WO2022194066A1 - Kras g12d inhibitor and applications thereof in medicine - Google Patents

Kras g12d inhibitor and applications thereof in medicine Download PDF

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Publication number
WO2022194066A1
WO2022194066A1 PCT/CN2022/080545 CN2022080545W WO2022194066A1 WO 2022194066 A1 WO2022194066 A1 WO 2022194066A1 CN 2022080545 W CN2022080545 W CN 2022080545W WO 2022194066 A1 WO2022194066 A1 WO 2022194066A1
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Prior art keywords
compound
alkylene
cycloalkyl
alkyl
substituted
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PCT/CN2022/080545
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French (fr)
Chinese (zh)
Inventor
吴颢
陈小平
路渊
徐人奇
黄传龙
何将旗
王维
李波燕
湛波
张运来
王冬
王国建
赵志昌
张洪波
周晓
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202280018826.3A priority Critical patent/CN116964058A/en
Publication of WO2022194066A1 publication Critical patent/WO2022194066A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound having KRAS inhibitory activity, especially KRAS G12D inhibitory activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
  • RAS is the gene with the highest mutation rate in human tumors, about 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations.
  • the most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which codon 12 is the most common mutation, such as G12C, G12D or G12V.
  • KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; MIRATI is leading the way in the development of G12D inhibitors (WO2021041671A1).
  • the present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
  • Ring A is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl
  • L 1 is selected from -O-(CH 2 ) 0-3 , -S-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene;
  • L 2 is selected from a bond or a C 1-3 alkylene group
  • R 1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14-membered heterocyclyl, C 6-14 aryl and 5-14-membered heteroaryl, the C 3-14 cycloalkyl, 3-14-membered heteroaryl Cyclic, C 6-14 aryl and 5-14 membered heteroaryl are optionally further 1-4 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heterocortyl, aryl and heteroaryl Substituents are substituted, and the R a is independently selected from H or C 1-6 alkyl;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
  • R4 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with one or more R3a ;
  • R 5 is selected from H, amino, substituted amino, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
  • R 6 is selected from H, halogen or C 1-6 alkyl
  • n is selected from 0, 1, 2, 3 or 4.
  • ring A in formula (I) is selected from C 3-6 cycloalkyl; preferably cyclopropyl;
  • L 1 in formula (I) is selected from -O-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene; preferably -O- (CH 2 ) 0-3 ;
  • L in formula (I) is selected from C 1-3 alkylene
  • R 1 in formula (I) is selected from H, halogen or alkyl; preferably H;
  • R 2 in formula (I) is selected from C 3-14 cycloalkyl or 3-14 membered heterocyclyl; the C 3-14 cycloalkyl or 3-14 membered heterocyclyl is optionally is further selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heteroalkyi, aryl and heteroaryl substituents, the R a is independently selected from H or C 1-6 alkyl;
  • R in formula (I) is selected from
  • R 3 in formula (I) is selected from H, halogen or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
  • R4 in formula (I) is selected from aryl or heteroaryl, optionally further substituted with one or more R3a ; said R3a is independently selected from H, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted Substituted C 2-6 alkynyl;
  • R in formula (I) is selected from
  • R 5 in formula (I) is selected from H, C 1-6 alkyl, cyclopropyl, halogen, C 1-6 haloalkyl, C 2-6 alkenyl.
  • R 6 in formula (I) is selected from H.
  • the compound of formula (I) is selected from formula (IA):
  • L 1 is selected from -O-(CH 2 ) 0-3 ;
  • L 2 is selected from C 1-3 alkylene
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same as those shown in formula (I).
  • the compound represented by formula (I) is selected from:
  • the present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
  • the present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
  • the present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
  • the application is in the preparation of a drug for treating and/or preventing cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • “ 1-8 " in “base 1-8 alkyl” refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.
  • C 1-3 alkylene refers to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring.
  • the aryl group is a 6- to 14-membered monocyclic or polycyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. system, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively Quaternized.
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • the heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.
  • heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14 membered benzo-fused
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • substitution of compounds of formula (I) with heavier isotopes may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.
  • some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration.
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
  • the first step introduce substituents through substitution reaction under basic conditions such as cesium carbonate to obtain compound 1-2, wherein L can be O, S or NL a ;
  • Step II Under the action of a Pa catalyst such as X-Phos Pd G2, a substituent R 4 is introduced through a Suzuki coupling reaction to obtain compound I-3;
  • Step III Compound I-3 is deprotected under acidic conditions such as trifluoroacetic acid to obtain the target product I.
  • CDI carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO triethylenediamine
  • DIEA N,N-diisopropylethylamine
  • Dioxane Dioxane
  • TBS-Cl tert-butyldimethylsilyl chloride
  • NBS N-bromosuccinimide
  • Tf 2 O trifluoromethanesulfonic anhydride
  • HOAc glacial acetic acid
  • POCl 3 phosphorus oxychloride
  • TFA trifluoroacetic acid
  • LiAlH 4 lithium aluminum hydride
  • TBAF tetrabutylammonium fluoride
  • LiHMDS Lithium Bistrimethylsilylamide
  • X-Phos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)]palladium(II);
  • Pre-HPLC preparation of high performance liquid phase
  • 2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na 2 SO 4 (503.4 g) were dissolved in water (560 mL) and then heated to 55°C.
  • the resulting mixture was stirred at 90°C for 3 hours and a yellow precipitate formed.
  • the mixture was cooled to room temperature.
  • the solid was collected by filtration, rinsed with water, and air-dried to give the product as a tan solid (47 g, 99% yield), compound M1-3.
  • the compound ethynyltriisopropylsilane (20 g) was dissolved in acetone (500 mL), NBS (21.08 g) was added, and silver nitrate (1.86 g) was added, and the reaction was carried out at room temperature for 12 hours.
  • the reaction solution was concentrated, water (500 mL) was added thereto, extracted with petroleum ether (3 ⁇ 500 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound M3-1 (28 g, yield 93%).
  • Example 1 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-( Synthesis of (S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)naphthalen-2-ol
  • compound 1-2 (129.16 mg) was added to compound M1 (300.00 mg), DABCO (14.27 mg), Cs 2 CO 3 (621.57 mg) in DMF (6.00 mL) solution, and the reaction was stirred at room temperature for 14 h.
  • Example 65 Compound 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R, Synthesis of 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-5-ethynylnaphthalen-2-ol
  • intermediate M2 500 mg was dissolved in DMF (5 mL), NaH (340 mg) was added in portions, and the mixture was stirred at room temperature for 30 min.
  • the above solution was added dropwise to a solution of intermediate M1 (1.01 g, 2.15 mmol) in DMF (5 mL) at 0° C., and stirred at room temperature for 2-4 h after the addition.
  • the reaction solution was poured into 20 mL of saturated ammonium chloride, and EA (20 mL) was added for extraction twice. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated.
  • ESI-MS m/z 616 [M+H] + .
  • Two KRas-G12D mutant tumor cells AGS ( CRL- 1739TM ) or Panc 04.03 ( CRL-2555 TM ) was plated in a 96-well plate at a cell density of 5 ⁇ 10 4 /well, and cultured overnight in a cell incubator. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and cultured.
  • the lysis buffer (50 ⁇ L) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit was used to extract the protein lysate of each treated cell sample in the 96-well plate, and the protein lysate was quantified by BCA method.
  • lysis buffer to dilute the protein sample concentration to 0.1 ⁇ g/ ⁇ L.
