 LC/MS (m/z, MH + ): 388.1
实施例2：(R)-2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮Example 2: (R)-2-Chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl )-1,6-Naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000038
Figure PCTCN2022078929-appb-000038
步骤1：2,4-二羟基-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Step 1: Synthesis of 2,4-dihydroxy-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000039
Figure PCTCN2022078929-appb-000039
参考专利CN111372932A中P127页中间体E-6a的制备方法，不同的是将E-4a制备过程中的C-1a替换为1-甲基环丙胺，同法制得4-乙酰胺-1-(1-甲基环丙基)-6-氧代-1,6-二氢吡啶-3-羧酸甲酯。Referring to the preparation method of intermediate E-6a on page P127 in patent CN111372932A, the difference is that C-1a in the preparation process of E-4a is replaced with 1-methylcyclopropylamine, and 4-acetamide-1-(1 -methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate methyl ester.
将4-乙酰胺-1-(1-甲基环丙基)-6-氧代-1,6-二氢吡啶-3-羧酸甲酯(5.00g)溶于无水四氢呋喃 (50mL)中，乙醇-液氮控温-80～-78℃滴加双(三甲基硅烷基)氨基钾(1M in THF)(56.8mmol,56.8mL)，滴毕自然回温室温反应过夜。向体系中加入50mL水淬灭反应，加入50mL乙酸乙酯萃取，分液后水相加入4N HCl调节pH≈4，加入50mL二氯甲烷，有大量固体析出，抽滤，滤饼干燥得标题化合物。Methyl 4-acetamide-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (5.00 g) was dissolved in dry tetrahydrofuran (50 mL) , ethanol-liquid nitrogen temperature control -80～-78 ℃, add bis(trimethylsilyl) potassium amide (1M in THF) (56.8mmol, 56.8mL) dropwise, and the dropwise reaction is naturally returned to room temperature overnight. 50 mL of water was added to the system to quench the reaction, 50 mL of ethyl acetate was added for extraction, after separation, 4N HCl was added to the aqueous phase to adjust pH ≈ 4, 50 mL of dichloromethane was added, a large amount of solid was precipitated, suction filtration, and the filter cake was dried to obtain the title compound .
步骤2：2,4-二氯-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Step 2: Synthesis of 2,4-dichloro-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000040
Figure PCTCN2022078929-appb-000040
将2,4-二羟基-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮(500mg)置于乙腈(5mL)中，氩气置换，加入三氯氧磷(1.65g)，白色浊液，升温80℃，搅拌反应2小时反应完毕。除去过量的三氯氧磷，乙腈稀释，倒入冰中，加入固体碳酸氢钠调节pH≈8，乙酸乙酯萃取，有机相干燥后得标题化合物。2,4-Dihydroxy-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one (500 mg) was placed in acetonitrile (5 mL), replaced with argon, and tris Phosphorus oxychloride (1.65 g), white cloudy liquid, was heated to 80° C. and stirred for 2 hours to complete the reaction. Remove excess phosphorus oxychloride, dilute with acetonitrile, pour into ice, add solid sodium bicarbonate to adjust pH ≈ 8, extract with ethyl acetate, and dry the organic phase to obtain the title compound.
步骤3：4-氯-6-(1-甲基环丙基)-1,6-萘啶-2,7(1H，6H)-二酮的合成Step 3: Synthesis of 4-chloro-6-(1-methylcyclopropyl)-1,6-naphthyridine-2,7(1H,6H)-dione
Figure PCTCN2022078929-appb-000041
Figure PCTCN2022078929-appb-000041
将2,4-二氯-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮(300mg)用1,4-二氧六环(7mL)溶解，加入稀盐酸(4M)，所得反应液在室温下搅拌反应1小时。将反应液倒入水中，用饱和碳酸氢钠溶液调节pH至8，然后用乙酸乙酯萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，除去大部分溶剂，有大量固体析出，过滤，滤饼干燥后得标题化合物。2,4-Dichloro-6-(1-methylcyclopropyl)-1,6-naphthyridin-7(6H)-one (300 mg) was dissolved in 1,4-dioxane (7 mL), Dilute hydrochloric acid (4M) was added, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water, adjusted to pH 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent. , a large amount of solid was precipitated, filtered, and the filter cake was dried to obtain the title compound.
步骤4：(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-2,7(1H，6H)-二酮的合成Step 4: (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1, Synthesis of 6-naphthyridine-2,7(1H,6H)-dione
Figure PCTCN2022078929-appb-000042
Figure PCTCN2022078929-appb-000042
将4-氯-6-(1-甲基环丙基)-1,6-萘啶-2,7(1H，6H)-二酮(150mg)，(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺(124mg)，醋酸钯(26.9mg)，1,1'-联萘-2,2'-双二苯膦(74.5mg)和碳酸铯(585mg)加入到反应瓶中，加入甲苯(6mL)，然后装上氩气球，置换气体三次，气体保护下放入110℃油浴中反应过夜。将反应液减压浓缩，经正相柱层析纯化(二氯甲烷/甲醇＝10/1)后再经反相C 18柱纯化(乙腈/水(含1‰碳酸氢铵)：5％～80％)得标题化合物。 4-Chloro-6-(1-methylcyclopropyl)-1,6-naphthyridine-2,7(1H,6H)-dione (150mg), (1R)-1-[3-(dione) Fluoromethyl)-2-fluoro-phenyl]ethanamine (124mg), palladium acetate (26.9mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (74.5mg) and cesium carbonate ( 585 mg) was added to the reaction flask, toluene (6 mL) was added, then an argon balloon was installed, the gas was replaced three times, and the reaction was carried out in an oil bath at 110° C. overnight under gas protection. The reaction solution was concentrated under reduced pressure, purified by normal phase column chromatography (dichloromethane/methanol=10/1), and then purified by reverse phase C 18 column (acetonitrile/water (containing 1‰ ammonium bicarbonate): 5%～ 80%) to obtain the title compound.
步骤5：(R)-2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Step 5: (R)-2-Chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl) Synthesis of -1,6-Naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000043
Figure PCTCN2022078929-appb-000043
将(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-2,7(1H，6H)-二酮(100mg)加入到反应瓶中，加入三氯氧磷(4.8mL)，然后放入80℃油浴中反应1小时。将反应液减压浓缩，除去三氯氧磷，然后用乙腈稀释，倒入碎冰中，用饱和碳酸氢钠溶液调节pH至7-8，然后用乙酸乙酯萃取，有机相合并，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经反相C 18柱纯化(乙腈/水(含1‰碳酸氢铵)：5％～80％)，冻干得标题化合物。 (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6- Naphthyridine-2,7(1H,6H)-dione (100mg) was added to the reaction flask, phosphorous oxychloride (4.8mL) was added, and then placed in an oil bath at 80°C for 1 hour. The reaction solution was depressurized Concentrate to remove phosphorus oxychloride, then dilute with acetonitrile, pour into crushed ice, adjust pH to 7-8 with saturated sodium bicarbonate solution, then extract with ethyl acetate, combine the organic phases, wash with saturated brine, anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate under reduced pressure, purify by reverse-phase C 18 column (acetonitrile/water (containing 1‰ ammonium bicarbonate): 5%-80%), and lyophilize to obtain the title compound.
1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.14(d,J＝5.8Hz,1H),7.65(t,J＝7.2Hz,1H),7.57(t,J＝7.0Hz,1H),7.40-7.13(m,2H),6.18(s,1H),5.59(s,1H),5.09-5.06(m,1H),1.63(d,J＝6.8Hz,3H),1.54(s,3H),1.23-1.06(m,4H). 1 H NMR (400MHz, DMSO-d6) δ 9.25 (s, 1H), 8.14 (d, J=5.8Hz, 1H), 7.65 (t, J=7.2Hz, 1H), 7.57 (t, J=7.0 Hz,1H),7.40-7.13(m,2H),6.18(s,1H),5.59(s,1H),5.09-5.06(m,1H),1.63(d,J＝6.8Hz,3H),1.54 (s,3H),1.23-1.06(m,4H).
LC/MS(m/z,MH +):422.2 LC/MS (m/z, MH + ): 422.2
实施例3：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮的合成Example 3: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropane) Synthesis of )-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000044
Figure PCTCN2022078929-appb-000044
将(R)-2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(1-甲基环丙基)-1,6-萘啶-7(6H)-酮(67.0mg)加入到反应瓶中，依次加入双(三苯基膦)二氯化钯(22.3mg)，无水N,N-二甲基甲酰胺和四甲基锡(114mg)，氩气保护下升温至130℃反应1.5小时。反应液冷却后过滤，经制备HPLC(流动相：乙腈/水)纯化得标题化合物。(R)-2-Chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1 ,6-Naphthyridin-7(6H)-one (67.0mg) was added to the reaction flask, followed by bis(triphenylphosphine) palladium dichloride (22.3mg), anhydrous N,N-dimethylmethane Amide and tetramethyltin (114 mg) were heated to 130°C under argon protection and reacted for 1.5 hours. The reaction solution was cooled, filtered, and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.67(d,J＝6.8Hz,1H),7.62(t,J＝7.3Hz,1H),7.55(t,J＝7.0Hz,1H),7.40-7.12(m,2H),6.15(s,1H),5.54(s,1H),5.04-4.99(m,1H),2.14(s,3H),1.62(d,J＝6.8Hz,3H),1.54(s,3H),1.18-1.05(m,4H). 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.67(d,J=6.8Hz,1H),7.62(t,J=7.3Hz,1H),7.55(t,J=7.0 Hz, 1H), 7.40-7.12(m, 2H), 6.15(s, 1H), 5.54(s, 1H), 5.04-4.99(m, 1H), 2.14(s, 3H), 1.62(d, J= 6.8Hz, 3H), 1.54(s, 3H), 1.18-1.05(m, 4H).
LC/MS(m/z,MH +):402.2 LC/MS (m/z, MH + ): 402.2
实施例4：((R)-3-(1-乙酰基-4-甲氧基哌啶-4-基)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮Example 4: ((R)-3-(1-Acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorobenzene (yl)ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000045
Figure PCTCN2022078929-appb-000045
步骤1：4-氯-3-(1,3-二氧戊环-2-基)-2-氟吡啶的合成Step 1: Synthesis of 4-chloro-3-(1,3-dioxolan-2-yl)-2-fluoropyridine
Figure PCTCN2022078929-appb-000046
Figure PCTCN2022078929-appb-000046
将4-氯-2-氟-吡啶-3-甲醛(1.00g)，乙二醇(584mg)加入到反应中，加入甲苯(25mL)和对甲苯磺酸一水合物(59.6mg)，所得反应液装上分水器，放入140℃油浴中回流反应4小时。将反应液冷却，减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。4-Chloro-2-fluoro-pyridine-3-carbaldehyde (1.00 g), ethylene glycol (584 mg) were added to the reaction, toluene (25 mL) and p-toluenesulfonic acid monohydrate (59.6 mg) were added, and the resulting reaction The liquid was installed on a water separator, and put into an oil bath at 140°C for reflux reaction for 4 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤2：4-氯-3-(1,3-二氧戊环-2-基)-N-甲基吡啶-2-胺的合成Step 2: Synthesis of 4-chloro-3-(1,3-dioxolan-2-yl)-N-methylpyridin-2-amine
Figure PCTCN2022078929-appb-000047
Figure PCTCN2022078929-appb-000047
将4-氯-3-(1,3-二氧戊环-2-基)-2-氟吡啶(500mg)，甲胺盐酸盐(199mg)加入到反应瓶中，加入无水二甲基亚砜(5mL)，然后加入N,N-二异丙基乙胺(635mg)，拧紧瓶盖，将反应瓶放在70℃油浴中反应18小时。将反应液冷却后倒入水中，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。4-Chloro-3-(1,3-dioxolan-2-yl)-2-fluoropyridine (500mg), methylamine hydrochloride (199mg) were added to the reaction flask, and anhydrous dimethyl Sulfoxide (5 mL), then N,N-diisopropylethylamine (635 mg) was added, the cap was tightened, and the reaction flask was placed in an oil bath at 70° C. for 18 hours. The reaction solution was cooled, poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate) ester gradient) to give the title compound.
步骤3：4-氯-2-(甲胺基)烟醛的合成Step 3: Synthesis of 4-chloro-2-(methylamino)nicotinaldehyde
Figure PCTCN2022078929-appb-000048
Figure PCTCN2022078929-appb-000048
将4-氯-3-(1,3-二氧戊环-2-基)-N-甲基吡啶-2-胺(305mg)加入到反应瓶中，加入四氢呋喃(3.2mL)，然后加入稀盐酸(2M,1.4mL)，所得反应液在室温下搅拌反应3小时。将反应液倒入水中稀释，用乙酸乙酯萃取，有机相合并后饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物，不纯化直接用于下一步反应。4-Chloro-3-(1,3-dioxolan-2-yl)-N-methylpyridin-2-amine (305 mg) was added to the reaction flask, tetrahydrofuran (3.2 mL) was added, followed by dilute Hydrochloric acid (2M, 1.4 mL), the resulting reaction solution was stirred at room temperature for 3 hours. The reaction solution was poured into water to dilute, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound, which was used in the next reaction without purification.
步骤4：5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸甲酯的合成Step 4: Synthesis of methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate
Figure PCTCN2022078929-appb-000049
Figure PCTCN2022078929-appb-000049
将4-氯-2-(甲胺基)烟醛(800mg)和丙二酸二甲酯(682mg)加入到三口反应瓶中，装上氩气球，置换气体三次，氩气保护下加入无水四氢呋喃(13mL)，然后将用冰浴冷却至0℃，依次缓慢加入四氯化钛(1M in DCM,9.38mL)和吡啶(742mg)。反应液升温至40℃反应16小时。将反应液倒入冰水中，用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得到标题化合物。4-Chloro-2-(methylamino)nicotinic aldehyde (800mg) and dimethyl malonate (682mg) were added to a three-neck reaction flask, fitted with an argon balloon, the gas was replaced three times, and anhydrous was added under argon protection. Tetrahydrofuran (13 mL) was then cooled to 0 °C with an ice bath, and titanium tetrachloride (1 M in DCM, 9.38 mL) and pyridine (742 mg) were slowly added sequentially. The reaction solution was heated to 40°C and reacted for 16 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound .
步骤5：5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸的合成Step 5: Synthesis of 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid
Figure PCTCN2022078929-appb-000050
Figure PCTCN2022078929-appb-000050
将5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸甲酯(398mg)加入到反应瓶中，加入甲醇(8mL)溶解，然后加入氢氧化钠水溶液(2M,7.88mL)，所得反应液在室温下搅拌反应1小时。用2M稀盐酸调节体系pH至2-3，有大量白色固体析出，抽滤，滤饼用少量水洗涤，收集滤饼干燥得标题化合物。Methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (398 mg) was added to the reaction flask, and methanol (8 mL) was added to dissolve , and then an aqueous sodium hydroxide solution (2M, 7.88 mL) was added, and the resulting reaction solution was stirred at room temperature for 1 hour. The pH of the system was adjusted to 2-3 with 2M dilute hydrochloric acid, a large amount of white solid was precipitated, suction filtered, the filter cake was washed with a small amount of water, the filter cake was collected and dried to obtain the title compound.