  • p-ERK% value ((2 ⁇ phosphorylation signal value)/(phosphorylation signal value+total signal value)) ⁇ 100
  • Inhibition percentage (Maximum value - Measured value) / (Maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-G12D mutant tumor cells AGS ( CRL-1739 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and cultured in a cell incubator overnight. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 ⁇ L of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (Maximum value - Measured value) / (Maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-WT tumor cells NCI-H1975 ( CRL-5908 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 ⁇ L of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (Maximum value-Measured value)/(Maximum value-Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • the compounds of the present invention have good selectivity. And the selectivity between compounds 2/50 and 65/51 is higher than 10 times, indicating that R 3 in general formula (I) is optionally substituted by 1-2 R 3a When X is alkynyl or halogen, it has better selectivity.

Abstract

Provided are a compound having KRAS G12D modulating activity, a preparation method for same, and a pharmaceutical composition comprising same.

Description

KRAS G12D抑制剂及其在医药上的应用KRAS G12D inhibitor and its application in medicine 技术领域technical field
本发明涉及一种新型化合物，其具有KRAS抑制活性，特别是KRAS G12D抑制活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。The present invention relates to a novel compound having KRAS inhibitory activity, especially KRAS G12D inhibitory activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
背景技术Background technique
临床数据显示，RAS是人类肿瘤中发生突变率最高的基因，所有肿瘤中，约20-30％有RAS突变，大约98％的胰腺癌，52％的结肠癌,43％的多发性骨髓瘤，及32％的肺腺癌中存在RAS基因突变。RAS最常见的突变方式是点突变，经常发生在12、13、61密码子，其中又以第12位密码子突变最常见，例如G12C、G12D或G12V。Clinical data show that RAS is the gene with the highest mutation rate in human tumors, about 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which codon 12 is the most common mutation, such as G12C, G12D or G12V.
目前针对KRAS突变的药物研发是当前新药研究热点之一。KRAS G12C抑制剂AMG510(WO2018217651A1)和MRTX849(WO2019099524A1)已进入后期临床阶段；而MIRATI在G12D抑制剂(WO2021041671A1)研发上进展领先。Currently, drug development targeting KRAS mutations is one of the hotspots in current new drug research. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; MIRATI is leading the way in the development of G12D inhibitors (WO2021041671A1).
发明内容SUMMARY OF THE INVENTION
本发明提供一种通式(I)所示的化合物、其互变异构体、氘代物或药用盐：The present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
Figure PCTCN2022080545-appb-000001
Figure PCTCN2022080545-appb-000001
其中，in,
环A选自C 3-6环烷基或3-6元杂环基； Ring A is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
L 1选自-O-(CH 2) 0-3、-S-(CH 2) 0-3、-NH-(CH 2) 0-3或C 1-3亚烷基； L 1 is selected from -O-(CH 2 ) 0-3 , -S-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene;
L 2选自键或C 1-3亚烷基； L 2 is selected from a bond or a C 1-3 alkylene group;
R 1独立地选自H、卤素、烷基、烷氧基、卤代烷基、羟基和羟烷基； R 1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
R 2选自C 3-14环烷基、3-14元杂环基、C 6-14芳基和5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基和5-14元杂芳基任选进一步被1-4个选自卤素、C 1-6烷基、C 1-6 烷氧基、C 1-6卤代烷基、氰基、氨基、硝基、羟基、C 1-6羟烷基、-C 0-3亚烷基-N(R a) 2、环烷基、杂坏基、芳基和杂芳基的取代基所取代，所述R a独立地选自H或C 1-6烷基； R 2 is selected from C 3-14 cycloalkyl, 3-14-membered heterocyclyl, C 6-14 aryl and 5-14-membered heteroaryl, the C 3-14 cycloalkyl, 3-14-membered heteroaryl Cyclic, C 6-14 aryl and 5-14 membered heteroaryl are optionally further 1-4 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heterocortyl, aryl and heteroaryl Substituents are substituted, and the R a is independently selected from H or C 1-6 alkyl;
R 3选自H、卤素、C 1-6烷基或-OR 2a，所述R 2a选自C 1-6烷基、C 3-8环烷基或卤代烷基； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
R 4选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 3a取代；R 3a独立地选自H、＝O、＝S、酰基、羟基、氰基、卤素、硝基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、-C 0-3亚烷基-OR b、-OC(＝O)C 1-6烷基、-C 0-3亚烷基-SR b、-C 0-3亚烷基-N(R b) 2、-C 0-3亚烷基-S(＝O)R b、-C 0-3亚烷基-S(＝O) 2R b、-C 0-3亚烷基-SR b、-C 0-3亚烷基-S(R b) 5、-C 0-3亚烷基-C(＝O)R b、-C 0-3亚烷基-C(＝O)OR b、-C 0-3亚烷基-C(＝O)N(R b) 2、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的-C 0-3亚烷基-C 3-14环烷基、取代或未取代的-C 0-3亚烷基-(3-14元杂环烷基)、取代或未取代的-C 0-3亚烷基-C 6-14芳基或取代或未取代的-C 0-3亚烷基-(5-14元杂芳基)，每个R b独立地为H、C 1-6烷基、C 3-6环烷基或C 1-6卤代烷基； R4 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with one or more R3a ; R3a independently selected from H, =O, =S, acyl, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -C 0- 3 alkylene-OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene-SR b , -C 0-3 alkylene-N(R b ) 2 , - C 0-3 alkylene-S(=O)R b , -C 0-3 alkylene-S(=O) 2 R b , -C 0-3 alkylene-SR b , -C 0- 3 alkylene-S(R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0- 3 alkylene-C(=O)N(R b ) 2 , substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted -C 0- 3 alkylene-C 3-14 cycloalkyl, substituted or unsubstituted-C 0-3 alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene base-C 6-14 aryl or substituted or unsubstituted-C 0-3 alkylene-(5-14-membered heteroaryl ) , each R is independently H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
R 5选自H、氨基、取代的氨基、C 1-6烷基、取代的C 1-6烷基、卤素、C 2-6烯基、取代的C 2-6烯基、C 3-6环烷基或取代的C 3-6环烷基； R 5 is selected from H, amino, substituted amino, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
R 6选自H、卤素或C 1-6烷基； R 6 is selected from H, halogen or C 1-6 alkyl;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
一些实施方式中，式(I)中的环A选自C 3-6环烷基；优选为环丙基； In some embodiments, ring A in formula (I) is selected from C 3-6 cycloalkyl; preferably cyclopropyl;
一些实施方式中，式(I)中的L 1选自-O-(CH 2) 0-3、-NH-(CH 2) 0-3或C 1-3亚烷基；优选为-O-(CH 2) 0-3； In some embodiments, L 1 in formula (I) is selected from -O-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene; preferably -O- (CH 2 ) 0-3 ;
一些实施方式中，式(I)中的L 2选自C 1-3亚烷基； In some embodiments, L in formula (I) is selected from C 1-3 alkylene;
一些实施方式中，式(I)中的R 1选自H、卤素或烷基；优选为H； In some embodiments, R 1 in formula (I) is selected from H, halogen or alkyl; preferably H;
一些实施方式中，式(I)中的R 2选自C 3-14环烷基或3-14元杂环基；所述C 3-14环烷基或3-14元杂环基任选进一步被1-4个选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、氰基、氨基、硝基、羟基、C 1-6羟烷基、-C 0-3亚烷基-N(R a) 2、环烷基、杂坏基、芳基和杂芳基的取代基所取代，所述R a独立地选自H或C 1-6烷基； In some embodiments, R 2 in formula (I) is selected from C 3-14 cycloalkyl or 3-14 membered heterocyclyl; the C 3-14 cycloalkyl or 3-14 membered heterocyclyl is optionally is further selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heteroalkyi, aryl and heteroaryl substituents, the R a is independently selected from H or C 1-6 alkyl;
一些实施方式中，式(I)中的R 2选自 In some embodiments, R in formula (I) is selected from
Figure PCTCN2022080545-appb-000002
Figure PCTCN2022080545-appb-000002
一些实施方式中，式(I)中的R 3选自H、卤素或-OR 2a，所述R 2a选自C 1-6烷基、C 3-8环烷基或卤代烷基； In some embodiments, R 3 in formula (I) is selected from H, halogen or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
一些实施方式中，式(I)中的R 4选自芳基或杂芳基，所述芳基或杂芳基任选地进一步被一个或多个R 3a取代；所述R 3a独立地选自H、羟基、氰基、卤素、硝基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、取代或未取代的C 2-6烯基或取代或未取代的C 2-6炔基； In some embodiments, R4 in formula (I) is selected from aryl or heteroaryl, optionally further substituted with one or more R3a ; said R3a is independently selected from H, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted Substituted C 2-6 alkynyl;
一些实施方式中，式(I)中的R 4选自 In some embodiments, R in formula (I) is selected from
Figure PCTCN2022080545-appb-000003
Figure PCTCN2022080545-appb-000003
一些实施方式中，式(I)中的R 5选自H、C 1-6烷基、环丙基、卤素、C 1-6卤代烷基、C 2-6烯基。 In some embodiments, R 5 in formula (I) is selected from H, C 1-6 alkyl, cyclopropyl, halogen, C 1-6 haloalkyl, C 2-6 alkenyl.
一些实施方式中，式(I)中的R 6选自H。 In some embodiments, R 6 in formula (I) is selected from H.
一些实施方式中，式(I)所示的化合物选自式(IA)：In some embodiments, the compound of formula (I) is selected from formula (IA):
Figure PCTCN2022080545-appb-000004
Figure PCTCN2022080545-appb-000004
其中，in,
L 1选自-O-(CH 2) 0-3； L 1 is selected from -O-(CH 2 ) 0-3 ;
L 2选自C 1-3亚烷基； L 2 is selected from C 1-3 alkylene;
R 2、R 3、R 4、R 5、R 6的定义同式(I)所示。 The definitions of R 2 , R 3 , R 4 , R 5 and R 6 are the same as those shown in formula (I).
一些实施方式中，式(I)所示的化合物选自：In some embodiments, the compound represented by formula (I) is selected from:
Figure PCTCN2022080545-appb-000005
Figure PCTCN2022080545-appb-000005
本发明还提供了一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
本发明进一步提供了一种药物组合物，其特征在于，所述的治疗有效量的至少一种式(I)所示的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
本发明提供了结构式(I)所示化合物或药物组合物在制备药物中的应用。The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
本发明进一步提供了所述应用的优选技术方案：The present invention further provides the preferred technical solution of the application:
作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。Preferably, the application is in the preparation of a drug for treating and/or preventing cancer.
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
本发明还提供了一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“基 1-8烷基”中的“ 1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。 In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " 1-8 " in "base 1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.
“C 1-3亚烷基”是指亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。 "C 1-3 alkylene" refers to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。"Alkoxy" refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团。优选芳基为6到14元的单环或多环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体 结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring. Preferably, the aryl group is a 6- to 14-membered monocyclic or polycyclic aromatic ring group. Preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的3-14元稳定环***，其为饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个碳原子，其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. system, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively Quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环***或未取代或取代的9-14元苯并稠合杂芳族环***或多环杂芳族环***，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14 membered benzo-fused A heteroaromatic ring system or a polycyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally replaced by oxidation, the nitrogen heteroatom can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
术语“环烷基”是指具有3-14个碳原子的环状饱和或部分不饱和单环或多环环状烃取代基，例如，环丙基、环丁基、环戊基或环己基。所述环烷基可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . The cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于H、＝O、＝S、酰基、氰基、卤素、硝基、C 1-6烷基、C 1-6卤代烷基、-C 0-3亚烷基-OR b、-OC(＝O)C 1-6烷基、-C 0-3亚烷基-SR b、-C 0-3亚烷基-N(R b) 2、-C 0-3亚烷基-S(＝O)R b、-C 0-3亚烷基-S(＝O) 2R b、-C 0-3亚烷基-SR b、-C 0-3亚烷基-S(R b) 5、-C 0-3亚烷基-C(＝O)R b、-C 0-3亚烷基-C(＝O)OR b、-C 0-3亚烷基-C(＝O)N(R b) 2、C 2-6烯基、C 2-6炔基、取代或未取代的-C 0-3亚烷基-C 3-14环烷基、取代或未取代的-C 0-3亚烷基-(3-14元杂环烷基)、取代或未取代的-C 0-3亚烷基-C 6-14芳基或取代或未取代的-C 0-3亚烷基-(5-14元杂芳基)，每个R b独立地为H、C 1-6烷基、C 3-6环烷基或C 1-6卤代烷基。在一些实施例中，取代 基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。 The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, H, =O, =S, acyl, cyano, halogen, nitro, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-3 alkylene-OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene-SR b , -C 0-3 alkylene-N(R b ) 2 , -C 0-3 alkylene group-S(=O)R b , -C 0-3 alkylene-S(=O) 2 R b , -C 0-3 alkylene-SR b , -C 0-3 alkylene-S (R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C (=O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, substituted or unsubstituted -C 0-3 alkylene-C 3-14 cycloalkyl, substituted or unsubstituted Substituted -C 0-3 alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted -C 0-3 alkylene-C 6-14 aryl or substituted or unsubstituted -C 0-3 alkylene-(5-14 membered heteroaryl), each R b is independently H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
由于式(I)所示化合物将作为药物应用，较优地，使用一定纯度，例如，至少为60％纯度，比较合适的纯度为至少75％，特别合适地纯度为至少98％(％是重量比)。Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When the compound represented by formula (I) exists as a tautomer, unless otherwise stated, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.
术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围 内。The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although the most suitable mode of administration of the active ingredient in any given situation will depend on the particular subject being administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
具体实施方式Detailed ways
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.
合成方案：Synthesis scheme:
Figure PCTCN2022080545-appb-000006
Figure PCTCN2022080545-appb-000006
第I步：在碱性如碳酸铯等条件下通过取代反应引入取代基
Figure PCTCN2022080545-appb-000007
得到化合物I-2，其中L可以是O、S或NL a； The first step: introduce substituents through substitution reaction under basic conditions such as cesium carbonate
Figure PCTCN2022080545-appb-000007
to obtain compound 1-2, wherein L can be O, S or NL a ;
第II步：在Pa催化剂如X-Phos Pd G2作用下，通过Suzuki偶联反应引入取代基R 4，得到化合物I-3； Step II: Under the action of a Pa catalyst such as X-Phos Pd G2, a substituent R 4 is introduced through a Suzuki coupling reaction to obtain compound I-3;
第III步：化合物I-3在酸性如三氟乙酸条件下脱去保护基即得到目标产物I。Step III: Compound I-3 is deprotected under acidic conditions such as trifluoroacetic acid to obtain the target product I.