步骤6：3-溴-5-氯-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 6: Synthesis of 3-bromo-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000051
Figure PCTCN2022078929-appb-000051
将5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸(302mg)加入到史莱克管中，加入无水吡啶(4mL)，然后塞上瓶塞，装上氩气球置换气体三次，将反应液用冰浴冷却至0℃，然后向其中缓慢加入溴素(809mg)，然后将反应管移至70℃油浴中反应1小时。将反应液冷却后倒入水中，用浓盐酸调节体系pH至1-2，然后用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid (302 mg) was added to a Shrek tube, followed by anhydrous pyridine (4 mL) , then stoppered the bottle, replaced the gas with an argon balloon three times, cooled the reaction solution to 0 °C with an ice bath, then slowly added bromine (809 mg) to it, and then moved the reaction tube to a 70 °C oil bath for reaction 1 Hour. The reaction solution was cooled and poured into water, and the pH of the system was adjusted to 1-2 with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (petroleum ether/ethyl acetate gradient) afforded the title compound.
步骤7：3-(1-乙酰基-4-羟基哌啶-4-基)-5-氯-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 7: Synthesis of 3-(1-Acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000052
Figure PCTCN2022078929-appb-000052
将3-溴-5-氯-1-甲基-1,8-萘啶-2(1H)-酮(294mg)加入到三口烧瓶中，加入N-乙酰基-4-哌啶酮(167mg)，然后装上氩气球，置换气体三次。气体保护下加入无水四氢呋喃(20mL)，然后将反应液冷却至-78℃，缓慢加入二碘化钐的四氢呋喃溶液(0.1M,32.3mL)，加完后保持-78℃反 应1小时，将反应液升至室温搅拌一段时间，待过量的二碘化钐颜色褪去，加甲醇将反应淬灭，然后将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。3-Bromo-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one (294mg) was added to a three-necked flask, and N-acetyl-4-piperidinone (167mg) was added , and then fitted with an argon balloon to replace the gas three times. Anhydrous tetrahydrofuran (20 mL) was added under gas protection, then the reaction solution was cooled to -78°C, and a solution of samarium diiodide in tetrahydrofuran (0.1M, 32.3mL) was slowly added. After the addition, the reaction was kept at -78°C for 1 hour. The reaction solution was raised to room temperature and stirred for a period of time. When the color of excess samarium diiodide faded, methanol was added to quench the reaction. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined and washed with saturated brine. Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤8：3-(1-乙酰基-4-甲氧基哌啶-4-基)-5-氯-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 8: Synthesis of 3-(1-Acetyl-4-methoxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000053
Figure PCTCN2022078929-appb-000053
将3-(1-乙酰基-4-羟基哌啶-4-基)-5-氯-1-甲基-1,8-萘啶-2(1H)-酮(55mg)加入到反应瓶中，加入无水四氢呋喃(0.9mL)，然后用冰浴冷却至0℃，加入氢化钠(26.2mg,含量60％)，冰浴下搅拌5分钟，然后加入碘甲烷(116mg)，升至室温反应3小时。加入少量水将反应淬灭，将反应液减压浓缩后经柱层析纯化(二氯甲烷/甲醇梯度洗脱)得到标题化合物。3-(1-Acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one (55 mg) was added to the reaction flask , anhydrous tetrahydrofuran (0.9 mL) was added, then cooled to 0°C with an ice bath, sodium hydride (26.2 mg, content 60%) was added, stirred for 5 minutes under an ice bath, then iodomethane (116 mg) was added, and the reaction was carried out at room temperature. 3 hours. A small amount of water was added to quench the reaction, and the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
步骤9：(R)-3-(1-乙酰基-4-甲氧基哌啶-4-基)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 9: (R)-3-(1-Acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000054
Figure PCTCN2022078929-appb-000054
将3-(1-乙酰基-4-甲氧基哌啶-4-基)-5-氯-1-甲基-1,8-萘啶-2(1H)-酮(30mg)，(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(17.8mg)，Brettphos Pd G3(7.77mg)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯(4.60mg,0.0086mmol)，叔丁醇钠(24.7mg)加入到反应瓶中，加入无水1,4-二氧六环(0.8mL)，装上氩气球，置换气体三次，气体保护下放入100℃油浴中反应4小时。将反应液冷却后减压浓缩经柱层析纯化(二氯甲烷/甲醇梯度洗脱),再经制备HPLC(流动相：乙腈/水)纯化，冻干得标题化合物。3-(1-Acetyl-4-methoxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one (30 mg), (1R )-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine (17.8 mg), Brettphos Pd G3 (7.77 mg), 2-(dicyclohexylphosphine)-3,6-di Methoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (4.60mg, 0.0086mmol), sodium tert-butoxide (24.7mg) was added to the reaction flask, and anhydrous 1,4-dioxane (0.8 mL) was installed with an argon balloon, the gas was replaced three times, and the reaction was placed in an oil bath at 100° C. for 4 hours under gas protection. The reaction solution was cooled, concentrated under reduced pressure, purified by column chromatography (dichloromethane/methanol gradient elution), purified by preparative HPLC (mobile phase: acetonitrile/water), and lyophilized to obtain the title compound.
DMSO-d6 δ H 8.34(d,J＝2.5Hz,1H),8.04(d,J＝5.8Hz,1H),7.72(d,J＝6.8Hz,1H),7.64-7.55(m,1H),7.53(t,J＝7.0Hz,1H),7.30(t,J＝7.7Hz,1H),7.25(t,J＝54.4Hz,1H),6.14(d,J＝5.5Hz,1H),5.13-5.00(m,1H),4.34-4.31(m,1H),3.73-3.70(m,1H),3.59(s,3H),3.42-3.30(m,1H),3.13(d,J＝4.3Hz,3H),2.90-2.78(m,1H),2.32-2.16(m,2H),2.10-2.00(m,5H),1.63(d,J＝6.7Hz,3H). DMSO-d6 δ H 8.34(d,J=2.5Hz,1H),8.04(d,J=5.8Hz,1H),7.72(d,J=6.8Hz,1H),7.64-7.55(m,1H), 7.53(t,J＝7.0Hz,1H),7.30(t,J＝7.7Hz,1H),7.25(t,J＝54.4Hz,1H),6.14(d,J＝5.5Hz,1H),5.13- 5.00(m, 1H), 4.34-4.31(m, 1H), 3.73-3.70(m, 1H), 3.59(s, 3H), 3.42-3.30(m, 1H), 3.13(d, J=4.3Hz, 3H), 2.90-2.78(m, 1H), 2.32-2.16(m, 2H), 2.10-2.00(m, 5H), 1.63(d, J=6.7Hz, 3H).
LC/MS(m/z,MH +):503.2 LC/MS (m/z, MH + ): 503.2
实施例5：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮Example 5: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000055
Figure PCTCN2022078929-appb-000055
步骤1：3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯的合成Step 1: 3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid tert. Synthesis of Butyl Ester
Figure PCTCN2022078929-appb-000056
Figure PCTCN2022078929-appb-000056
将3-溴-5-氯-1-甲基-1,8-萘啶-2(1H)-酮(400mg)，1-叔丁氧羰基-3-吡咯烷酮(298mg)加入到三口烧瓶中，装上氩气球，置换气体三次，气体保护下加入无水四氢呋喃(20mL)。将反应液冷却至-78℃，然后缓慢加入二碘化钐的四氢呋喃溶液(0.1M,43.9mL)，所得反应液在-78℃下反应1小时。将反应液移至室温搅拌一段时间，待二碘化钐颜色褪去，加入少量甲醇将反应淬灭，然后倒入水中，用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。3-Bromo-5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one (400mg), 1-tert-butoxycarbonyl-3-pyrrolidone (298mg) were added to the three-necked flask, An argon balloon was installed, the gas was replaced three times, and anhydrous tetrahydrofuran (20 mL) was added under the protection of gas. The reaction solution was cooled to -78°C, then a solution of samarium diiodide in tetrahydrofuran (0.1 M, 43.9 mL) was slowly added, and the resulting reaction solution was reacted at -78°C for 1 hour. The reaction solution was moved to room temperature and stirred for a period of time. When the color of samarium diiodide faded, a small amount of methanol was added to quench the reaction, then poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous sulfuric acid. Dry over sodium, filter, and concentrate the filtrate under reduced pressure and purify by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
步骤2：3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 2: 3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylate Synthesis of tert-butyl acid
Figure PCTCN2022078929-appb-000057
Figure PCTCN2022078929-appb-000057
将3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯(60mg)加入到反应瓶中，加入无水四氢呋喃(0.8mL)，然后用冰浴冷却至0℃，加入氢化钠(25.3mg,60％纯度)，在冰浴下搅拌5分钟，然后加入碘甲烷(112mg)，升至室温反应3小时。加少量水将反应淬灭，然后减压浓缩经柱层析纯化(二氯甲烷/甲醇梯度洗脱)得标题化合物。3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (60 mg) was added to the reaction flask, anhydrous tetrahydrofuran (0.8 mL) was added, then cooled to 0°C with an ice bath, sodium hydride (25.3 mg, 60% purity) was added, stirred for 5 minutes under an ice bath, and then iodine was added Methane (112 mg), warmed to room temperature and reacted for 3 hours. The reaction was quenched by adding a small amount of water, then concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol gradient) to give the title compound.
步骤3：3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 3: 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1, Synthesis of 2-dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2022078929-appb-000058
Figure PCTCN2022078929-appb-000058
将3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(43mg)，(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(22.7mg)，Brettphos Pd G3(9.90mg)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯(5.86mg)，叔丁醇钠(31.5mg)加入到反应瓶中，加入无水1,4-二氧六环(1mL)，装上氩气球，置换气体三次，放入100℃油浴中反应2小时。将反应液冷却，减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tertiary Butyl ester (43mg), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine (22.7mg), Brettphos Pd G3 (9.90mg), 2-(dicyclohexyl) Phosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (5.86mg), sodium tert-butoxide (31.5mg) was added to the reaction flask Add anhydrous 1,4-dioxane (1 mL) to the solution, install an argon balloon, replace the gas three times, and put it into a 100° C. oil bath to react for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤4：5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 4: 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl) Synthesis of -1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000059
Figure PCTCN2022078929-appb-000059
将3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(51mg)用二氯甲烷(0.8mL)溶解，加入三氟乙酸(0.2mL)，室温搅拌反应1小时。将反应液减压浓缩后得到标题化合物粗品，不纯化直接用于下一步反应。3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2- Dihydro-1,8-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylate tert-butyl ester (51 mg) was dissolved in dichloromethane (0.8 mL), trifluoroacetic acid (0.2 mL) was added ), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was used in the next reaction without purification.
步骤5：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 5: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000060
Figure PCTCN2022078929-appb-000060
将粗品5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1-甲基-1,8-萘啶-2(1H)-酮(40mg)用二氯甲烷(1mL)溶解，加入N,N-二异丙基乙胺(34.7mg)和乙酸酐(18.3mg)，然后室温搅拌反应2小时。将反应液减压浓缩后经制备HPLC(流动相：乙腈/水)纯化得标题化合物。The crude 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl)- 1-Methyl-1,8-naphthyridin-2(1H)-one (40 mg) was dissolved in dichloromethane (1 mL), N,N-diisopropylethylamine (34.7 mg) and acetic anhydride (18.3 mg) were added. mg), and then the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
DMSO-d6 δ H 8.42-8.40(m,1H),8.07-8.05(m,1H),7.75-7.68(m,1H),7.59-7.52(m,2H),7.39-7.12(m,2H),6.17-6.14(m,1H),5.10-5.19(m,1H),4.38-4.25(m,1H),3.74-3.65(m,1H),3.62-3.61(m,3H),3.57-3.50(m,1H),3.45-3.25(m,1H),3.07-3.02(m,3H),2.87-2.68(m,1H),2.35-2.22(m,1H),1.99-1.97(m,3H),1.66-1.65(m,3H). DMSO-d6 δ H 8.42-8.40(m, 1H), 8.07-8.05(m, 1H), 7.75-7.68(m, 1H), 7.59-7.52(m, 2H), 7.39-7.12(m, 2H), 6.17-6.14(m, 1H), 5.10-5.19(m, 1H), 4.38-4.25(m, 1H), 3.74-3.65(m, 1H), 3.62-3.61(m, 3H), 3.57-3.50(m ,1H),3.45-3.25(m,1H),3.07-3.02(m,3H),2.87-2.68(m,1H),2.35-2.22(m,1H),1.99-1.97(m,3H),1.66 -1.65(m,3H).
LC/MS(m/z,MH +):489.2 LC/MS (m/z, MH + ): 489.2
实施例6：(R)-6-(1-乙酰基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮Example 6: (R)-6-(1-Acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino) -2,7-Lutidinepyrido[3,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000061
Figure PCTCN2022078929-appb-000061
步骤1：3-氨基-6-溴-2-氯异烟酸的合成Step 1: Synthesis of 3-amino-6-bromo-2-chloroisonicotinic acid
Figure PCTCN2022078929-appb-000062
Figure PCTCN2022078929-appb-000062
将5-氨基-2-溴异烟酸(0.80g)，N-氯代丁二酰亚胺(0.49g)加入到8mL N,N-二甲基甲酰胺中，60℃搅拌10小时反应完毕。将反应液滴加到100mL水中，过滤，滤饼用水洗涤，收集滤饼，烘干后制得标题化合物。5-Amino-2-bromoisonicotinic acid (0.80g), N-chlorosuccinimide (0.49g) were added to 8mL of N,N-dimethylformamide, and the reaction was completed by stirring at 60°C for 10 hours . The reaction was added dropwise to 100 mL of water, filtered, the filter cake was washed with water, the filter cake was collected and dried to obtain the title compound.
步骤2：6-溴-8-氯-2-甲基-4H-吡啶并[3,4-d][1,3]恶嗪-4-酮的合成Step 2: Synthesis of 6-bromo-8-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one
Figure PCTCN2022078929-appb-000063
Figure PCTCN2022078929-appb-000063
将3-氨基-6-溴-2-氯异烟酸(0.70g)溶于10mL乙酸酐中，120℃搅拌2小时后反应完毕。将反应液浓缩，直接用于下一步反应。3-Amino-6-bromo-2-chloroisonicotinic acid (0.70 g) was dissolved in 10 mL of acetic anhydride, and the reaction was completed after stirring at 120° C. for 2 hours. The reaction solution was concentrated and used directly for the next reaction.
步骤3：6-溴-8-氯-2-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮的合成Step 3: Synthesis of 6-bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one
Figure PCTCN2022078929-appb-000064
Figure PCTCN2022078929-appb-000064
将6-溴-8-氯-2-甲基-4H-吡啶并[3,4-d][1,3]恶嗪-4-酮(0.80g)加入到10mL氨水中，100℃搅拌2小时后反应完毕。将反应液浓缩后制得标题化合物。6-Bromo-8-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one (0.80 g) was added to 10 mL of ammonia water, stirred at 100 °C for 2 The reaction was completed after an hour. The title compound was obtained by concentrating the reaction solution.