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。实施例中使用了下列缩略语：All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated. The following abbreviations are used in the examples:
CDI：羰基二咪唑；CDI: carbonyldiimidazole;
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯；DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;
DABCO：三乙烯二胺；DABCO: triethylenediamine;
DIEA：N，N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
DCM:二氯甲烷；DCM: dichloromethane;
Dioxane：二氧六环；Dioxane: Dioxane;
ESI-MS：电喷雾电离质谱；ESI-MS: Electrospray Ionization Mass Spectrometry;
EtOH：乙醇；EtOH: ethanol;
TBS-Cl：叔丁基二甲基氯硅烷；TBS-Cl: tert-butyldimethylsilyl chloride;
NBS：N-溴代丁二酰亚胺；NBS: N-bromosuccinimide;
Tf 2O：三氟甲磺酸酐； Tf 2 O: trifluoromethanesulfonic anhydride;
HOAc：冰醋酸；HOAc: glacial acetic acid;
MeOH：甲醇；MeOH: methanol;
POCl 3：三氯氧磷； POCl 3 : phosphorus oxychloride;
SOCl 2：二氯亚砜； SOCl 2 : thionyl chloride;
THF：四氢呋喃；THF: tetrahydrofuran;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
LiAlH 4：氢化铝锂； LiAlH 4 : lithium aluminum hydride;
TBAF：四丁基氟化铵；TBAF: tetrabutylammonium fluoride;
LiHMDS：双三甲基硅基胺基锂；LiHMDS: Lithium Bistrimethylsilylamide;
Pd(dppf)Cl 2·DCM：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物； Pd(dppf) Cl2.DCM : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;
X-Phos Pd G2：氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)；X-Phos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)]palladium(II);
Pre-HPLC：制备高效液相；Pre-HPLC: preparation of high performance liquid phase;
Pre-TLC：制备薄层板。Pre-TLC: Preparation of thin layer plates.
中间体M1的合成：Synthesis of Intermediate M1:
Figure PCTCN2022080545-appb-000008
Figure PCTCN2022080545-appb-000008
步骤1：化合物M1-2的合成Step 1: Synthesis of Compound M1-2
在室温下，向化合物M1-1(40g)，HOAc(77g)，EtOH(400mL)与H 2O(160mL)的混合物中逐份添加铁粉(27g)。所得混合物在室温下搅拌2小时，随后用NaOH(5N)溶液中和。随后用乙酸乙酯萃取混合物，有机层用盐水洗涤，经Na 2SO 4干燥且真空浓缩得褐色油状的所要粗品产物(34g，98％产率)，即化合物M1-2。ESI-MS m/z:190[M+H] +。 To a mixture of compound M1-1 (40 g), HOAc (77 g), EtOH (400 mL) and H 2 O (160 mL) was added iron powder (27 g) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then neutralized with NaOH (5N) solution. The mixture was then extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired crude product as a brown oil (34 g, 98% yield), compound M1-2. ESI-MS m/z: 190 [M+H] + .
步骤2：化合物M1-3的合成Step 2: Synthesis of Compound M1-3
将2,2,2-三氯乙烷-1,1-二醇(66.4g)与Na 2SO 4(503.4g)溶于水(560mL)中，然后升温热至55℃。添加含有化合物M1-2(34g)的水(240mL)和35％HC1(72mL)，再添加盐酸羟胺(81.4g)的水溶液(100mL)。所得混合物在90℃搅拌3小时且形成黄色沉淀物。将混合物冷却至室温。通过过滤收集固体,用水冲洗,且风干,得到黄褐色固体产物(47g，99％产率)，即化合物M1-3。ESI-MS m/z:261[M+H] +。 2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na 2 SO 4 (503.4 g) were dissolved in water (560 mL) and then heated to 55°C. Water (240 mL) and 35% HCl (72 mL) containing compound M1-2 (34 g) were added, followed by an aqueous solution (100 mL) of hydroxylamine hydrochloride (81.4 g). The resulting mixture was stirred at 90°C for 3 hours and a yellow precipitate formed. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with water, and air-dried to give the product as a tan solid (47 g, 99% yield), compound M1-3. ESI-MS m/z: 261 [M+H] + .
步骤3：化合物M1-4的合成Step 3: Synthesis of Compounds M1-4
在60℃，向浓硫酸(300mL)中添加化合物M1-3(47g),将温度升高至90℃且维持3小时，反应完全，将反应混合物冷却至室温且倾注入冰水中。通过过滤收集黄色沉淀物且干燥，得到黑色固体产物(43g，99％产率)，即化合物M1-4。Compound M1-3 (47 g) was added to concentrated sulfuric acid (300 mL) at 60 °C, the temperature was raised to 90 °C and maintained for 3 hours, the reaction was complete, the reaction mixture was cooled to room temperature and poured into ice water. The yellow precipitate was collected by filtration and dried to give the product as a black solid (43 g, 99% yield), compound M1-4.
步骤4：化合物M1-5的合成Step 4: Synthesis of Compounds M1-5
在0℃，将化合物M1-4(43g)于NaOH(2N)中的溶液中添加H 2O 2溶液(30％，80mL)且所得混合物在0℃搅拌30分钟。再移至室温下搅拌2小时，反应完全，将混合物倾注入冰水中再用浓HCI溶液酸化,通过过滤收集沉淀物且风干，得到呈白色固体状产物(20g， 49％产率)，即化合物M1-5。ESI-MS m/z:233[M+H] +。 To a solution of compound M1-4 (43 g) in NaOH (2N) was added H2O2 solution (30%, 80 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. Then moved to room temperature and stirred for 2 hours, the reaction was complete, the mixture was poured into ice water and acidified with concentrated HCl solution, the precipitate was collected by filtration and air-dried to obtain a white solid product (20 g, 49% yield), that is, compound M1-5. ESI-MS m/z: 233 [M+H] + .
步骤6：化合物M1-6的合成Step 6: Synthesis of Compounds M1-6
在室温下，将二(咪唑-1-基)甲酮(2.70g)加入到粗品化合物M1-5(4.0g)的THF(20mL)中，再将N-乙基-N-异丙基丙-2-胺(1.4g)加入其中，混合物移至50℃反应，约反应2小时化合物M1-6基本完全转化为中间产物，接着将混合物逐滴加入到冰的氨水(35mL)中，搅拌5min即反应完全。将混合物倾注入冰水中，用乙酸乙酯萃取混合物，有机层用盐水洗涤，经Na 2SO 4干燥且真空浓缩，剩余物通过快速硅胶柱色谱(石油醚/乙酸乙酯＝70:30)纯化，得到褐色固体状的所要目标产物化合物M1-6(1.6g)。 At room temperature, bis(imidazol-1-yl)methanone (2.70 g) was added to crude compound M1-5 (4.0 g) in THF (20 mL), followed by N-ethyl-N-isopropylpropane -2-amine (1.4g) was added to it, the mixture was moved to 50°C for reaction, and compound M1-6 was almost completely converted into an intermediate product after about 2 hours of reaction, then the mixture was added dropwise to iced ammonia water (35mL), stirred for 5min That is, the reaction is complete. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 70:30) , the desired target product compound M1-6 (1.6 g) was obtained as a brown solid.
步骤7：化合物M1-7的合成Step 7: Synthesis of Compounds M1-7
将化合物M1-6与脲的混合物在200℃搅拌反应3小时。将混合物冷却至室温，用乙酸乙酯洗涤固体，将固体干燥即得所要粗品固体产物M1-7(209mg,78％产率)。The mixture of compound M1-6 and urea was stirred and reacted at 200°C for 3 hours. The mixture was cooled to room temperature, the solid was washed with ethyl acetate, and the solid was dried to give the desired crude solid product M1-7 (209 mg, 78% yield).
步骤8：化合物M1-8的合成Step 8: Synthesis of Compounds M1-8
在室温下，将DIPEA加入到M1-7的POCl 3的溶液中，110℃回流16小时。将混合物冷却至室温，真空浓缩除去POCl 3，将残余物通过硅胶管柱色谱法(石油醚/乙酸乙酯＝100:1至50:1)纯化，得到呈棕色固体状所要产物M1-8(209mg,78％产率)。 DIPEA was added to a solution of M1-7 in POCl3 at room temperature and refluxed at 110 °C for 16 h. The mixture was cooled to room temperature, concentrated in vacuo to remove POCl3 , and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100:1 to 50:1) to give the desired product M1-8 as a brown solid ( 209 mg, 78% yield).
步骤9：化合物M1的合成Step 9: Synthesis of Compound M1
在室温下，向M1-8(3.0g)溶于1,4-二氧六环(20ml)中，向溶液中添加叔丁基(1R，5S)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸盐(1.6g)及DIPEA(2.8g)，所得混合物在室温搅拌10分钟。使混合物真空浓缩，残余物通过硅胶管柱色谱法(石油醚/乙酸乙酯＝75:25至65:35)纯化,得到呈黄色固体状的所要产物M1(2.5g，57％产率)。ESI-MS m/z:471[M+H] +。 M1-8 (3.0 g) was dissolved in 1,4-dioxane (20 ml) at room temperature, and to the solution was added tert-butyl(1R,5S)-3,8-diazacyclo[3.2 .1] Octane-8-carboxylate (1.6 g) and DIPEA (2.8 g) and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 75:25 to 65:35) to give the desired product M1 (2.5 g, 57% yield) as a yellow solid. ESI-MS m/z: 471 [M+H] + .
中间体M2的合成：Synthesis of Intermediate M2:
Figure PCTCN2022080545-appb-000009
Figure PCTCN2022080545-appb-000009
步骤1：化合物M2-1的合成Step 1: Synthesis of Compound M2-1
在0℃下，将1,1-环丙基二甲酸单甲酯(667mg)溶于DCM(20mL)，滴加DMF(0.04mL)，再滴加草酰氯(1.57mL)，加完后升温至35℃搅拌3h。将反应液浓缩除去DCM和草酰氯。继续加入DCM(20mL)，冰浴下滴加三乙胺(3.2mL)，再加7-氮杂双环[2.2.1]庚烷(450mg)，加完后室温搅拌3h。反应完成后，加DCM(20mL)稀释，用水(20mL)洗一遍，饱和食盐水(20mL)洗一遍，无水硫酸钠干燥，旋干，得到化合物M2-1粗品(920 mg，产率89％)。ESI-MS m/z＝238[M+H] +。 At 0°C, monomethyl 1,1-cyclopropyldicarboxylate (667 mg) was dissolved in DCM (20 mL), DMF (0.04 mL) was added dropwise, and oxalyl chloride (1.57 mL) was added dropwise, and the temperature was raised after the addition was complete. Stir to 35°C for 3h. The reaction solution was concentrated to remove DCM and oxalyl chloride. DCM (20 mL) was continued to be added, triethylamine (3.2 mL) was added dropwise under ice bath, 7-azabicyclo[2.2.1]heptane (450 mg) was added, and the mixture was stirred at room temperature for 3 h. After the completion of the reaction, add DCM (20 mL) to dilute, wash once with water (20 mL), once with saturated brine (20 mL), dry over anhydrous sodium sulfate, spin dry to obtain the crude compound M2-1 (920 mg, yield 89%) ). ESI-MS m/z=238 [M+H] + .
步骤2：化合物M2的合成Step 2: Synthesis of Compound M2
在室温下将上述化合物M2-1(920mg)溶于THF(20mL)中，降温至-30℃，分批次加入四氢铝锂(313mg)，加完后缓慢升温至40℃并搅拌2h。反应完成后，降至室温，依次加入0.3mL水、0.3mL 15％氢氧化钠水溶液、1mL水，搅拌1h。加入无水硫酸钠干燥，过滤，滤液浓缩，浓缩物经柱色谱分离纯化(MeOH:DCM＝0-20％)得到目标中间体M2(500mg，产率67％)。ESI-MS m/z＝182[M+H] +。 The above compound M2-1 (920 mg) was dissolved in THF (20 mL) at room temperature, cooled to -30°C, lithium aluminum tetrahydride (313 mg) was added in batches, and the temperature was slowly raised to 40°C and stirred for 2 h. After the reaction was completed, it was lowered to room temperature, 0.3 mL of water, 0.3 mL of 15% aqueous sodium hydroxide solution, and 1 mL of water were added in sequence, and the mixture was stirred for 1 h. Anhydrous sodium sulfate was added to dry, filtered, the filtrate was concentrated, and the concentrate was separated and purified by column chromatography (MeOH:DCM=0-20%) to obtain the target intermediate M2 (500 mg, yield 67%). ESI-MS m/z=182 [M+H] + .
中间体M3的合成：Synthesis of Intermediate M3:
Figure PCTCN2022080545-appb-000010
Figure PCTCN2022080545-appb-000010
步骤1：化合物M3-1的合成Step 1: Synthesis of Compound M3-1
在室温下，将化合物乙炔基三异丙基硅烷(20g)溶于丙酮(500mL)中，加入NBS(21.08g)，再加入硝酸银(1.86g)，室温反应12小时。将反应液浓缩，向其中加入水(500mL)，石油醚(3x 500mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，得到化合物M3-1(28g，产率93％)。At room temperature, the compound ethynyltriisopropylsilane (20 g) was dissolved in acetone (500 mL), NBS (21.08 g) was added, and silver nitrate (1.86 g) was added, and the reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated, water (500 mL) was added thereto, extracted with petroleum ether (3×500 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound M3-1 (28 g, yield 93%).
步骤2：化合物M3-2的合成Step 2: Synthesis of Compound M3-2
在室温下，将上述化合物M3-1(4.89g),萘-1,3-二醇(2.5g),乙酸钾(3.06g)和二氯双(4-甲基异丙基苯基)钌(II)(0.96g)溶于二氧六环(30mL)中，氮气置换三次，110℃反应12小时。冷却至室温，旋干，加入100mL水淬灭，乙酸乙酯(3x50mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，浓缩物经柱层析纯化得到化合物M3-2(4g，产率64％)。ESI-MS m/z＝341[M+H] +。 The above compound M3-1 (4.89g), naphthalene-1,3-diol (2.5g), potassium acetate (3.06g) and dichlorobis(4-methylisopropylphenyl)ruthenium were mixed at room temperature (II) (0.96 g) was dissolved in dioxane (30 mL), replaced with nitrogen three times, and reacted at 110° C. for 12 hours. It was cooled to room temperature, spin-dried, quenched by adding 100 mL of water, extracted with ethyl acetate (3×50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the concentrate was purified by column chromatography to obtain compound M3-2 (4 g, yield 64%). ESI-MS m/z=341 [M+H] + .
步骤3：化合物M3-3的合成Step 3: Synthesis of Compound M3-3
在室温下，将化合物M3-2(4.00g)溶于二氯甲烷(35mL)中，加入DIEA(4.95mL)，0℃下加入TBS-Cl(2.26g)，室温搅拌2小时。将反应液直接浓缩，浓缩物经柱层析分 离纯化得到化合物M3-3(4.4g，产率92％)。ESI-MS m/z＝455[M+H] +。 Compound M3-2 (4.00 g) was dissolved in dichloromethane (35 mL) at room temperature, DIEA (4.95 mL) was added, TBS-Cl (2.26 g) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated, and the concentrate was separated and purified by column chromatography to obtain compound M3-3 (4.4 g, yield 92%). ESI-MS m/z=455 [M+H] + .