步骤4：(R)-6-溴-8-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺的合成Step 4: (R)-6-Bromo-8-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4 Synthesis of -d]pyrimidin-4-amine
Figure PCTCN2022078929-appb-000065
Figure PCTCN2022078929-appb-000065
将6-溴-8-氯-2-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮(200mg)，(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺(138mg)加入到反应瓶中，加入无水N,N-二甲基甲酰胺(3.00mL)，1,8-二氮杂二环[5.4.0]十一碳-7-烯(277mg)和(7-氮杂苯并***-1-氧)三吡咯磷六氟磷酸盐(684mg)，所得反应液在室温下搅拌反应2小时。将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。6-Bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (200 mg), (1R)-1-[3-(difluoromethyl)- 2-Fluoro-phenyl]ethylamine (138mg) was added to the reaction flask, anhydrous N,N-dimethylformamide (3.00mL), 1,8-diazabicyclo[5.4.0]deca Monocarbon-7-ene (277 mg) and (7-azabenzotriazole-1-oxy)tripyrrophosphine hexafluorophosphate (684 mg), and the resulting reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate gradient wash) removal) to obtain the title compound.
步骤5：(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 5: (R)-6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4- Synthesis of d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000066
Figure PCTCN2022078929-appb-000066
将(R)-6-溴-8-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺(200mg)加入到反应瓶中，加入二甲基亚砜(3mL)，然后依次加入氢氧化钾(296mg,4.49mmol,85％纯度)，水(1mL)和18-冠-6(11.9mg)，所得反应液放入80℃油浴中反应过夜。将反应液冷却后倒入水中，用稀盐酸(2M)调节体系pH至7-8，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后得标题化合物粗品，不纯化直接用于下一步反应。(R)-6-Bromo-8-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d ] Pyrimidine-4-amine (200 mg) was added to the reaction flask, dimethyl sulfoxide (3 mL) was added, followed by potassium hydroxide (296 mg, 4.49 mmol, 85% purity), water (1 mL) and 18-crown -6 (11.9 mg), the resulting reaction solution was placed in an oil bath at 80°C for overnight reaction. The reaction solution was cooled and poured into water, the pH of the system was adjusted to 7-8 with dilute hydrochloric acid (2M), extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. After concentration under pressure, the crude title compound was obtained, which was used in the next reaction without purification.
步骤6：(R)-6-溴-4–((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 6: (R)-6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3 Synthesis of ,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000067
Figure PCTCN2022078929-appb-000067
将粗品(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-8(7H)-酮(200mg)加入到反应瓶中，加入N,N-二甲基甲酰胺(3mL)溶解，然后依次加入碳酸钾(97.1mg)，碘甲烷(73.1mg)，所得反应液在室温下搅拌反应过夜。将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(100％乙酸乙酯)得标题化合物。The crude (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d ] Pyrimidine-8(7H)-one (200mg) was added to the reaction flask, N,N-dimethylformamide (3mL) was added to dissolve, then potassium carbonate (97.1mg), methyl iodide (73.1mg) were added successively, The resulting reaction solution was stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (100% ethyl acetate) to obtain title compound.
步骤7：(R)-6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 7: (R)-6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-(difluoromethyl)-2- Synthesis of Fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000068
Figure PCTCN2022078929-appb-000068
将(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮(50mg)，1-乙酰基-5,6-二氢-2H-吡啶-4-硼酸频哪醇酯(34.2mg)，碳酸钾(31.3mg)，1,1-双(二苯基膦)二荗铁二氯化钯(8.29mg)加入到反应瓶中，加入混合溶剂1,4-二氧六环(1mL)和水(0.1mL)，然后装上氩气球，置换气体三次，气体保护下放入90℃油浴中反应4小时。反应液减压浓缩后经柱层析纯化(二氯甲烷/甲醇梯度洗脱)得到标题化合物。(R)-6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4 -d]pyrimidin-8(7H)-one (50mg), 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34.2mg), potassium carbonate (31.3mg), 1,1-Bis(diphenylphosphine)pyridinium palladium dichloride (8.29mg) was added to the reaction flask, mixed solvent 1,4-dioxane (1mL) and water (0.1mL) were added, and then An argon balloon was installed, the gas was replaced three times, and the reaction was placed in an oil bath at 90°C for 4 hours under gas protection. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
步骤8：(R)-6-(1-乙酰哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 8: (R)-6-(1-Acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2 Synthesis of ,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000069
Figure PCTCN2022078929-appb-000069
将(R)-6-(1-乙酰基-1,2,3,6-四氢吡啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮(48.0mg)溶于甲醇(2mL)中，加入Pd/C(10mg，10％Pd)和乙酸(0.098mmol)，装上氢气球，置换气体三次，然后在氢气氛围下室温搅拌反应过夜。将反应液过滤，滤液减压浓缩后经制备HPLC(流动相：乙腈/水)纯化，冻干得到标题化合物。(R)-6-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorobenzene yl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (48.0 mg) was dissolved in methanol (2 mL), Pd/C (10 mg) was added , 10% Pd) and acetic acid (0.098 mmol), filled with a hydrogen balloon, replaced the gas three times, and then stirred the reaction at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, purified by preparative HPLC (mobile phase: acetonitrile/water), and lyophilized to obtain the title compound.
DMSO-d6 δ H 8.19(d,J＝7.2Hz,1H),7.62(t,J＝7.2Hz,1H),7.50(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.81(s,1H),5.71(m,1H),4.62-4.59(m,1H),3.98-3.94(m,1H),3.59(s,3H),3.25-3.08(m,2H),2.69-2.63(m,1H),2.32(s,3H),2.05(s,3H),2.03-1.89(m,2H),1.68-1.53(m,5H). DMSO-d6 δ H 8.19(d,J=7.2Hz,1H),7.62(t,J=7.2Hz,1H),7.50(t,J=6.9Hz,1H),7.30(t,J=7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.81(s, 1H), 5.71(m, 1H), 4.62-4.59(m, 1H), 3.98-3.94(m, 1H), 3.59(s) ,3H),3.25-3.08(m,2H),2.69-2.63(m,1H),2.32(s,3H),2.05(s,3H),2.03-1.89(m,2H),1.68-1.53(m , 5H).
LC/MS(m/z,MH +):488.2 LC/MS (m/z, MH + ): 488.2
实施例7：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,6-萘啶-2(1H)-酮Example 7: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-1-methyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000070
Figure PCTCN2022078929-appb-000070
步骤1：5-氯-2-甲氧基-1,6-萘啶-3-羧酸甲酯的合成Step 1: Synthesis of methyl 5-chloro-2-methoxy-1,6-naphthyridine-3-carboxylate
Figure PCTCN2022078929-appb-000071
Figure PCTCN2022078929-appb-000071
将4-氨基-2-氯烟醛(1.00g)，丙二酸二甲酯(928mg)加入到三口烧瓶中，装上氩气球，置换气体三次，气体保护下加入无水四氢呋喃(18mL)，然后用冰浴冷却至0℃，依次加入四氯化钛的二氯甲烷溶液(1M,12.8mL)和吡啶(1.01g)，所得反应液升温至40℃反应过夜。反应液冷却后加入水将反应淬灭，然后用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。4-Amino-2-chloronicotinic aldehyde (1.00g) and dimethyl malonate (928mg) were added to a three-necked flask, an argon balloon was installed, the gas was replaced three times, and anhydrous tetrahydrofuran (18mL) was added under gas protection, Then it was cooled to 0°C with an ice bath, titanium tetrachloride in dichloromethane solution (1M, 12.8mL) and pyridine (1.01g) were added successively, and the resulting reaction solution was heated to 40°C and reacted overnight. After the reaction solution was cooled, water was added to quench the reaction, then extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ ethyl acetate gradient) to give the title compound.
步骤2：5-氯-2-氧代-1,2-二氢-1,6-萘啶-3-羧酸的合成Step 2: Synthesis of 5-chloro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid
Figure PCTCN2022078929-appb-000072
Figure PCTCN2022078929-appb-000072
将5-氯-2-甲氧基-1,6-萘啶-3-羧酸甲酯(500mg)加入到三口烧瓶中，装上氩气球置换气体三次，加入无水二氯甲烷(10mL)，将反应液用冰浴冷却至0℃，加入三溴化硼的二氯甲烷溶液(2M,2.97mL)。将反应液升至室温反应3小时。加水将反应淬灭，有大量固体析出，抽滤，滤饼干燥得标题化合物。5-Chloro-2-methoxy-1,6-naphthyridine-3-carboxylate methyl ester (500 mg) was added to a three-necked flask, filled with an argon balloon to replace the gas three times, and anhydrous dichloromethane (10 mL) was added , the reaction solution was cooled to 0° C. with an ice bath, and a solution of boron tribromide in dichloromethane (2M, 2.97 mL) was added. The reaction solution was warmed to room temperature for 3 hours. Water was added to quench the reaction, and a large amount of solid was precipitated, which was filtered off with suction, and the filter cake was dried to obtain the title compound.
步骤3：3-溴-5-氯-1,6-萘啶-2(1H)-酮的合成Step 3: Synthesis of 3-bromo-5-chloro-1,6-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000073
Figure PCTCN2022078929-appb-000073
将5-氯-2-氧代-1,2-二氢-1,6-萘啶-3-羧酸(260mg)加入到史莱克管中，加入吡啶(4mL)，装上氩气球，置换气体三次。冰浴冷却至0℃，加入溴素(740mg)，然后将反应液升温至70℃反应1小时。反应液冷却后倒入水中，用浓盐酸调节pH至1-2，然后用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。5-Chloro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid (260 mg) was added to a Shrek tube, pyridine (4 mL) was added, an argon balloon was placed, and the Gas three times. After cooling to 0°C in an ice bath, bromine (740 mg) was added, and then the reaction solution was heated to 70°C and reacted for 1 hour. After cooling, the reaction solution was poured into water, and the pH was adjusted to 1-2 with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and passed through a column. Chromatography (petroleum ether/ethyl acetate gradient) afforded the title compound.
步骤4：3-溴-5-氯-1-甲基-1,6-萘啶-2(1H)-酮的合成Step 4: Synthesis of 3-bromo-5-chloro-1-methyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000074
Figure PCTCN2022078929-appb-000074
将3-溴-5-氯-1,6-萘啶-2(1H)-酮(150mg)加入到反应瓶中，加入N,N-二甲基甲酰胺(2.3mL)，碳酸钾(160mg,1.16mmol)和碘甲烷(86.2mg)，所得反应液在室温下搅拌反应过夜。将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得到标题化合物。3-Bromo-5-chloro-1,6-naphthyridin-2(1H)-one (150mg) was added to the reaction flask, N,N-dimethylformamide (2.3mL), potassium carbonate (160mg) were added , 1.16 mmol) and iodomethane (86.2 mg), the resulting reaction solution was stirred at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
步骤5：3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯的合成Step 5: Tertiary 3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid Synthesis of Butyl Ester
Figure PCTCN2022078929-appb-000075
Figure PCTCN2022078929-appb-000075
将3-溴-5-氯-1-甲基-1,6-萘啶-2(1H)-酮(75mg)，1-叔丁氧羰基-3-吡咯烷酮(55.9mg)加入到三口烧瓶中，装上氩气球，置换气体三次，气体保护下加入无水四氢呋喃(4mL)。将反应液冷却至-78℃，然后缓慢加入二碘化钐的四氢呋喃溶液(0.1M,8.23mL)，所得反应液在-78℃下反应1小时。将反应液移至室温搅拌一段时间，待二碘化钐颜色褪去，加入少量甲醇将反应淬灭，然后倒入水中，用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(二氯甲烷/甲醇＝92/8)得标题化合物。3-Bromo-5-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (75mg), 1-tert-butoxycarbonyl-3-pyrrolidone (55.9mg) were added to a three-necked flask , installed an argon balloon, replaced the gas three times, and added anhydrous tetrahydrofuran (4 mL) under gas protection. The reaction solution was cooled to -78°C, then a solution of samarium diiodide in tetrahydrofuran (0.1 M, 8.23 mL) was slowly added, and the resulting reaction solution was reacted at -78°C for 1 hour. The reaction solution was moved to room temperature and stirred for a period of time. When the color of samarium diiodide faded, a small amount of methanol was added to quench the reaction, then poured into water, extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous sulfuric acid. Dry over sodium, filter, and concentrate the filtrate under reduced pressure and purify by column chromatography (dichloromethane/methanol=92/8) to obtain the title compound.
步骤6：3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 6: 3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylate Synthesis of tert-butyl acid
Figure PCTCN2022078929-appb-000076
Figure PCTCN2022078929-appb-000076
将3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯(70mg)加入到反应瓶中，加入无水四氢呋喃(0.9mL)，然后用冰浴冷却至0℃，加入氢化钠(29.5mg,0.737mmol,含量60％)，在冰浴下搅拌5分钟，然后加入碘甲烷(131mg,0.921mmol)，升至室温反应3小时。加少量水将反应淬灭，然后减压浓缩经柱层析纯化(石油醚/乙酸乙酯＝1/10)得标题化合物。3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (70 mg) was added to the reaction flask, anhydrous tetrahydrofuran (0.9 mL) was added, then cooled to 0° C. with an ice bath, sodium hydride (29.5 mg, 0.737 mmol, content 60%) was added, and stirred for 5 minutes under an ice bath, Then methyl iodide (131 mg, 0.921 mmol) was added, and the mixture was warmed to room temperature and reacted for 3 hours. The reaction was quenched by adding a small amount of water, then concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate=1/10) to obtain the title compound.
步骤7：3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 7: 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1, Synthesis of 2-dihydro-1,6-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2022078929-appb-000077
Figure PCTCN2022078929-appb-000077
将3-(5-氯-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(40mg,0.102mmol)，(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(21.1mg,0.112mmol)，叔丁醇钠(19.5mg,0.203mmol)，Brettphos Pd G3(9.2mg)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯(5.5mg)加入到反应瓶中，加入无水1,4-二氧六环(2mL)，装上氩气球，置换气体三次，放入100℃油浴中反应2小时。将反应液冷却，减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)得标题化合物。3-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tertiary Butyl ester (40 mg, 0.102 mmol), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine (21.1 mg, 0.112 mmol), sodium tert-butoxide (19.5 mg, 0.203 mmol), Brettphos Pd G3 (9.2 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-bi Benzene (5.5 mg) was added to the reaction flask, anhydrous 1,4-dioxane (2 mL) was added, an argon balloon was installed, the gas was replaced three times, and the reaction was placed in an oil bath at 100° C. for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤8：5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1-甲基-1,6-萘啶-2(1H)-酮的合成Step 8: 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl) Synthesis of -1-methyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000078
Figure PCTCN2022078929-appb-000078
将3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,6-萘啶-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(51mg)用二氯甲烷(0.8mL)溶解，加入三氟乙酸(0.2mL)，室温搅拌反应1小时。将反应液减压浓缩后得到标题化合物粗品，不纯化直接用于下一步反应。3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-3-methoxypyrrolidine-1-carboxylate tert-butyl ester (51 mg) was dissolved in dichloromethane (0.8 mL), trifluoroacetic acid (0.2 mL) was added ), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was used in the next reaction without purification.