步骤4：化合物M3-4的合成Step 4: Synthesis of Compound M3-4
在室温下，将上述化合物M3-3(4.4g)和DIEA(4.56mL)溶于DCM(50mL)，在-40℃下滴加加入Tf 2O(2.32mL),在-40摄氏度下反应1小时。在-40摄氏度下滴加入5毫升水，缓慢升至室温，加入50毫升水，二氯甲烷(3x 40mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，浓缩物经柱层析分离纯化得到化合物M3-4(5g，产率83％)。ESI-MS m/z＝587[M+H] +。 At room temperature, the above compound M3-3 (4.4 g) and DIEA (4.56 mL) were dissolved in DCM (50 mL), Tf 2 O (2.32 mL) was added dropwise at -40 °C, and the reaction was carried out at -40 °C for 1 Hour. 5 mL of water was added dropwise at -40 degrees Celsius, slowly warmed to room temperature, 50 mL of water was added, extracted with dichloromethane (3 x 40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the concentrate was subjected to column chromatography Isolation and purification gave compound M3-4 (5 g, yield 83%). ESI-MS m/z=587 [M+H] + .
步骤5：化合物M3的合成Step 5: Synthesis of Compound M3
在室温下，将上述化合物M3-4(5g)，4,4,4',4',5,5',5',5'-八甲基-2,2'-二(1,3,2-二氧苯甲醛)(4.33g)，乙酸钾(2.93g)，Pd(dppf)Cl 2·DCM(0.7g)溶于甲苯(30mL)中，氮气置换三次，110℃反应1小时。冷却至室温，过滤，滤液旋干，加入75毫升水，乙酸乙酯(3x50mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，浓缩物经柱层析分离纯化得到目标中间体M3(2.8g，产率58％)。 1H NMR(500MHz,CDCl 3)δ7.68(dd,J＝7.2,1.2Hz,1H),7.64(dd,J＝8.2,0.9Hz,1H),7.36-7.30(m,2H),7.17(d,J＝2.5Hz,1H),1.43(s,12H),1.18–1.14(m,21H),1.02(s,9H),0.25(s,6H)。ESI-MS m/z＝565[M+H] +。 At room temperature, the above compound M3-4 (5g), 4,4,4',4',5,5',5',5'-octamethyl-2,2'-bis(1,3, 2-Dioxybenzaldehyde) (4.33 g), potassium acetate (2.93 g), Pd(dppf)Cl 2 ·DCM (0.7 g) were dissolved in toluene (30 mL), replaced with nitrogen three times, and reacted at 110° C. for 1 hour. Cool to room temperature, filter, spin dry the filtrate, add 75 mL of water, extract with ethyl acetate (3×50 mL), wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. The concentrate is separated and purified by column chromatography to obtain the target intermediate M3 (2.8 g, 58% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 7.68 (dd, J=7.2, 1.2 Hz, 1H), 7.64 (dd, J=8.2, 0.9 Hz, 1H), 7.36-7.30 (m, 2H), 7.17 ( d, J=2.5Hz, 1H), 1.43 (s, 12H), 1.18–1.14 (m, 21H), 1.02 (s, 9H), 0.25 (s, 6H). ESI-MS m/z=565 [M+H] + .
中间体M4的合成：Synthesis of Intermediate M4:
Figure PCTCN2022080545-appb-000011
Figure PCTCN2022080545-appb-000011
步骤1：化合物M4-1的合成Step 1: Synthesis of Compound M4-1
在室温下，向反应瓶中加入1,1-环丙基二甲酸单甲酯(2.50g)，二氯甲烷(35.00mL)，草酰氯(5.87mL)，N,N-二甲基甲酰胺(0.13mL)，40℃反应1h。将溶剂浓缩，加入二氯甲烷(35.00mL)溶解，降温至0℃，加入三乙胺(12.06mL)调pH＝8，然后加3-氮杂-二环[3.1.0]己烷(1.44g)，该温度下反应1h。用DCM和水萃取，有机相干燥，浓缩。浓缩物经柱层析分离纯化(PE:EA＝8:1)得到黄色液体M4-1(3.01g，产率82.93％)。At room temperature, 1,1-cyclopropyldicarboxylate monomethyl ester (2.50g), dichloromethane (35.00mL), oxalyl chloride (5.87mL), N,N-dimethylformamide were added to the reaction flask (0.13 mL), reacted at 40°C for 1 h. The solvent was concentrated, dichloromethane (35.00 mL) was added to dissolve, the temperature was lowered to 0 °C, triethylamine (12.06 mL) was added to adjust pH=8, and then 3-aza-bicyclo[3.1.0]hexane (1.44 g), reacted at this temperature for 1 h. Extracted with DCM and water, the organic phase was dried and concentrated. The concentrate was separated and purified by column chromatography (PE:EA=8:1) to obtain yellow liquid M4-1 (3.01 g, yield 82.93%).
步骤2：化合物M4的合成Step 2: Synthesis of Compound M4
在反应瓶中加入M4-1(3.0g)，四氢呋喃(50.00mL)，降温至-5℃，分批加入四氢铝锂(2.5M in THF)(0.82g)，加完恢复室温反应2h。0℃下加入0.8mL水淬灭反应，加15％的NaOH水溶液0.8mL，再加2.4mL水，搅拌，加入无水硫酸镁，搅拌10min后过滤，滤饼用DCM洗三次。滤液浓缩，浓缩物经柱层析分离纯化得到黄色液体状目标中间体 M4(1.58g，产率65.89％)。M4-1 (3.0g) and tetrahydrofuran (50.00mL) were added to the reaction flask, the temperature was lowered to -5°C, lithium tetrahydroaluminum (2.5M in THF) (0.82g) was added in batches, and the reaction was returned to room temperature for 2h. Add 0.8 mL of water at 0°C to quench the reaction, add 0.8 mL of 15% NaOH aqueous solution, add 2.4 mL of water, stir, add anhydrous magnesium sulfate, stir for 10 min, filter, and wash the filter cake three times with DCM. The filtrate was concentrated, and the concentrate was separated and purified by column chromatography to obtain the target intermediate M4 as a yellow liquid (1.58 g, yield 65.89%).