步骤9：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-1,6-萘啶-2(1H)-酮的合成Step 9: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)-1-methyl-1,6-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000079
Figure PCTCN2022078929-appb-000079
将粗品5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1-甲基-1,6-萘啶-2(1H)-酮(40mg)用二氯甲烷(1mL)溶解，加入N,N-二异丙基乙胺(34.7mg)和乙酸酐(18.3mg)，然后室温搅拌反应2小时。将反应液减压浓缩后经制备HPLC(流动相：乙腈/水)纯化得 标题化合物。The crude 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl)- 1-Methyl-1,6-naphthyridin-2(1H)-one (40 mg) was dissolved in dichloromethane (1 mL), N,N-diisopropylethylamine (34.7 mg) and acetic anhydride (18.3 mg) were added. mg), and then the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
DMSO-d6 δ H 8.37-8.29(m,1H),7.96-7.94(m,1H),7.82-7.76(m,1H),7.62-7.58(m,1H),7.49-7.45(m,1H),7.37-7.10(m,2H),6.65-6.62(m,1H),5.71-5.65(m,1H),4.36-4.23(m,1H),3.75-3.63(m,2H),3.52-3.51(m,3H),3.43-3.38(m,1H),3.06-3.02(m,3H),2.86-2.83(m,1H),2.33-2.23(m,1H),1.99-1.96(m,3H),1.59-1.57(m,3H). DMSO-d6 δ H 8.37-8.29(m,1H),7.96-7.94(m,1H),7.82-7.76(m,1H),7.62-7.58(m,1H),7.49-7.45(m,1H), 7.37-7.10(m, 2H), 6.65-6.62(m, 1H), 5.71-5.65(m, 1H), 4.36-4.23(m, 1H), 3.75-3.63(m, 2H), 3.52-3.51(m ,3H),3.43-3.38(m,1H),3.06-3.02(m,3H),2.86-2.83(m,1H),2.33-2.23(m,1H),1.99-1.96(m,3H),1.59 -1.57(m,3H).
LC/MS(m/z,MH +):489.2 LC/MS (m/z, MH + ): 489.2
实施例8：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-3-吗啉-1,8-萘啶-2(1H)-酮Example 8: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholine-1,8- Naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000080
Figure PCTCN2022078929-appb-000080
步骤1：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸甲酯的合成Step 1: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-di Synthesis of Hydrogen-1,8-Naphthyridine-3-Carboxylic Acid Methyl Esters
Figure PCTCN2022078929-appb-000081
Figure PCTCN2022078929-appb-000081
将5-氯-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸甲酯(500mg)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺(400mg)，N,N-二异丙基乙胺(300mg)加入到5mL DMSO中，加热至130℃，搅拌4小时后反应完毕，将反应液加入到20mL水中，乙酸乙酯萃取，合并有机层，浓缩后柱层析(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。Methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (500mg), (R)-1-(3-(di Fluoromethyl)-2-fluorophenyl)ethan-1-amine (400mg), N,N-diisopropylethylamine (300mg) was added to 5mL DMSO, heated to 130°C, and the reaction was completed after stirring for 4 hours , the reaction solution was added to 20 mL of water, extracted with ethyl acetate, the organic layers were combined, concentrated and column chromatography (petroleum ether/ethyl acetate gradient elution) was performed to obtain the title compound.
步骤2：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸的合成Step 2: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-di Synthesis of Hydrogen-1,8-Naphthyridine-3-Carboxylic Acid
Figure PCTCN2022078929-appb-000082
Figure PCTCN2022078929-appb-000082
将(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸甲 酯(309mg)加入到反应瓶中，用甲醇(3mL)和四氢呋喃(1.5mL)溶解，加入氢氧化钠水溶液(2M,3.81mL)，所得反应液在室温下搅拌3小时。将反应液用水稀释，稀盐酸调pH至4-5，有大量固体析出，抽滤，滤饼水洗，干燥后制得标题化合物。(R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro- Methyl 1,8-naphthyridine-3-carboxylate (309 mg) was added to the reaction flask, dissolved in methanol (3 mL) and tetrahydrofuran (1.5 mL), sodium hydroxide aqueous solution (2 M, 3.81 mL) was added, and the resulting reaction solution was Stir at room temperature for 3 hours. The reaction solution was diluted with water, and the pH was adjusted to 4-5 with dilute hydrochloric acid, a large amount of solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain the title compound.
步骤3：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-碘-1-甲基-1,8-萘啶-2(1H)-酮的合成Step 3: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-iodo-1-methyl-1,8-naphthyridine Synthesis of -2(1H)-ketone
Figure PCTCN2022078929-appb-000083
Figure PCTCN2022078929-appb-000083
将(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸(103mg)，碘(267mg)，无水磷酸钾(55.9mg)加入到反应瓶中，加入超干的乙腈(1.3mL)，用氩气球吹走瓶中的空气，拧紧瓶盖，放入100℃油浴中反应6小时。将反应液冷却后用乙酸乙酯稀释，倒入饱和硫代硫酸钠溶液中洗涤，分液，水相再用乙酸乙酯萃取，有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。(R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro- 1,8-Naphthyridine-3-carboxylic acid (103mg), iodine (267mg), anhydrous potassium phosphate (55.9mg) were added to the reaction flask, ultra-dry acetonitrile (1.3mL) was added, and the flask was blown away with an argon balloon In the air, tighten the cap, and put it into a 100 °C oil bath to react for 6 hours. The reaction solution was cooled, diluted with ethyl acetate, poured into saturated sodium thiosulfate solution, washed, separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤4：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-3-吗啉代-1,8-萘啶-2(1H)-酮的合成Step 4: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholino-1,8- Synthesis of Naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000084
Figure PCTCN2022078929-appb-000084
将(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-碘-1-甲基-1,8-萘啶-2(1H)-酮(30.0mg)，吗啉(11.1mg)，2-二环己基膦-2',4',6'-三异丙基联苯(6.04mg)，三(二亚苄基丙酮)二钯(5.81mg)，碳酸铯(41.3mg)加入到反应瓶中，加入二氧六环(0.6mL)，装上氩气球置换气体三次，气体保护下放入100℃油浴中反应16小时。将反应液冷却后过滤，滤液减压浓缩后经制备HPLC(流动相：乙腈/水)纯化制得标题化合物。(R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-iodo-1-methyl-1,8-naphthyridine-2 (1H)-ketone (30.0 mg), morpholine (11.1 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (6.04 mg), tris(dibenzylidene) Acetone) dipalladium (5.81mg), cesium carbonate (41.3mg) were added to the reaction flask, dioxane (0.6mL) was added, an argon balloon was installed to replace the gas three times, and the reaction was placed in a 100 ℃ oil bath under gas protection 16 hours. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
实施例9：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基-3-吗啉并吡啶并[2,3-d]哒嗪-2(1H)-酮Example 9: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-3-morpholinopyridine Ipo[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000085
Figure PCTCN2022078929-appb-000085
步骤1：2-乙酰基-1-甲基-6-氧代-1,6-二氢吡啶-3-羧酸乙酯的合成Step 1: Synthesis of 2-acetyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester
Figure PCTCN2022078929-appb-000086
Figure PCTCN2022078929-appb-000086
将2-氯-1-甲基-6-氧代-1,6-二氢吡啶-3-羧酸甲酯(1.00g)溶解于10mL的1，4-二氧六环中，加入双三苯基膦二氯化钯(348mg)和三丁基(1-乙氧基乙烯基)锡烷(2.15g)于氩气保护下升温至100℃反应6小时后，将反应液冷却至室温，并加入3M的稀盐酸调节pH＝1后继续搅拌1小时，加入10mL饱和氟化钾溶液和10mL乙酸乙酯搅拌30分钟，过滤，滤液分液，水相经乙酸乙酯萃取后，合并有机相，用无水硫酸钠干燥，过滤，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1.00 g) was dissolved in 10 mL of 1,4-dioxane, and bistris Phenylphosphine palladium dichloride (348mg) and tributyl(1-ethoxyvinyl)stannane (2.15g) were heated to 100°C for 6 hours under argon protection, and the reaction solution was cooled to room temperature. And add 3M dilute hydrochloric acid to adjust pH=1, continue to stir for 1 hour, add 10 mL of saturated potassium fluoride solution and 10 mL of ethyl acetate, stir for 30 minutes, filter, and separate the filtrate. After the aqueous phase is extracted with ethyl acetate, the organic phases are combined. , dried over anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
步骤2：1,8-二甲基吡啶并[2,3-d]哒嗪-2,5(1H,6H)-二酮的合成Step 2: Synthesis of 1,8-Lutidinepyrido[2,3-d]pyridazine-2,5(1H,6H)-dione
Figure PCTCN2022078929-appb-000087
Figure PCTCN2022078929-appb-000087
将2-乙酰基-1-甲基-6-氧代-1,6-二氢吡啶-3-羧酸乙酯(1.07g)溶解于10mL乙醇中，加入5mL的水合肼，随后升温至75℃反应8小时后，有大量固体析出，反应液冷却至室温后，过滤，滤饼烘干后制得标题化合物。2-Acetyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.07 g) was dissolved in 10 mL of ethanol, 5 mL of hydrazine hydrate was added, and then the temperature was raised to 75 After reacting at ℃ for 8 hours, a large amount of solid was precipitated, the reaction solution was cooled to room temperature, filtered, and the filter cake was dried to obtain the title compound.
步骤3：3-溴-5-羟基-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 3: Synthesis of 3-bromo-5-hydroxy-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000088
Figure PCTCN2022078929-appb-000088
将1,8-二甲基吡啶并[2,3-d]哒嗪-2,5(1H,6H)-二酮(1.13g)分散于10mL的N,N-二甲基甲酰胺中，随后加入二溴海因(3.38g)于室温下反应8小时后，反应液浓缩后柱层析(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。1,8-Dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (1.13 g) was dispersed in 10 mL of N,N-dimethylformamide, Dibromohydantoin (3.38 g) was then added to react at room temperature for 8 hours, the reaction solution was concentrated, and the title compound was obtained by column chromatography (gradient elution of petroleum ether/ethyl acetate).
步骤4：3-溴-5-氯-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 4: Synthesis of 3-bromo-5-chloro-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000089
Figure PCTCN2022078929-appb-000089
将3-溴-5-羟基-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮(800mg)分散于8mL的乙腈中，向 其中滴加三氯氧磷(2.27g)，随后升高温度至80℃反应10小时后，将反应液浓缩后经乙腈稀释后倒入碎冰中，经饱和碳酸氢钠调节pH＝8后，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。3-Bromo-5-hydroxy-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one (800 mg) was dispersed in 8 mL of acetonitrile, to which was added dropwise trichloride Phosphorus oxide (2.27g), then the temperature was raised to 80°C and reacted for 10 hours, the reaction solution was concentrated, diluted with acetonitrile, poured into crushed ice, adjusted to pH=8 with saturated sodium bicarbonate, and extracted with ethyl acetate , the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
步骤5：5-氯-1,8-二甲基-3-吗啉代吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 5: Synthesis of 5-chloro-1,8-dimethyl-3-morpholinopyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000090
Figure PCTCN2022078929-appb-000090
将3-溴-5-氯-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮(100mg)溶解于1mL的二甲基亚砜中，随后加入***啉(45.3mg)和氟化铯(45.8mg)升温至100℃反应1小时后，将反应液冷却至室温，用乙酸乙酯稀释，经饱和氯化钠溶液洗涤后，用无水硫酸钠干燥有机相，过滤，浓缩经柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。3-Bromo-5-chloro-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one (100 mg) was dissolved in 1 mL of dimethylsulfoxide, followed by the addition of Morphine (45.3 mg) and cesium fluoride (45.8 mg) were heated to 100 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium chloride solution, and then washed with anhydrous sodium sulfate. The organic phase was dried, filtered, concentrated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
步骤6：(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基-3-吗啉并吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 6: (R)-5-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-3-morpholinopyrido Synthesis of [2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000091
Figure PCTCN2022078929-appb-000091
将5-氯-1,8-二甲基-3-吗啉吡啶并[2,3-d]哒嗪-2(1H)-酮(50.0mg)溶解于1mL的二甲基亚砜中，随后加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺(48.1mg)和氟化铯(22.4mg)升温至110℃反应20小时后反应完毕。将反应液冷却至室温，用乙酸乙酯稀释，经饱和氯化钠溶液洗涤，干燥有机相经制备HPLC(流动相：乙腈/水)纯化制得标题化合物。5-Chloro-1,8-dimethyl-3-morpholinopyrido[2,3-d]pyridazin-2(1H)-one (50.0 mg) was dissolved in 1 mL of dimethyl sulfoxide, Then (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (48.1 mg) and cesium fluoride (22.4 mg) were added and the temperature was raised to 110°C for 20 hours. complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium chloride solution, and the dried organic phase was purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
1H NMR(400MHz,DMSO)δ7.57(t,J＝7.4Hz,1H),7.46(t,J＝6.8Hz,1H),7.39-7.09(m,4H),5.71–5.62(m,1H),3.83-3.76(m,4H),3.74(s,3H),3.36-3.30(m,4H),2.75(s,3H),1.59(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ7.57(t,J=7.4Hz,1H),7.46(t,J=6.8Hz,1H),7.39-7.09(m,4H),5.71-5.62(m,1H) ), 3.83-3.76(m, 4H), 3.74(s, 3H), 3.36-3.30(m, 4H), 2.75(s, 3H), 1.59(d, J=7.0Hz, 3H).
LC/MS(m/z,MH +):448.2 LC/MS (m/z, MH + ): 448.2
实施例10：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮Example 10: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000092
Figure PCTCN2022078929-appb-000092
步骤1：3-(5-氯-1,8-二甲基-2-氧代-1,2-二氢吡啶并[2,3-d]哒嗪-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯的合成Step 1: 3-(5-Chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-hydroxypyrrole Synthesis of tert-butyl alkane-1-carboxylate
Figure PCTCN2022078929-appb-000093
Figure PCTCN2022078929-appb-000093
将3-溴-5-氯-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮(200mg)溶解于5mL的四氢呋喃中，氩气保护下加入3-氧代吡咯烷-1-羧酸叔丁酯(154mg)，降温至-78℃后，向其中缓慢滴加二碘化钐的四氢呋喃溶液(0.1M,34.66mL)，滴加完毕后于该温度下继续反应3小时，向其中加入饱和氯化铵溶液淬灭，分液，水相经乙酸乙酯萃取后，合并有机相，用无水硫酸钠干燥，过滤，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。3-Bromo-5-chloro-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one (200 mg) was dissolved in 5 mL of tetrahydrofuran, and 3 was added under argon protection. -Oxopyrrolidine-1-carboxylate tert-butyl ester (154mg), after cooling to -78°C, a solution of samarium diiodide in tetrahydrofuran (0.1M, 34.66mL) was slowly added dropwise thereto. The reaction was continued for 3 hours at the temperature, saturated ammonium chloride solution was added to it to quench, and the layers were separated. After the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography ( (petroleum ether/ethyl acetate gradient) to give the title compound.
步骤2：3-(5-氯-1,8-二甲基-2-氧代-1,2-二氢吡啶并[2,3-d]哒嗪-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 2: 3-(5-Chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-methoxy Synthesis of tert-butyl pyrrolidine-1-carboxylate
Figure PCTCN2022078929-appb-000094
Figure PCTCN2022078929-appb-000094
将3-(5-氯-1,8-二甲基-2-氧代-1,2-二氢吡啶并[2,3-d]哒嗪-3-基)-3-羟基吡咯烷-1-羧酸叔丁酯(100mg)溶解于5mL的四氢呋喃中，降温至0℃，加入NaH(20.2mg)继续搅拌30分钟，滴加碘甲烷(53.9mg)，滴毕后移至室温继续反应1小时后反应完毕，将反应液倒入10mL的冰水中，乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。3-(5-Chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-hydroxypyrrolidine- 1-Carboxylic acid tert-butyl ester (100mg) was dissolved in 5mL of tetrahydrofuran, cooled to 0°C, NaH (20.2mg) was added to continue stirring for 30 minutes, iodomethane (53.9mg) was added dropwise, after the drop was completed, it was moved to room temperature to continue the reaction After 1 hour, the reaction was completed, the reaction solution was poured into 10 mL of ice water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate gradient elution). ) was purified to obtain the title compound.
步骤3：3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基-2-氧代-1,2-二氢吡啶[2,3-d]哒嗪-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯的合成Step 3: 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-2-oxo Synthesis of -1,2-dihydropyridine[2,3-d]pyridazin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2022078929-appb-000095
Figure PCTCN2022078929-appb-000095
将3-(5-氯-1,8-二甲基-2-氧代-1,2-二氢吡啶并[2,3-d]哒嗪-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(60.0mg)溶解于1mL的二甲基亚砜中，随后加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺(55.5mg)和氟化铯(19.4mg)。升温至110℃搅拌10小时后反应完毕，将反应液冷却至室温，乙酸乙酯稀释，饱和食盐水洗涤，用无水硫酸钠干燥，过滤，浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)纯化制得标题化合物。3-(5-Chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-methoxypyrrole Alkane-1-carboxylate tert-butyl ester (60.0 mg) was dissolved in 1 mL of dimethyl sulfoxide, followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl- 1-amine (55.5 mg) and cesium fluoride (19.4 mg). The reaction was completed after the temperature was raised to 110°C and stirred for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated and subjected to column chromatography (dichloromethane/methanol gradient). elution) to give the title compound.
步骤4：5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 4: 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl) Synthesis of -1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000096
Figure PCTCN2022078929-appb-000096
将3-(5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基-2-氧代-1,2-二氢吡啶[2,3-d]哒嗪-3-基)-3-甲氧基吡咯烷-1-羧酸叔丁酯(80.0mg)溶解于1mL的1,4-二氧六环中，随后向其中滴加1mL的盐酸-二氧六环溶液(4M)，滴完后室温下反应30分钟，将反应液浓缩后直接投入下一步中。3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-2-oxo-1 , 2-dihydropyridine[2,3-d]pyridazin-3-yl)-3-methoxypyrrolidine-1-carboxylate tert-butyl ester (80.0 mg) was dissolved in 1 mL of 1,4-dioxane Then, 1 mL of hydrochloric acid-dioxane solution (4M) was added dropwise into the hexacyclic ring, and after dropping, the reaction was performed at room temperature for 30 minutes, and the reaction solution was concentrated and directly put into the next step.
步骤5：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮的合成Step 5: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one
Figure PCTCN2022078929-appb-000097
Figure PCTCN2022078929-appb-000097
将5-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(3-甲氧基吡咯烷-3-基)-1,8-二甲基吡啶并[2,3-d]哒嗪-2(1H)-酮粗品(60.0mg)溶解于3mL的二氯甲烷中，向其中滴加N,N-二异丙基乙胺(84.0mg)和乙酸酐(26.6mgl)，室温下继续搅拌30分钟后反应完毕，反应液浓缩后经制备HPLC(流动相：乙腈/水)分离纯化制得标题化合物。5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidin-3-yl)-1 The crude ,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one (60.0 mg) was dissolved in 3 mL of dichloromethane, and N,N-diisopropyl was added dropwise thereto. Ethylamine (84.0 mg) and acetic anhydride (26.6 mgl) were stirred at room temperature for 30 minutes and the reaction was completed. The reaction solution was concentrated and separated and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
1H NMR(400MHz,DMSO)δ8.47-8.28(m,1H),7.74-7.43(m,3H),7.40-7.03(m,2H),5.72-5.05(m,1H),4.34-4.11(m,1H),3.76-3.70(m,3H),3.70-3.33(m,3H),3.11-3.01(m,3H),2.84-2.73(m,3H),2.70-2.53(m,1H),2.44-2.24(m,1H),2.01-1.82(m,3H),1.64-1.20(m,3H). 1 H NMR(400MHz, DMSO)δ8.47-8.28(m,1H),7.74-7.43(m,3H),7.40-7.03(m,2H),5.72-5.05(m,1H),4.34-4.11( m,1H),3.76-3.70(m,3H),3.70-3.33(m,3H),3.11-3.01(m,3H),2.84-2.73(m,3H),2.70-2.53(m,1H), 2.44-2.24(m,1H),2.01-1.82(m,3H),1.64-1.20(m,3H).
LC/MS(m/z,MH +):504.2 LC/MS (m/z, MH + ): 504.2
实施例11：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基-6-吗啉吡啶并[3,4-d]嘧啶-8(7H)-酮Example 11: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6-morpholinopyrido [3,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000098
Figure PCTCN2022078929-appb-000098
步骤1：(R)-4–((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基-6-吗啉代吡啶并[3,4-d]嘧啶-8(7H)-酮的合成Step 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6-morpholinopyrido Synthesis of [3,4-d]pyrimidin-8(7H)-one
Figure PCTCN2022078929-appb-000099
Figure PCTCN2022078929-appb-000099
将(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2,7-二甲基吡啶并[3,4-d]嘧啶-8(7H)-酮(20.0mg)，吗啉(11.9mg)，碳酸铯(59.1mg)，三(二亚苄基丙酮)二钯(4.15mg)，1,1'-联萘-2,2'- 双二苯膦(5.64mg)加入到反应瓶中，加入1,4-二氧六环(0.8mL)，气体保护下加热至100℃搅拌10小时后反应完毕。将反应液过滤，滤液减压浓缩后经制备HPLC(流动相：乙腈/水)纯化得标题化合物。(R)-6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4 -d]pyrimidin-8(7H)-one (20.0 mg), morpholine (11.9 mg), cesium carbonate (59.1 mg), tris(dibenzylideneacetone)dipalladium (4.15 mg), 1,1'- Binaphthyl-2,2'-bisdiphenylphosphine (5.64 mg) was added to the reaction flask, 1,4-dioxane (0.8 mL) was added, and the reaction was completed by heating to 100° C. under gas protection and stirring for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile/water) to obtain the title compound.
1H NMR(400MHz,DMSO)δ8.11(d,J＝7.2Hz,1H),7.64(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.57(s,1H),5.72(m,1H),3.79(bs,4H),3.50(s,3H),2.98(bs,4H),2.32(d,J＝6.0Hz,3H),1.59(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO) δ 8.11 (d, J=7.2Hz, 1H), 7.64 (t, J=7.3Hz, 1H), 7.50 (t, J=6.9Hz, 1H), 7.30 (t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.57(s, 1H), 5.72(m, 1H), 3.79(bs, 4H), 3.50(s, 3H), 2.98( bs,4H),2.32(d,J=6.0Hz,3H),1.59(d,J=7.1Hz,3H).
LC/MS(m/z,MH +):448.2 LC/MS (m/z, MH + ): 448.2
实施例12：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-1-甲基-5-(((R)-1-(2-甲基-3-硝基苯基)乙基)氨基)-1,8-萘啶-2(1H)–酮Example 12: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-1-methyl-5-(((R)-1-(2-methyl-3-nitro) Phenyl)ethyl)amino)-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000100
Figure PCTCN2022078929-appb-000100
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺替换为(1R)-1-(2-甲基-3-硝基苯基)乙胺，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine in step 3 is replaced by (1R)-1-( 2-methyl-3-nitrophenyl)ethanamine, the title compound was obtained by the same method.
1H NMR(400MHz,DMSO)δ8.49-8.37(m,1H),8.09-7.99(m,1H),7.82-7.62(m,3H),7.44-7.35(m,1H),6.05-5.94(m,1H),5.13-4.95(m,1H),4.40-4.22(m,1H),3.76-3.40(m,6H),3.12-2.99(m,3H),2.93-2.63(m,1H),2.50-2.48(m,3H),2.37-2.20(m,1H),2.04-1.89(m,3H),1.65-1.53(m,3H). 1 H NMR(400MHz, DMSO)δ8.49-8.37(m,1H),8.09-7.99(m,1H),7.82-7.62(m,3H),7.44-7.35(m,1H),6.05-5.94( m,1H),5.13-4.95(m,1H),4.40-4.22(m,1H),3.76-3.40(m,6H),3.12-2.99(m,3H),2.93-2.63(m,1H), 2.50-2.48(m, 3H), 2.37-2.20(m, 1H), 2.04-1.89(m, 3H), 1.65-1.53(m, 3H).
LC/MS(m/z,MH +):480.2 LC/MS (m/z, MH + ): 480.2
(1R)-1-(2-甲基-3-硝基苯基)乙胺的合成：Synthesis of (1R)-1-(2-methyl-3-nitrophenyl)ethanamine:
Figure PCTCN2022078929-appb-000101
Figure PCTCN2022078929-appb-000101
步骤1：1-(2-甲基-3-硝基苯基)乙酮的合成Step 1: Synthesis of 1-(2-methyl-3-nitrophenyl)ethanone
Figure PCTCN2022078929-appb-000102
Figure PCTCN2022078929-appb-000102
将2-溴-6-硝基甲苯(5.00g)加入到30ml甲苯中，向其中加入三乙胺(5.86g)，三丁基(1-乙氧基乙烯)锡(10.0g)，双三苯基磷二氯化钯(649mg)，氩气置换三次，100℃反应16小时后反应完毕，反应液冷至室温，过滤，滤液减压蒸馏得粗品，再用THF溶解，在0℃下加入稀盐酸(1M，23.14ml)，反应液回至室温搅拌15分钟；用饱和碳酸氢钠溶液调pH至弱碱性，然后加入氟化钾(1.61g)，搅拌两小时，铺硅藻土过滤，滤液用乙酸乙酯萃取三次，合并有机相，有机层浓缩后柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。2-Bromo-6-nitrotoluene (5.00g) was added to 30ml of toluene, to which were added triethylamine (5.86g), tributyl(1-ethoxyethylene)tin (10.0g), bistris Phenylphosphonium palladium dichloride (649mg), replaced with argon three times, the reaction was completed after 16 hours at 100°C, the reaction solution was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain the crude product, which was dissolved in THF and added at 0°C Dilute hydrochloric acid (1M, 23.14ml), the reaction solution was returned to room temperature and stirred for 15 minutes; the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, then potassium fluoride (1.61g) was added, stirred for two hours, and filtered through celite , the filtrate was extracted three times with ethyl acetate, the organic phases were combined, the organic layer was concentrated and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
步骤2：(S)-2-甲基-N-(1-(2-甲基-3-硝基苯基)亚乙基)丙烷-2-亚磺酰胺Step 2: (S)-2-Methyl-N-(1-(2-methyl-3-nitrophenyl)ethylene)propane-2-sulfinamide
Figure PCTCN2022078929-appb-000103
Figure PCTCN2022078929-appb-000103
将1-(2-甲基-3-硝基苯基)乙酮(3.35g)加入到90ml四氢呋喃中，室温下加入(R)-(+)-叔丁基亚磺酰胺(3.40g)，钛酸四乙酯(10.6g)，氩气置换三次，70℃反应3小时反应完毕，加入50mL冰水，再加入乙酸乙酯稀释，铺硅藻土过滤，滤液分液，得有机层，用无水硫酸钠干燥，过滤，有机层浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。1-(2-Methyl-3-nitrophenyl)ethanone (3.35g) was added to 90ml of tetrahydrofuran, and (R)-(+)-tert-butylsulfinamide (3.40g) was added at room temperature, Tetraethyl titanate (10.6g) was replaced with argon three times, and the reaction was completed at 70 °C for 3 hours. After the reaction was completed, 50 mL of ice water was added, and then ethyl acetate was added to dilute it. Dry over anhydrous sodium sulfate, filter, concentrate the organic layer and purify by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤3：2-甲基-N-[(1R)-1-(2-甲基-3-硝基苯基)乙基]丙烷-2-亚砜酰胺的合成Step 3: Synthesis of 2-methyl-N-[(1R)-1-(2-methyl-3-nitrophenyl)ethyl]propane-2-sulfoxide amide
Figure PCTCN2022078929-appb-000104
Figure PCTCN2022078929-appb-000104
将(S)-2-甲基-N-(1-(2-甲基-3-硝基苯基)亚乙基)丙烷-2-亚磺酰胺(4.00g)加入到30mL四氢呋喃中，冰浴下，分批次加入硼氢化钠(520mg)，室温反应12小时反应完毕，加入饱和氯化铵水溶液淬灭，加入乙酸乙酯稀释，饱和食盐水萃取，有机相用无水硫酸钠干燥，过滤，有机层浓缩后柱层析(石油醚/乙酸乙酯梯度洗脱)纯化制得标题化合物。(S)-2-methyl-N-(1-(2-methyl-3-nitrophenyl)ethylene)propane-2-sulfinamide (4.00 g) was added to 30 mL of tetrahydrofuran, ice Under the bath, sodium borohydride (520 mg) was added in batches, the reaction was completed at room temperature for 12 hours, quenched by adding saturated aqueous ammonium chloride solution, diluted by adding ethyl acetate, extracted with saturated brine, and the organic phase was dried with anhydrous sodium sulfate, After filtration, the organic layer was concentrated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
步骤4：(1R)-1-(2-甲基-3-硝基苯基)乙胺的合成Step 4: Synthesis of (1R)-1-(2-methyl-3-nitrophenyl)ethanamine
Figure PCTCN2022078929-appb-000105
Figure PCTCN2022078929-appb-000105
将2-甲基-N-[(1R)-1-(2-甲基-3-硝基苯基)乙基]丙烷-2-亚砜酰胺(1.77g)加入到20mL二氧六环中，冰浴下加入盐酸二氧六环(4M,4.67mL)，室温反应10分钟反应完毕。反应液浓缩后用饱和碳酸氢钠溶液调节pH至8-9，乙酸乙酯萃取，合并有机层，浓缩后制得标题化合物。2-Methyl-N-[(1R)-1-(2-methyl-3-nitrophenyl)ethyl]propane-2-sulfoxide amide (1.77 g) was added to 20 mL of dioxane , and dioxane hydrochloride (4M, 4.67 mL) was added under an ice bath, and the reaction was completed at room temperature for 10 minutes. The reaction solution was concentrated and adjusted to pH 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic layers were combined and concentrated to obtain the title compound.
实施例13：3-((1R)-1-((6-(1-乙酰基-3-甲氧基吡咯烷-3-基)-8-甲基-7-氧代-7,8-二氢-1,8-萘啶-4-基)氨基)乙基)-2-甲基苯甲腈Example 13: 3-((1R)-1-((6-(1-Acetyl-3-methoxypyrrolidin-3-yl)-8-methyl-7-oxo-7,8- Dihydro-1,8-naphthyridin-4-yl)amino)ethyl)-2-methylbenzonitrile
Figure PCTCN2022078929-appb-000106
Figure PCTCN2022078929-appb-000106
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺替换为(R)-3-(1-氨基乙基)-2-甲苯腈，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine in step 3 is replaced by (R)-3-( 1-Aminoethyl)-2-toluonitrile, the title compound was obtained by the same method.