实施例1：化合物4-(4-((1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-((1-((S)-2-甲基吡咯烷-1-基)甲基)环丙基)甲氧基)喹唑啉-7-基)萘-2-醇的合成Example 1: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-( Synthesis of (S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)naphthalen-2-ol
Figure PCTCN2022080545-appb-000012
Figure PCTCN2022080545-appb-000012
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
0℃下，向1-甲氧基羰基环丙烷-1-羧酸(3.00g)的DCM(75.00mL)中，加入草酰氯(7.05mL)，DMF(5滴)，0℃下反应10min，然后升温至35℃反应3h。将反应液减压浓缩，残留物用DCM 10ml带1次，残留物溶于60ml DCM，0℃下，加入TEA(14.47mL)，滴加含有(2S)-2-甲基吡咯烷(2.13g)的5ml DCM溶液，然后转为20℃下反应2h。反应液减压浓缩，浓缩物经过硅胶柱纯化(EA：PE＝1％-50％)得到浅棕色液体状目标产物1-1(3.20g，产率72.77％)。ESI-MS:212[M+H] +。 To 1-methoxycarbonylcyclopropane-1-carboxylic acid (3.00 g) in DCM (75.00 mL) at 0 °C, add oxalyl chloride (7.05 mL), DMF (5 drops), and react at 0 °C for 10 min, Then the temperature was raised to 35 °C for 3 h. The reaction solution was concentrated under reduced pressure, the residue was taken once with 10 ml of DCM, the residue was dissolved in 60 ml of DCM, TEA (14.47 mL) was added at 0°C, and (2S)-2-methylpyrrolidine (2.13 g) was added dropwise. ) in 5 ml of DCM, and then transferred to 20 °C for reaction for 2 h. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column (EA: PE=1%-50%) to obtain the target product 1-1 (3.20 g, yield 72.77%) as light brown liquid. ESI-MS: 212[M+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of Compounds 1-2
在0℃下，向化合物1-1(1.60g)的四氢呋喃(24mL)溶液中，分批加入四氢锂铝(0.60g)，然后升温至20℃反应2h。反应液冷却至0℃，加入0.6ml清水，0.6ml 15％氢氧化钠溶液，1.8ml清水，然后20℃下搅拌0.5h，加入适量无水硫酸钠，过滤，减压浓缩得到无色油状目标产物1-2(1.12g，产率87.36％)。ESI-MS:170[M+H] +。 To a solution of compound 1-1 (1.60 g) in tetrahydrofuran (24 mL) at 0 °C, lithium aluminum tetrahydride (0.60 g) was added in batches, and then the temperature was raised to 20 °C for reaction for 2 h. The reaction solution was cooled to 0 °C, 0.6 ml of clear water, 0.6 ml of 15% sodium hydroxide solution, and 1.8 ml of clear water were added, then stirred at 20 °C for 0.5 h, an appropriate amount of anhydrous sodium sulfate was added, filtered, and concentrated under reduced pressure to obtain a colorless oily target Product 1-2 (1.12 g, 87.36% yield). ESI-MS: 170 [M+H] + .
步骤3：化合物1-3的合成Step 3: Synthesis of Compounds 1-3
在室温下，化合物1-2(129.16mg)加入到化合物M1(300.00mg)，DABCO(14.27mg), Cs 2CO 3(621.57mg)的DMF(6.00mL)溶液中，室温搅拌反应14h。过滤，滤饼用少许EA洗涤，滤液加入20ml清水中，加入15ml EA，分出有机相，水相弃，有机相饱和食盐水洗(2*15ml)，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经硅胶柱纯化(MeOH：DCM＝1：10)得到无色油状目标产物1-3(266.00mg，产率69.19％)。ESI-MS:604[M+H] +。 At room temperature, compound 1-2 (129.16 mg) was added to compound M1 (300.00 mg), DABCO (14.27 mg), Cs 2 CO 3 (621.57 mg) in DMF (6.00 mL) solution, and the reaction was stirred at room temperature for 14 h. Filter, wash the filter cake with a little EA, add the filtrate into 20ml of clear water, add 15ml of EA, separate the organic phase, discard the aqueous phase, wash the organic phase with saturated brine (2*15ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the concentrate was purified by silica gel column (MeOH:DCM=1:10) to obtain the target product 1-3 (266.00 mg, yield 69.19%) as colorless oil. ESI-MS: 604[M+H] + .
步骤4：化合物1-4的合成Step 4: Synthesis of Compounds 1-4
在室温下，向化合物1-3(150.00mg)加入到二甲基叔丁基-[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环-2-基)萘-2-基]氧基硅烷(143.07mg,0.37mmol)，SPhos Pd G2(26.77mg)和K 3PO 4(157.99mg)的H 2O(0.40mL)和1,4-二氧六环(4.0mL)的混合溶液中，氮气保护下，升温至85℃反应40min。反应液冷却至室温，加入10ml清水，10ml EA，分出有机相，水相弃，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物经pre-TLC纯化(MeOH：DCM＝1：12)得到浅棕色固体状目标产物1-4(140.00mg，产率72.15％)。ESI-MS:782[M+H] +。 At room temperature, to compound 1-3 (150.00 mg) was added dimethyl tert-butyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)naphthalen-2-yl]oxysilane (143.07 mg, 0.37 mmol), SPhos Pd G2 (26.77 mg) and K 3 PO 4 (157.99 mg) in H 2 O (0.40 mL) and 1,4- In the mixed solution of dioxane (4.0 mL), the temperature was raised to 85° C. for 40 min under nitrogen protection. The reaction solution was cooled to room temperature, 10 ml of clear water and 10 ml of EA were added, the organic phase was separated, the aqueous phase was discarded, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by pre-TLC (MeOH:DCM=1: 12) The target product 1-4 (140.00 mg, 72.15% yield) was obtained as a light brown solid. ESI-MS: 782[M+H] + .
步骤5：化合物1-5的合成Step 5: Synthesis of Compounds 1-5
在室温下，向化合物1-4(100.00mg)的THF(2.00mL)中，加入TBAF(0.13mL)，20℃下反应15min。反应液减压浓缩(不加热)，加入10ml EA，饱和食盐水洗(2*10ml)，水相弃，有机相无水硫酸钠干燥，过滤，减压浓缩得到浅棕色油状目标产物1-5(80.00mg，产率93.66％)，直接投下步。ESI-MS:668[M+H] +。 At room temperature, TBAF (0.13 mL) was added to compound 1-4 (100.00 mg) in THF (2.00 mL), and the reaction was carried out at 20° C. for 15 min. The reaction solution was concentrated under reduced pressure (without heating), 10ml of EA was added, washed with saturated brine (2*10ml), the aqueous phase was discarded, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the light brown oily target product 1-5 ( 80.00 mg, yield 93.66%), directly into the next step. ESI-MS: 668[M+H] + .
步骤6：化合物1的合成Step 6: Synthesis of Compound 1
在室温下，向上述化合物1-5(80.00mg)的DCM(3.60mL)溶液中，加入TFA(0.89mL)，20℃下反应1h。反应液加入10ml饱和碳酸氢钠溶液中，补加10ml DCM，分出有机相，有机相无水硫酸钠干燥，过滤，减压浓缩，浓缩物经pre-HPLC纯化得到白色粉末状目标产物1(29.30mg，产率43.08％)。ESI-MS:568[M+H] +。 At room temperature, TFA (0.89 mL) was added to a solution of the above compound 1-5 (80.00 mg) in DCM (3.60 mL), and the reaction was carried out at 20° C. for 1 h. The reaction solution was added to 10 ml of saturated sodium bicarbonate solution, 10 ml of DCM was added, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by pre-HPLC to obtain the target product 1 ( 29.30 mg, 43.08% yield). ESI-MS: 568[M+H] + .
实施例65：化合物4-(2-((1-((7-氮杂双环[2.2.1]庚-7-基)甲基)环丙基)甲氧基)-4-((1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟喹唑啉-7-基)-5-乙炔基萘-2-醇的合成Example 65: Compound 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R, Synthesis of 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-5-ethynylnaphthalen-2-ol
Figure PCTCN2022080545-appb-000013
Figure PCTCN2022080545-appb-000013
步骤1：化合物65-1的合成Step 1: Synthesis of Compound 65-1
在0℃下，将中间体M2(500mg)溶于DMF(5mL)，分批次加NaH(340mg)，室温搅拌30min。在0℃下，将上述溶液滴加到中间体M1(1.01g，2.15mmol)的DMF(5mL)溶液中，加完后室温搅拌2-4h。反应完成后，将反应液倒入20mL饱和氯化铵中，加EA(20mL)萃取两次。有机相用饱和食盐水(20mL)洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱分离纯化(MeOH:DCM＝0-10％)得到产物65-1(1.0g，产率75％)。ESI-MS m/z＝616[M+H] +。 At 0°C, intermediate M2 (500 mg) was dissolved in DMF (5 mL), NaH (340 mg) was added in portions, and the mixture was stirred at room temperature for 30 min. The above solution was added dropwise to a solution of intermediate M1 (1.01 g, 2.15 mmol) in DMF (5 mL) at 0° C., and stirred at room temperature for 2-4 h after the addition. After the reaction was completed, the reaction solution was poured into 20 mL of saturated ammonium chloride, and EA (20 mL) was added for extraction twice. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to give the product 65-1 (1.0 g, 75% yield). ESI-MS m/z=616 [M+H] + .