1H NMR(400MHz,DMSO)δ8.47-8.38(m,1H),8.06-7.98(m,1H),7.81-7.59(m,3H),7.42-7.29(m,1H),6.03-5.93(m,1H),5.06-4.93(m,1H),4.43-4.19(m,1H),3.77-3.38(m,6H),3.13-2.99(m,3H),2.92-2.67(m,1H),2.65(s,3H),2.37-2.21(m,1H),2.02-1.93(m,3H),1.64-1.52(m,3H). 1 H NMR(400MHz, DMSO)δ8.47-8.38(m,1H), 8.06-7.98(m,1H), 7.81-7.59(m,3H), 7.42-7.29(m,1H), 6.03-5.93( m,1H),5.06-4.93(m,1H),4.43-4.19(m,1H),3.77-3.38(m,6H),3.13-2.99(m,3H),2.92-2.67(m,1H), 2.65(s, 3H), 2.37-2.21(m, 1H), 2.02-1.93(m, 3H), 1.64-1.52(m, 3H).
LC/MS(m/z,MH +):460.2 LC/MS (m/z, MH + ): 460.2
实施例14：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-((R)-1-(3,3-二氟-2,3-二氢苯并呋喃-7-基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮Example 14: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-((R)-1-(3,3-difluoro-2,3-dihydrobenzo Furan-7-yl)ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000107
Figure PCTCN2022078929-appb-000107
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺替换为(R)-1-(3,3-二氟-2,3-二氢苯并呋喃-7-基)乙烷-1-胺，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine in step 3 is replaced by (R)-1-( 3,3-Difluoro-2,3-dihydrobenzofuran-7-yl)ethane-1-amine, the title compound was obtained by the same method.
实施例15：3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-((R)-1-(1,1-二氟-2,3-二氢-1H-茚-4-基)乙基)氨基)-1-甲基-1,8-萘啶-2(1H)-酮Example 15: 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-((R)-1-(1,1-difluoro-2,3-dihydro-1H -Inden-4-yl)ethyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000108
Figure PCTCN2022078929-appb-000108
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1(-(3-(二氟甲基)-2-氟-苯基)乙胺替换为(R)-1-(1,1-二氟-2,3-二氢-1H-茚-4-基)乙烷-1-胺，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1(-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine in step 3 is replaced by (R)-1- (1,1-Difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine, the title compound was obtained by the same method.
实施例16 3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-1-甲基-5-(((R)-1-(3-(五氟-λ6-硫烷基)苯基)乙基)氨基)-1,8-萘啶-2(1H)-酮Example 16 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-1-methyl-5-(((R)-1-(3-(pentafluoro-λ6-sulfane) yl)phenyl)ethyl)amino)-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000109
Figure PCTCN2022078929-appb-000109
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺替换为(R)-1-(3-(五氟-λ6-硫烷基)苯基)乙-1-胺，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine in step 3 is replaced by (R)-1-( 3-(Pentafluoro-λ6-sulfanyl)phenyl)ethan-1-amine, the title compound was obtained by the same method.
1H NMR(400MHz,DMSO)δ8.42-8.37(m,1H),8.08-8.03(m,1H),8.02-7.97(m,1H),7.80-7.69(m,3H),7.63-7.55(m,1H),6.33-6.23(m,1H),5.12-4.95(m,1H),4.41-4.20(m,1H),3.77-3.23(m,6H),3.09-3.00(m,3H),2.89-2.63(m,1H),2.38-2.20(m,1H),2.03-1.93(m,3H),1.63(d,J＝6.7Hz,3H). 1 H NMR(400MHz, DMSO)δ8.42-8.37(m,1H), 8.08-8.03(m,1H), 8.02-7.97(m,1H), 7.80-7.69(m,3H), 7.63-7.55( m,1H),6.33-6.23(m,1H),5.12-4.95(m,1H),4.41-4.20(m,1H),3.77-3.23(m,6H),3.09-3.00(m,3H), 2.89-2.63(m, 1H), 2.38-2.20(m, 1H), 2.03-1.93(m, 3H), 1.63(d, J=6.7Hz, 3H).
LC/MS(m/z,MH +):547.2 LC/MS (m/z, MH + ): 547.2
实施例17 3-(1-乙酰基-3-甲氧基吡咯烷-3-基)-5-(((R)-1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基))氨基)-1-甲基--1,8-萘啶-2(1H)-酮Example 17 3-(1-Acetyl-3-methoxypyrrolidin-3-yl)-5-(((R)-1-(3-(1,1-difluoro-2-hydroxy-2 -Methylpropyl)-2-fluorophenyl)ethyl))amino)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000110
Figure PCTCN2022078929-appb-000110
参考实施例5的制备方法，不同的是将步骤3中的(1R)-1-[3-(二氟甲基)-2-氟-苯基]乙胺替换为(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇，同法制得标题化合物。Refer to the preparation method of Example 5, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine in step 3 is replaced by (R)-1-( 3-(1-Aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol, the title compound was obtained by the same method.
1H NMR(400MHz,DMSO)δ8.45-8.38(m,1H),8.09-8.03(m,1H),7.79-7.68(m,1H),7.56-7.48(m,1H),7.39-7.32(m,1H),7.28-7.21(m,1H),6.16-6.11(m,1H),5.37(br,1H),5.12-5.00(m,1H),4.40-4.23(m,1H),3.76-3.39(m,6H),3.09-2.99(m,3H),2.90-2.65(m,1H),2.37-2.18(m,1H),2.06-1.88(m,3H),1.65(d,J＝6.3Hz,3H),1.23(s,6H). 1 H NMR(400MHz, DMSO)δ8.45-8.38(m,1H), 8.09-8.03(m,1H), 7.79-7.68(m,1H), 7.56-7.48(m,1H), 7.39-7.32( m,1H),7.28-7.21(m,1H),6.16-6.11(m,1H),5.37(br,1H),5.12-5.00(m,1H),4.40-4.23(m,1H),3.76- 3.39(m, 6H), 3.09-2.99(m, 3H), 2.90-2.65(m, 1H), 2.37-2.18(m, 1H), 2.06-1.88(m, 3H), 1.65(d, J=6.3 Hz,3H),1.23(s,6H).
LC/MS(m/z,MH +):547.2 LC/MS (m/z, MH + ): 547.2
实施例18：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-7(6H)-酮Example 18: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-methyl-1,2,3, 6-Tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000111
Figure PCTCN2022078929-appb-000111
步骤1：4-((叔丁氧基羰基)氨基)-1-吗啉代-6-氧代-1,6-二氢吡啶-3-羧酸甲酯的合成Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate
参考文献WO2019122129中intermediates E-5a的制备方法制备1-吗啉代-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-羧酸甲酯，不同的是将1-(二氟甲基)环丙基-1-胺替换为N-氨基吗啉。Preparation method of intermediates E-5a in reference WO2019122129 Preparation of methyl 1-morpholino-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylate, different is the replacement of 1-(difluoromethyl)cyclopropyl-1-amine with N-aminomorpholine.
Figure PCTCN2022078929-appb-000112
Figure PCTCN2022078929-appb-000112
将1-吗啉代-6-氧代-4-(甲苯磺酰氧基)-1,6-二氢吡啶-3-羧酸甲酯(3.00g)，氨基甲酸叔丁酯 (1.72g)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(425mg)，氯化钯(π-肉桂基)二聚物(190mg)和磷酸钾(3.12g)加入到反应瓶中，加入无水1,4-二氧六环(20mL)，氩气保护下加热至100℃搅拌10小时后反应完毕。反应液冷却后减压浓缩，经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。1-Morpholino-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid methyl ester (3.00g), tert-butyl carbamate (1.72g) , 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (425mg), palladium chloride (π-cinnamyl) dimer (190mg) and potassium phosphate (3.12g) were added to the reaction In the bottle, anhydrous 1,4-dioxane (20 mL) was added, and the mixture was heated to 100° C. under argon protection and stirred for 10 hours, and the reaction was completed. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
步骤2：5-溴-4-((叔丁氧基羰基)氨基)-1-吗啉代-6-氧代-1,6-二氢吡啶-3-羧酸甲酯的合成Step 2: Synthesis of methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate
Figure PCTCN2022078929-appb-000113
Figure PCTCN2022078929-appb-000113
将4-((叔丁氧基羰基)氨基)-1-吗啉代-6-氧代-1,6-二氢吡啶-3-羧酸甲酯(2.11g)加入到N,N-二甲基甲酰胺(30mL)中，室温搅拌下加入N-溴代丁二酰亚胺(1.17g)，室温搅拌2小时后反应完毕。将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用无水硫酸钠干燥，过滤，浓缩后制得标题化合物，直接用于下一步反应。Methyl 4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate (2.11 g) was added to N,N-dihydropyridine To methylformamide (30 mL), N-bromosuccinimide (1.17 g) was added under stirring at room temperature, and the reaction was completed after stirring at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, which was directly used in the next reaction.
步骤3：(3-溴-5-(甲氧基(甲基)氨基甲酰基)-1-吗啉代-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯的合成Step 3: tert-butyl (3-bromo-5-(methoxy(methyl)carbamoyl)-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate Synthesis of Esters
Figure PCTCN2022078929-appb-000114
Figure PCTCN2022078929-appb-000114
将5-溴-4-((叔丁氧基羰基)氨基)-1-吗啉代-6-氧代-1,6-二氢吡啶-3-羧酸甲酯(3.58g)加入到反应瓶中，加入二甲基亚砜(30mL)和乙腈(15mL)溶解，然后加入氢氧化钠水溶液(4.97g,20％w/w)，室温搅拌反应4小时，然后加入N,N-二异丙基乙胺(2.14g)，二甲羟胺盐酸盐(1.05g)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(4.69g)，室温下继续搅拌搅拌1小时后反应完毕。将反应液倒入水中，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去大部分溶剂后有大量白色固体析出，抽滤，滤饼干燥后得标题化合物。Methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylate (3.58 g) was added to the reaction Into the bottle, add dimethyl sulfoxide (30mL) and acetonitrile (15mL) to dissolve, then add sodium hydroxide aqueous solution (4.97g, 20%w/w), stir at room temperature for 4 hours, then add N,N-diiso Propylethylamine (2.14g), dimethylhydroxylamine hydrochloride (1.05g) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate (4.69 g) was stirred at room temperature for 1 hour and the reaction was completed. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. , the title compound was obtained after the filter cake was dried.
步骤4：(5-乙酰基-3-溴-1-吗啉代-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯的合成Step 4: Synthesis of tert-butyl (5-acetyl-3-bromo-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate
Figure PCTCN2022078929-appb-000115
Figure PCTCN2022078929-appb-000115
将(3-溴-5-(甲氧基(甲基)氨基甲酰基)-1-吗啉代-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯(2.20g)加入到无水四氢呋喃(85mL)中，氩气保护下缓慢加入甲基溴化镁的***溶液(3M,6.36mL)，继续搅拌0.5小时，然后移至室温搅拌5小时后反应完毕。向反应液中加入饱和氯化铵溶液将反应淬灭，然后倒入水中，用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)制得标题化合物。tert-butyl (3-bromo-5-(methoxy(methyl)carbamoyl)-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate ( 2.20 g) was added to anhydrous tetrahydrofuran (85 mL), and a solution of methylmagnesium bromide in ether (3M, 6.36 mL) was slowly added under the protection of argon, continued stirring for 0.5 hours, and then moved to room temperature and stirred for 5 hours after the reaction was completed. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, then poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, Purification by column chromatography (petroleum ether/ethyl acetate gradient) afforded the title compound.
步骤5：8-溴-6-吗啉代-1,6-萘啶-4,7(1H,6H)-二酮的合成Step 5: Synthesis of 8-bromo-6-morpholino-1,6-naphthyridine-4,7(1H,6H)-dione
Figure PCTCN2022078929-appb-000116
Figure PCTCN2022078929-appb-000116
将(5-乙酰基-3-溴-1-吗啉代-2-氧代-1,2-二氢吡啶-4-基)氨基甲酸叔丁酯(250mg)加入到反应瓶中，加入N,N-二甲基甲酰胺二甲基缩醛(3mL)，然后升温至110℃搅拌1小时。将反应液浓缩，然后用四氢呋喃溶解(4mL)，加入稀盐酸(1.49mL,4M)，所得反应液在50℃条件下反应2小时。将反应液冷却，加入浓氨水，调节体系pH至8-9，然后减压浓缩，加入乙酸乙酯，将不溶物过滤，滤液减压浓缩后经柱层析纯化(乙酸乙酯/甲醇梯度洗脱)制得标题化合物。(5-Acetyl-3-bromo-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamic acid tert-butyl ester (250mg) was added to the reaction flask, N , N-dimethylformamide dimethyl acetal (3 mL), then the temperature was raised to 110° C. and stirred for 1 hour. The reaction solution was concentrated, then dissolved in tetrahydrofuran (4 mL), diluted hydrochloric acid (1.49 mL, 4 M) was added, and the resulting reaction solution was reacted at 50° C. for 2 hours. The reaction solution was cooled, concentrated ammonia water was added, the pH of the system was adjusted to 8-9, then concentrated under reduced pressure, ethyl acetate was added, the insolubles were filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate/methanol gradient wash) removal) to obtain the title compound.
步骤6：8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-4,7(1H,6H)-二酮的合成Step 6: 8-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridine-4,7(1H,6H)- Synthesis of Diketones
Figure PCTCN2022078929-appb-000117
Figure PCTCN2022078929-appb-000117
将8-溴-6-吗啉代-1,6-萘啶-4,7(1H,6H)-二酮(32.0mg)，1-甲基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯(32.8mg)，1,1’-双(二苯基膦)二茂铁二氯化钯(7.12mg)，碳酸钾(40.7mg)加入到1,4-二氧六环(0.8mL)和水(0.2mL)的混合溶剂重，氩气保护下加热至100℃搅拌2小时后反应完毕。将反应液冷却后减压浓缩，经柱层析纯化(二氯甲烷/甲醇梯度洗脱)制得标题化合物。8-Bromo-6-morpholino-1,6-naphthyridine-4,7(1H,6H)-dione (32.0 mg), 1-methyl-1,2,3,6-tetrahydropyridine -4-boronic acid pinacol ester (32.8 mg), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (7.12 mg), potassium carbonate (40.7 mg) was added to 1,4-bis The mixed solvent of oxane (0.8 mL) and water (0.2 mL) was heated to 100° C. under argon protection and stirred for 2 hours, and the reaction was completed. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
步骤7：4-氯-8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-7(6H)-酮的合成Step 7: 4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridine-7(6H)- Synthesis of Ketones
Figure PCTCN2022078929-appb-000118
Figure PCTCN2022078929-appb-000118
将8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-4,7(1H,6H)-二酮(20.0mg)加入到反应瓶中，加入无水乙腈(0.5mL)溶解，加入三氯氧磷(17.9mg)和N,N-二异丙基乙胺(15.9mg)，加热至70℃搅拌1小时后反应完毕。将反应液冷却后倒入冰中，用饱和碳酸氢钠溶液调节pH至7-8，然后用乙酸乙酯萃取，有机相合并后用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后得标题化合物，直接用于下一步反应。8-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridine-4,7(1H,6H)-dione (20.0 mg) was added to the reaction flask, anhydrous acetonitrile (0.5 mL) was added to dissolve, phosphorus oxychloride (17.9 mg) and N,N-diisopropylethylamine (15.9 mg) were added, heated to 70°C and stirred The reaction was completed after 1 hour. The reaction solution was cooled, poured into ice, adjusted to pH 7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. The title compound was obtained after concentration, which was directly used in the next reaction.
步骤8：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-7(6H)-酮的合成Step 8: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-methyl-1,2,3,6 -Synthesis of -tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridin-7(6H)-one
Figure PCTCN2022078929-appb-000119
Figure PCTCN2022078929-appb-000119
将4-氯-8-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-吗啉代-1,6-萘啶-7(6H)-酮(10.0mg)，(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(10.5mg)加入到反应瓶中，加入二甲基亚砜(1mL)溶解，随后加入N,N-二异丙基乙胺(14.3mg)，气体保护下加热至100℃搅拌10小时后反应完毕。将反应液冷却，倒入水中，用乙酸乙酯萃取，有机相合并后用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)纯化制得标题化合物。4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthyridin-7(6H)-one ( 10.0mg), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine (10.5mg) was added to the reaction flask, dimethyl sulfoxide (1mL) was added to dissolve, Subsequently, N,N-diisopropylethylamine (14.3 mg) was added, and the mixture was heated to 100° C. and stirred for 10 hours under gas protection, and the reaction was completed. The reaction solution was cooled, poured into water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and then subjected to column chromatography (dichloromethane/methanol gradient) elution) to give the title compound.
1H NMR(400MHz,DMSO)δ9.27(s,1H),8.09-7.98(m,2H),7.65-7.59(m,1H),7.58-7.52(m,1H),7.34-7.29(m,1H),7.25(t,J＝54.3Hz,1H),5.69-5.63(m,1H),5.52-5.45(m,1H),5.08-5.01(m,1H),3.97-3.55(m,8H),1.62(d,J＝6.7Hz,3H). 1 H NMR (400MHz, DMSO) δ9.27(s, 1H), 8.09-7.98(m, 2H), 7.65-7.59(m, 1H), 7.58-7.52(m, 1H), 7.34-7.29(m, 1H), 7.25(t, J＝54.3Hz, 1H), 5.69-5.63(m, 1H), 5.52-5.45(m, 1H), 5.08-5.01(m, 1H), 3.97-3.55(m, 8H) ,1.62(d,J=6.7Hz,3H).
LC/MS(m/z,MH +):514.2 LC/MS (m/z, MH + ): 514.2
实施例19(R)-5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-(4-甲氧基-1-(氧杂环丁烷-3-基)哌啶-4-基)-1-甲基-1,8-萘啶-2(1H)-酮Example 19 (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(4-methoxy-1-(oxoheterocycle) Butan-3-yl)piperidin-4-yl)-1-methyl-1,8-naphthyridin-2(1H)-one
Figure PCTCN2022078929-appb-000120
Figure PCTCN2022078929-appb-000120
参考实施例4的合成方法，不同的是将步骤7中的N-乙酰基-4-哌啶酮替换为1-(氧杂环丁烷-3-基)哌啶-4-酮，同法制得标题化合物。With reference to the synthetic method of Example 4, the difference is that the N-acetyl-4-piperidinone in step 7 is replaced by 1-(oxetan-3-yl)piperidin-4-one, and the same method is used. The title compound was obtained.
1H NMR(400MHz,DMSO-d 6)δ8.33(s,1H),8.03(d,J＝5.8Hz,1H),7.70(d,J＝7.0Hz,1H),7.59(t,J＝7.3Hz,1H),7.53(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.25(t,J＝54.4Hz,1H),6.13(d,J＝5.9Hz,1H),5.14-5.00(m,1H),4.56(t,J＝6.4Hz,2H),4.46(t,J＝6.0Hz,2H),3.60(s,3H),3.48-3.38(m,1H),3.07(s,3H),2.58-2.52(m,2H),2.48-2.32(m,2H),2.20-1.95(m,4H),1.63(d,J＝6.8Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.03 (d, J=5.8 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.59 (t, J= 7.3Hz, 1H), 7.53(t, J＝6.9Hz, 1H), 7.30(t, J＝7.7Hz, 1H), 7.25(t, J＝54.4Hz, 1H), 6.13(d, J＝5.9Hz ,1H),5.14-5.00(m,1H),4.56(t,J＝6.4Hz,2H),4.46(t,J＝6.0Hz,2H),3.60(s,3H),3.48-3.38(m, 1H), 3.07(s, 3H), 2.58-2.52(m, 2H), 2.48-2.32(m, 2H), 2.20-1.95(m, 4H), 1.63(d, J=6.8Hz, 3H).
LC/MS(m/z,MH +):517.2. LC/MS (m/z, MH + ): 517.2.
实施例20(R)-1-(5-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-1-甲基-2-氧代-1,2-二氢-1,8-萘啶-3-基)-N,4-二甲基哌啶-4-甲酰胺Example 20 (R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1, 2-Dihydro-1,8-naphthyridin-3-yl)-N,4-dimethylpiperidine-4-carboxamide
Figure PCTCN2022078929-appb-000121
Figure PCTCN2022078929-appb-000121
参考实施例8的合成方法，不同的是将步骤4中的吗啉替换为N,4-二甲基哌啶-4-甲酰胺，同法制得标题化合物。Referring to the synthesis method of Example 8, the difference is that the morpholine in step 4 is replaced by N,4-dimethylpiperidine-4-carboxamide, and the title compound is obtained by the same method.
1H NMR(400MHz,DMSO-d 6)δ7.90(d,J＝5.7Hz,1H),7.68-7.61(m,1H),7.59-7.46(m,3H),7.41-7.10(m,3H),6.08(d,J＝5.9Hz,1H),5.12-4.95(m,1H),3.63(s,3H),3.46-3.33(m,2H),2.92-2.75(m,2H),2.63(d,J＝4.4Hz,3H),2.24-2.12(m,2H),1.63(d,J＝6.8Hz,3H),1.60-1.47(m,2H),1.15(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.90 (d, J=5.7Hz, 1H), 7.68-7.61 (m, 1H), 7.59-7.46 (m, 3H), 7.41-7.10 (m, 3H) ),6.08(d,J＝5.9Hz,1H),5.12-4.95(m,1H),3.63(s,3H),3.46-3.33(m,2H),2.92-2.75(m,2H),2.63( d, J=4.4Hz, 3H), 2.24-2.12(m, 2H), 1.63(d, J=6.8Hz, 3H), 1.60-1.47(m, 2H), 1.15(s, 3H).
LC/MS(m/z,MH +):502.2. LC/MS (m/z, MH + ): 502.2.
生物学活性及相关性质测试Biological activity and related properties testing
实验例1：本发明实施例对H358细胞增殖抑制活性的测定Experimental Example 1: Determination of the Proliferation Inhibitory Activity of H358 Cells in the Examples of the Present Invention
通过CellTiter-Glo发光法细胞活力检测试剂盒方法评估本发明的化合物对H358细胞增殖的影响。The effects of the compounds of the present invention on the proliferation of H358 cells were evaluated by the CellTiter-Glo luminescence cell viability detection kit method.
实验方法：experimental method:
H358细胞(ATCC，CRL-5807)在含有10％FBS(Gibco，10100147)和100U/mL青链霉素混合液(Gibco，15140163)的RPMI1640(Hyclone，SH30256.01)完全培养基中培养，当细胞生长达80-90％时，将细胞消化吹散后种植于96孔板(Corning，4515)，每孔3000细胞(180μl RPMI1640完全培养基)，然后将96孔板置于37℃、5％CO 2的培养箱中培养过夜。 H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30256.01) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163), when When the cell growth reached 80-90%, the cells were digested and blown away and seeded in a 96-well plate (Corning, 4515), with 3000 cells per well (180 μl RPMI1640 complete medium), and then the 96-well plate was placed at 37°C, 5% Incubate overnight in a CO 2 incubator.
过夜后使用排枪每孔加入20uL稀释后的化合物，将96孔板置于37℃、5％CO 2的培养箱中继续培养。7天后吸取100uL上清液，弃去，每孔加50μL
Figure PCTCN2022078929-appb-000122
3D Cell Viability Assay液体，室温450rpm震荡30min，待细胞完全裂解之后，酶标仪选择“Luminescence”读板。该实验中，未加细胞组(用1640培养基替代)作为100％抑制组，加细胞未加化合物组作为0％抑制组。 After overnight, 20 uL of the diluted compound was added to each well using a row gun, and the 96-well plate was placed in an incubator at 37°C and 5% CO 2 to continue the culture. After 7 days, 100uL supernatant was aspirated, discarded, and 50μL was added to each well
Figure PCTCN2022078929-appb-000122
The 3D Cell Viability Assay liquid was shaken at 450rpm for 30min at room temperature. After the cells were completely lysed, the microplate reader selected "Luminescence" to read the plate. In this experiment, the cell-free group (replaced with 1640 medium) was regarded as a 100% inhibition group, and the cell-added and no-compound group was regarded as a 0% inhibition group.
化合物对H358细胞增殖抑制的百分比可以用以下公式计算：The percent inhibition of H358 cell proliferation by a compound can be calculated using the following formula:
抑制百分比＝100*(0％抑制组信号值-待测化合物特定浓度下信号值)/(0％抑制组信号值-100％抑制组信号值)。Inhibition percentage=100*(signal value in 0% inhibition group-signal value at a specific concentration of the compound to be tested)/(signal value in 0% inhibition group-signal value in 100% inhibition group).
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最小抑制百分比，Top为最大抑制百分比，slope factor为曲线斜率系数。where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and slope factor is the slope coefficient of the curve.
试验结果：在本实验条件下，本发明实施例对H358细胞具有良好的增殖抑制活性。测试化合物相应的活性测试结果具体见表1。Test results: Under the experimental conditions, the examples of the present invention have good proliferation inhibitory activity on H358 cells. The corresponding activity test results of the test compounds are shown in Table 1.
表1 本发明实施例对H358细胞增殖抑制活性测试结果Table 1 Test results of the embodiment of the present invention on H358 cell proliferation inhibitory activity
实施例Example IC 50(nM) IC50 (nM)
11 17.317.3
22 111.3111.3
33 31.231.2
44 80.280.2
55 52.552.5
77 195.3195.3
99 162.2162.2
1717 67.067.0
1818 65.765.7
实验例2 本发明化合物对H358细胞p-ERK通路的影响Experimental Example 2 Effects of the compounds of the present invention on the p-ERK pathway of H358 cells
通过Advanced phospho-ERK(Thr202/Tyr204)cellular kit试剂盒方法评估本发明的化合物对H358细胞p-ERK通路的影响。The effects of the compounds of the present invention on the p-ERK pathway of H358 cells were evaluated by the Advanced phospho-ERK (Thr202/Tyr204) cellular kit method.
实验方法概述如下：The experimental method is outlined as follows:
H358细胞(ATCC，CRL-5807)在含有10％FBS(Gibco，10100147)和100U/mL青链霉素混合液(Gibco，15140163)的RPMI1640(ThermoFisher，A1049101)完全培养基中培养，当细胞在培养容器中覆盖率达80-90％时，将细胞吹散后种植于96孔板(Corning，3599)，每孔50000细胞(90μLRPMI1640完全培养基)，静置5分钟之后放于37℃、5％CO 2的培养箱中培养6h，更换为无血清的RPMI1640饥饿过夜。 H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (ThermoFisher, A1049101) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163) When the coverage rate in the culture vessel reaches 80-90%, the cells are blown off and then planted in a 96-well plate (Corning, 3599), with 50,000 cells per well (90 μL PPMI1640 complete medium), and placed at 37°C, 5 minutes after standing for 5 minutes. Incubate for 6 h in a %CO 2 incubator, and replace with serum-free RPMI1640 starvation overnight.
过夜后用排枪每孔加入10μL稀释后的化合物，将96孔板置于37℃、5％CO 2的培养箱中培养1h。倾倒上清，PBS洗一遍，每孔加50μL裂解液(Advanced phospho-ERK(Thr202/Tyr204)cellular kit，64AERPEH)，室温450rpm震荡1h，待细胞完全裂解之后，取16μL上清加入到384孔(PE,6007299)，加入混合好的抗体(d2/Eu＝1:1),室温孵育4h，酶标仪选择HTRF读板，Ratio＝Signal 665nm/Signal 620nm x 10  4。该实验中，未加细胞组(用1640培养基替代)作为100％抑制组，加细胞但是未加化合物组作为0％抑制组。 After overnight, 10 μL of the diluted compound was added to each well with a spray gun, and the 96-well plate was placed in an incubator at 37°C and 5% CO 2 for 1 h. Pour the supernatant, wash it with PBS, add 50 μL of lysis solution (Advanced phospho-ERK (Thr202/Tyr204) cellular kit, 64AERPEH) to each well, shake at 450 rpm at room temperature for 1 h, and after the cells are completely lysed, take 16 μL of supernatant and add it to 384 wells ( PE, 6007299), add the mixed antibody (d2/Eu=1:1), incubate for 4 h at room temperature, select HTRF plate reader with microplate reader, Ratio=Signal 665nm/Signal 620nm x 10 4 . In this experiment, the group without cells (replaced with 1640 medium) was regarded as a 100% inhibition group, and the group with cells but no compound was regarded as a 0% inhibition group.
本发明化合物对H358细胞p-ERK通路抑制的百分比可以用以下公式计算：The percentage inhibition of the p-ERK pathway in H358 cells by the compounds of the present invention can be calculated by the following formula:
抑制百分比＝100*(0％抑制组信号值-待测化合物特定浓度下信号值)/(0％抑制组信号值-100％抑制组信号值)。Inhibition percentage=100*(signal value in 0% inhibition group-signal value at a specific concentration of the compound to be tested)/(signal value in 0% inhibition group-signal value in 100% inhibition group).
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算： Compound IC50 values were calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor)) Y=Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最小抑制百分比，Top为最大抑制百分比，slope factor为曲线斜率系数。使用默认拟合曲线来拟合S形曲线斜率以确定IC 50值。 where Y is the percentage of inhibition, X is the logarithm of the concentration of the test compound, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and slope factor is the slope coefficient of the curve. The default fit curve was used to fit the slope of the sigmoid curve to determine IC50 values.
表2 本发明化合物对p-ERK抑制测试结果Table 2 Compounds of the present invention inhibit p-ERK test results
实施例Example IC 50(nM) IC50 (nM)
11 41.941.9
22 81.381.3
33 80.280.2
55 141.8141.8
88 206.3206.3
1010 181.7181.7
1414 45.045.0
1616 137.0137.0
1717 42.942.9
实验例3：本发明实施例对SOS1与KRAS G12D结合抑制活性的测定Experimental Example 3: Determination of the inhibitory activity of SOS1 binding to KRAS G12D in the embodiment of the present invention
使用KRAS-G12D/SOS1BINDING ASSAY KITS(Cisbio，货号：63ADK000CB21PEH)评估本发明的化合物对KRASG12D::SOS1结合抑制的影响。The effect of compounds of the invention on inhibition of KRASG12D::SOS1 binding was assessed using KRAS-G12D/SOS1 BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB21PEH).
实验方法：experimental method:
用100％DMSO将阳性对照BAY-293和待测化合物(10mM储液)稀释5倍至0.1mM，在384孔稀释板中以1:3进行等比稀释11个浓度。使用Echo转移0.1μL梯度稀释的化合物溶液到384孔板中，每个化合物做2个复孔，1000rpm/min，离心1min。转移5μL 4X KRAS G12D(终浓度1X)及GTP溶液(终浓度10μΜ，sigma，货号：V900868)到384反应板中，1000rpm/min，离心1min，25℃孵育15min。转移5μL 4X SOS1溶液(终浓度1X)到384反应板中，1000rpm/min，离心1min，25℃孵育45min。BAY-293化合物终浓度为10，3.33，1.11，0.37，0.12，0.04，0.014，0.0046，0.0015，0.0005，0.00017，0μM。待测化合物终浓度10，3.33，1.11，0.37，0.12，0.04，0.014，0.0046，0.0015，0.0005，0.00017，0μM。DMSO终浓度均为0.5％。转移10μL 2X检测试剂溶液到384反应板中，1000rpm/min，离心1min，4℃孵育180min。使用Envision多功能酶标仪读取激发波长665nm和发射波长615nm。665/615Ratio信号强度用于表征酶的活性程度。Positive control BAY-293 and test compounds (10 mM stock) were diluted 5-fold to 0.1 mM in 100% DMSO and 11 equal dilutions were performed 1:3 in 384-well dilution plates. Use Echo to transfer 0.1 μL of serially diluted compound solution to 384-well plate, make 2 duplicate wells for each compound, 1000 rpm/min, and centrifuge for 1 min. Transfer 5 μL of 4X KRAS G12D (final concentration 1X) and GTP solution (final concentration 10 μM, sigma, Cat. No.: V900868) to a 384 reaction plate, 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 15 min. Transfer 5 μL of 4X SOS1 solution (final concentration 1X) to 384 reaction plate, 1000rpm/min, centrifuge for 1min, and incubate at 25°C for 45min. The final concentrations of BAY-293 compound were 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, 0.00017, 0 μM. The final concentration of the test compound was 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, 0.00017, 0 μM. The final concentration of DMSO was 0.5%. Transfer 10 μL of 2X detection reagent solution to the 384 reaction plate, centrifuge at 1000 rpm/min for 1 min, and incubate at 4°C for 180 min. Excitation wavelength 665 nm and emission wavelength 615 nm were read using Envision multi-plate reader. The 665/615Ratio signal intensity was used to characterize the degree of enzyme activity.
数据处理方法：通过Graphpad Prism 8非线性回归方程拟合化合物IC 50： Data processing method: Fitting compound IC50 by Graphpad Prism 8 nonlinear regression equation:
阴性对照：DMSONegative control: DMSO
阳性对照：10μM BAY-293Positive control: 10 μM BAY-293
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)： The IC50 ( 50% inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope)) Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
X:化合物浓度log值X: compound concentration log value
Y:665/615 RatioY:665/615 Ratio
试验结果：在本实验条件下，测试化合物对KRASG12D::SOS1结合具有良好的抑制活性。测试化合物相应的活性测试结果具体见表3。Test results: Under the experimental conditions, the test compounds have good inhibitory activity on the binding of KRASG12D::SOS1. The corresponding activity test results of the test compounds are shown in Table 3.
表3 本专利实施例对KRAS G12D::SOS1结合的抑制活性测试结果Table 3 Inhibitory activity test results of this patent example on the binding of KRAS G12D::SOS1
实施例Example IC 50(nM) IC50 (nM)
11 4.974.97
55 5.165.16
1818 8.938.93

Claims (19)

  1. 一种式(I)所示化合物或其药学上可接受的盐，A compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022078929-appb-100001
    Figure PCTCN2022078929-appb-100001
    其中，环B选自wherein Ring B is selected from
    Figure PCTCN2022078929-appb-100002
    Figure PCTCN2022078929-appb-100002
    R 1选自H、卤素、羟基、氰基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6氘代烷基、-O-C 1- 6烷基或C 3-6环烷基； R 1 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl;
    R 2选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 4-10环烯基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 4-10环烯基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代； R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 6-10 aryl, 3- 10-membered heterocyclyl or 5-10-membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 ring alkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b and/or R 2c ;
    R 2b选自-OR 2c、-N(R 2c) 2、-NHR 2c、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)N(R 2c) 2、-C(O)NHR 2c、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-S(O) 2NHR 2c、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c； R 2b is selected from -OR 2c , -N(R 2c ) 2 , -NHR 2c , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)N(R 2c ) 2 , - C(O)NHR 2c , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -S(O) 2 NHR 2c , -NHC(O ) R 2c or -N(C 1-4 alkyl)C(O)R 2c ;
    R 2c独立地选自C 1- 6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1- 6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2d取代； R 2c is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl , 3-10 membered heterocyclyl or 5-10 membered heteroaryl, the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d ;
    R 2d选自卤素、羟基、氰基、氨基、-C(O)R 2f、-C(O)N(R 2f) 2、-C(O)OR 2f、-S(O) 2R 2f、-S(O) 2N(R 2f) 2、-N(C 1-4烷基)R 2f、-NHC(O)R 2f、-N(C 1-4烷基)C(O)R 2f、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2f取代； R 2d is selected from halogen, hydroxyl, cyano, amino, -C(O)R 2f , -C(O)N(R 2f ) 2 , -C(O)OR 2f , -S(O) 2 R 2f , -S(O) 2 N(R 2f ) 2 , -N(C 1-4 alkyl)R 2f , -NHC(O)R 2f , -N(C 1-4 alkyl)C(O)R 2f , C 3-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, C 6-10 aryl, 3 -10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2f ;
    R 2f独立地选自H或C 1- 6烷基； R 2f is independently selected from H or C 1-6 alkyl ;
    R 3、R 4独立地选自H、氘、C 1-3氘代烷基、C 1- 6烷基或C 1-6卤代烷基； R 3 and R 4 are independently selected from H, deuterium, C 1-3 deuterated alkyl, C 1-6 alkyl or C 1-6 haloalkyl ;
    R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、-C(O)R 5b、-C(O)N(R 5b) 2、-C(O)OR 5b、
    Figure PCTCN2022078929-appb-100003
    3-8元杂环基或5-10元杂芳基，所述C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代；     R 5 is independently selected from SF 5 , nitro, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 ring Alkyl, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 , -C(O)R 5b , - C(O)N(R 5b ) 2 , -C(O)OR 5b ,
    Figure PCTCN2022078929-appb-100003
    3-8 -membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -OC 3-6 cycloalkyl group, -O-(3-8 membered heterocyclyl), -S(O) 2 -C 1-4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a ;
    R 5a独立地选自卤素、羟基、氰基或氨基； R 5a is independently selected from halogen, hydroxy, cyano or amino;
    R 5b独立地选自H或C 1- 6烷基； R 5b is independently selected from H or C 1-6 alkyl ;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    R 6选自H、卤素、羟基、氰基、氨基、C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基，所述C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 6a取代； R 6 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl , -O- (3-8-membered heterocyclic group), 3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group , -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted by R 6a ;
    R 6a选自卤素、羟基、氰基或氨基； R 6a is selected from halogen, hydroxy, cyano or amino;
    R 7选自H、卤素、羟基、氰基、氨基、C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基，所述C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 7a取代； R 7 is selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl , -O- (3-8-membered heterocyclic group), 3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group , -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted by R 7a ;
    R 7a选自卤素、羟基、氰基、氨基、C 1- 6烷基或C 1- 6卤代烷基； R 7a is selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 haloalkyl ;
    环A选自C 6-10芳基、5-10元杂环基或5-10元杂芳基。 Ring A is selected from C 6-10 aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl.
  2. 根据权利要求1所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 1选自H、卤素、C 1-6烷基或C 1-6氘代烷基；或者 The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, is characterized in that: R 1 is selected from H, halogen, C 1-6 alkyl or C 1-6 deuterated alkyl; or
    R 1选自H、卤素、C 1-3烷基或C 1-3氘代烷基；或者 R 1 is selected from H, halogen, C 1-3 alkyl or C 1-3 deuterated alkyl; or
    R 1选自H、卤素、CH 3或CD 3。 R 1 is selected from H, halogen, CH 3 or CD 3 .
  3. 根据权利要求1或2所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 2选自C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代；或者 The compound represented by the formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6- 10 -aryl, 3-10-membered heterocyclic or 5-10-membered heteroaryl, the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocycle or 5-10 membered heteroaryl optionally substituted with R 2b and/or R 2c ; or
    R 2选自C 1-6烷基、C 3-10环烷基或3-10元杂环基，所述C 1-6烷基、C 3-10环烷基或3-10元杂环基任选地被R 2b和/或R 2c取代；或者 R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic group, said C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic ring group is optionally substituted with R 2b and/or R 2c ; or
    R 2选自C 3-10环烷基或3-10元杂环基，所述C 3-10环烷基或3-10元杂环基任选地被R 2b和/或R 2c取代。 R 2 is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 2b and/or R 2c .
  4. 根据权利要求1-3任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c或-C(O)NHR 2c；或者 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxyl , cyano, amino, -C(O)R 2c or -C(O)NHR 2c ; or
    R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基或-C(O)R 2c。 R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino or -C(O)R 2c .
  5. 根据权利要求1-4任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 2c独立地选自C 1- 6烷基、3-10元杂环基或5-10元杂芳基，所述C 1- 6烷基、3-10元杂环基或5-10元杂芳基任选地被R 2d取代；或者 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that: R 2c is independently selected from C 1-6 alkyl, 3-10 - membered heterocycle or 5-10 membered heteroaryl, the C 1-6 alkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d ; or
    R 2c独立地选自C 1- 6烷基或4-9元杂环基，所述C 1- 6烷基或4-9元杂环基任选地被R 2d取代；或者 R 2c is independently selected from C 1-6 alkyl or 4-9 membered heterocyclyl optionally substituted with R 2d ; or
    R 2c独立地选自C 1- 6烷基，所述C 1- 6烷基任选地被R 2d取代。 R 2c is independently selected from C 1-6 alkyl optionally substituted with R 2d .
  6. 根据权利要求1-5任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 3、R 4独立地选自H、氘、C 1-3氘代烷基或C 1- 6烷基；或者 The compound represented by formula (I) according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, is characterized in that: R 3 , R 4 are independently selected from H, deuterium, C 1-3 deuterated alkyl or C 1-6 alkyl ; or
    R 3选自H或氘，R 4选自CH 3或CD 3。 R 3 is selected from H or deuterium, and R 4 is selected from CH 3 or CD 3 .
  7. 根据权利要求1-6任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
    Figure PCTCN2022078929-appb-100004
    3-8元杂环基或5-10元杂芳基，所述C 1- 6烷基、C 3-6环烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、3-8元杂环基或5-10元杂芳基任选地被R 5a取代；或者     The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R 5 is independently selected from SF 5 , nitro, halogen, hydroxyl, cyano, Amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl , -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
    Figure PCTCN2022078929-appb-100004
    3-8-membered heterocyclic group or 5-10-membered heteroaryl group, the C 1-6 alkyl group, C 3-6 cycloalkyl group, -OC 1-6 alkyl group, -S(O) 2 -C 1 -4 alkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R5a ; or
    R 5独立地选自SF 5、硝基、卤素、羟基、氰基、氨基、C 1- 6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2、
    Figure PCTCN2022078929-appb-100005
    或3-8元杂环基，所述C 1- 6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或3-8元杂环基任选地被R 5a取代；或者     R 5 is independently selected from SF 5 , nitro, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, -OC 1-6 alkyl , -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 ,
    Figure PCTCN2022078929-appb-100005
    or 3-8 membered heterocyclyl, the C 1-6 alkyl, -OC 1-6 alkyl , -S(O) 2 -C 1-4 alkyl or 3-8 membered heterocyclyl is optionally replaced by R 5a ; or
    R 5独立地选自SF 5、硝基、氰基、卤素、C 1- 6烷基、-S(O) 2-C 1-4烷基、-P(O)(R 5b) 2或
    Figure PCTCN2022078929-appb-100006
    所述C 1- 6烷基或-S(O) 2-C 1-4烷基任选地被R 5a取代。     R 5 is independently selected from SF 5 , nitro, cyano, halogen, C 1-6 alkyl, -S(O) 2 -C 1-4 alkyl, -P(O)(R 5b ) 2 or
    Figure PCTCN2022078929-appb-100006
    Said C 1-6 alkyl or -S(O) 2 -C 1-4 alkyl is optionally substituted with R 5a .
  8. 根据权利要求1-7任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 7选自H、C 1- 6烷基、C 3-6环烷基、4-7元杂环基或5-6元杂芳基，所述C 1- 6烷基、C 3-6环烷基、4-7元杂环基或5-6元杂芳基任选地被R 7a取代。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that: R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkane base, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 3-6 cycloalkyl , 4-7 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 7a .
  9. 根据权利要求1-8任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 6选自H。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R 6 is selected from H.
  10. 根据权利要求1-9任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：n选自0、1或2。The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein n is selected from 0, 1 or 2.
  11. 根据权利要求1-10任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：环A选自C 6-10芳基、9-10元杂环基或9-10元杂芳基。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein ring A is selected from C 6-10 aryl, 9-10-membered heterocyclic group or 9-10 membered heteroaryl.
  12. 根据权利要求11所述式(I)所示化合物或其药学上可接受的盐，其特征在于：环A选自
    Figure PCTCN2022078929-appb-100007
    The compound represented by formula (I) according to claim 11 or a pharmaceutically acceptable salt thereof, characterized in that: ring A is selected from
    Figure PCTCN2022078929-appb-100007
  13. 根据权利要求1-12任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(IIa)所示化合物或其药学上可接受的盐，The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula ( IIa) a compound or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022078929-appb-100008
    Figure PCTCN2022078929-appb-100008
    其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、R 7、n如权利要求1-12任一项所述定义。 Wherein, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined in any one of claims 1-12.
  14. 根据权利要求1-12任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(IV)所示化合物或其药学上可接受的盐，The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula ( IV) the compound shown or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022078929-appb-100009
    Figure PCTCN2022078929-appb-100009
    Figure PCTCN2022078929-appb-100010
    Figure PCTCN2022078929-appb-100010
    其中，环A、R 1、R 2、R 3、R 4、R 5、R 6、R 7、n如权利要求1-12任一项所述定义。 Wherein, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined in any one of claims 1-12.
  15. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or their pharmaceutically acceptable salts acceptable salt,
    Figure PCTCN2022078929-appb-100011
    Figure PCTCN2022078929-appb-100011
    Figure PCTCN2022078929-appb-100012
    Figure PCTCN2022078929-appb-100012
    Figure PCTCN2022078929-appb-100013
    Figure PCTCN2022078929-appb-100013
  16. 一种药物组合物，所述药物组合物包含权利要求1-15任一项式(I)所示化合物或其药学上可接受的盐，以及药学上可接受的辅料。A pharmaceutical composition comprising a compound represented by formula (I) in any one of claims 1-15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  17. 权利要求1-15任一项式(I)所示化合物或其药学上可接受的盐，或权利要求16所述药物组合物在制备预防或者治疗与SOS1相关疾病的药物中的用途。Use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in any one of claims 1-15, or the pharmaceutical composition of claim 16 in the preparation of a medicament for preventing or treating diseases related to SOS1.
  18. 一种预防或治疗SOS1相关疾病的方法，所述方法包括给以患者治疗上有效剂量的包含权利要求1-15任一项式(I)所示化合物或其药学上可接受的盐，或权利要求16所述药物组合物。A method for the prevention or treatment of SOS1 related diseases, the method comprises a compound or a pharmaceutically acceptable salt thereof shown in any one of the formula (I) of claim 1-15 containing an effective dose for the treatment of the patient, or a right The pharmaceutical composition of claim 16.
  19. 根据权利要求17所述的用途或权利要求18所述的方法，其特征在于：所述SOS1相关疾病选自癌症。The use of claim 17 or the method of claim 18, wherein the SOS1-related disease is selected from cancer.
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