步骤2：化合物65-2的合成Step 2: Synthesis of Compound 65-2
在室温下，在氮气氛围下，将中间体M3(275mg)、化合物65-1(200mg)、SPhos-Pd-G2(23.2mg)、碳酸铯(423mg)加入到环戊基甲基醚(2.5mL)和水(0.5mL)的混合溶液中中，100℃搅拌1h。将反应液用5mL EA稀释，用3mL水洗一遍，3mL饱和食盐水洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱分离纯化(MeOH:DCM＝0-10％)得到产物65-2(100mg，产率32％)。ESI-MS m/z＝975[M+H] +。 Intermediate M3 (275 mg), compound 65-1 (200 mg), SPhos-Pd-G2 (23.2 mg), cesium carbonate (423 mg) were added to cyclopentyl methyl ether (2.5 mg) at room temperature under nitrogen atmosphere mL) and water (0.5 mL), and stirred at 100 °C for 1 h. The reaction solution was diluted with 5 mL of EA, washed once with 3 mL of water, washed once with 3 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to give the product 65-2 (100 mg, 32% yield). ESI-MS m/z=975 [M+H] + .
步骤3：化合物65-3的合成Step 3: Synthesis of Compound 65-3
在室温下，将化合物65-2(100mg)溶于DCM(2mL)中，加入TFA(1mL)，加完后室温搅拌30min。反应结束后，将反应液滴加到10mL饱和碳酸氢钠溶液中，用4mL DCM萃取水相3遍。合并有机相，有机相用5mL饱和食盐水洗一遍，用无水硫酸钠干燥，浓缩。浓缩物经柱色谱分离纯化(MeOH:DCM＝1-10％，加1％氨水)得到产物65-3(70mg，产率78％)。ESI-MS m/z＝875[M+H] +。 At room temperature, compound 65-2 (100 mg) was dissolved in DCM (2 mL), TFA (1 mL) was added, and after addition, the mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction was added dropwise to 10 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted 3 times with 4 mL of DCM. The organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (MeOH:DCM=1-10%, plus 1% aqueous ammonia) to give the product 65-3 (70 mg, 78% yield). ESI-MS m/z=875 [M+H] + .
步骤4：化合物65的合成Step 4: Synthesis of Compound 65
在室温下，将化合物65-3(70mg)溶于THF(2mL)，滴加TBAF(0.2mL，0.2mmol)，加完后室温搅拌2h。将反应液浓缩，浓缩物经柱色谱分离纯化(MeOH:DCM＝1-10％，加 1％氨水)得到目标产物65(11mg，产率18％)。ESI-MS m/z＝604[M+H] +。 At room temperature, compound 65-3 (70 mg) was dissolved in THF (2 mL), TBAF (0.2 mL, 0.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated, and the concentrate was separated and purified by column chromatography (MeOH:DCM=1-10%, 1% ammonia water was added) to obtain the target product 65 (11 mg, yield 18%). ESI-MS m/z=604 [M+H] + .
下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。The following examples were synthesized using the methods described above, or analogously using the corresponding intermediates.
Figure PCTCN2022080545-appb-000014
Figure PCTCN2022080545-appb-000014
Figure PCTCN2022080545-appb-000015
Figure PCTCN2022080545-appb-000015
Figure PCTCN2022080545-appb-000016
Figure PCTCN2022080545-appb-000016
Figure PCTCN2022080545-appb-000017
Figure PCTCN2022080545-appb-000017
Figure PCTCN2022080545-appb-000018
Figure PCTCN2022080545-appb-000018
Figure PCTCN2022080545-appb-000019
Figure PCTCN2022080545-appb-000019
Figure PCTCN2022080545-appb-000020
Figure PCTCN2022080545-appb-000020
Figure PCTCN2022080545-appb-000021
Figure PCTCN2022080545-appb-000021
Figure PCTCN2022080545-appb-000022
Figure PCTCN2022080545-appb-000022
Figure PCTCN2022080545-appb-000023
Figure PCTCN2022080545-appb-000023
Figure PCTCN2022080545-appb-000024
Figure PCTCN2022080545-appb-000024
Figure PCTCN2022080545-appb-000025
Figure PCTCN2022080545-appb-000025
Figure PCTCN2022080545-appb-000026
Figure PCTCN2022080545-appb-000026
Figure PCTCN2022080545-appb-000027
Figure PCTCN2022080545-appb-000027
Figure PCTCN2022080545-appb-000028
Figure PCTCN2022080545-appb-000028
实施例48： 1H NMR(500MHz,CDCl 3)δ7.53(d,J＝8.2Hz,1H),7.30(d,J＝7.4Hz,2H),7.21(d,J＝7.5Hz,1H),7.09(s,1H),7.04-6.93(m,2H),6.87(s,1H),4.39(d,J＝10.4Hz,1H),4.26-4.06(m,3H),3.41(d,J＝13.9Hz,2H),3.27(dd,J＝22.0,12.4Hz,2H),2.69(d,J＝11.4Hz,1H),2.55(s,4H),2.41(d,J＝10.0Hz,1H),1.67(s,4H),1.56(s,4H),0.58(s,2H),0.42(d,J＝11.5Hz,2H)。 Example 48: 1 H NMR (500 MHz, CDCl 3 ) δ 7.53 (d, J=8.2 Hz, 1H), 7.30 (d, J=7.4 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H) ,7.09(s,1H),7.04-6.93(m,2H),6.87(s,1H),4.39(d,J＝10.4Hz,1H),4.26-4.06(m,3H),3.41(d,J ＝13.9Hz, 2H), 3.27(dd, J＝22.0, 12.4Hz, 2H), 2.69(d, J＝11.4Hz, 1H), 2.55(s, 4H), 2.41(d, J＝10.0Hz, 1H) ), 1.67(s, 4H), 1.56(s, 4H), 0.58(s, 2H), 0.42(d, J=11.5Hz, 2H).
实施例50： 1H NMR(500MHz,CDCl 3)δ7.63(d,J＝8.1Hz,1H),7.47(d,J＝6.4Hz,2H),7.31(dd,J＝15.1,7.6Hz,1H),7.24(s,1H),7.14(dd,J＝17.9,10.5Hz,2H),7.02(s,1H),4.48-4.21(m,5H),3.64(d,J＝15.7Hz,2H),3.62-3.50(m,2H),3.01(s,2H),2.45(s,2H),2.28(s,2H),1.79(s,4H),1.24(d,J＝12.1Hz,2H),0.64(t,J＝10.1Hz,1H),0.57(s,2H),0.37(s,2H),0.22(d,J＝3.8Hz,1H)。 Example 50: 1 H NMR (500 MHz, CDCl 3 ) δ 7.63 (d, J=8.1 Hz, 1H), 7.47 (d, J=6.4 Hz, 2H), 7.31 (dd, J=15.1, 7.6 Hz, 1H), 7.24(s, 1H), 7.14(dd, J=17.9, 10.5Hz, 2H), 7.02(s, 1H), 4.48-4.21(m, 5H), 3.64(d, J=15.7Hz, 2H) ), 3.62-3.50(m, 2H), 3.01(s, 2H), 2.45(s, 2H), 2.28(s, 2H), 1.79(s, 4H), 1.24(d, J=12.1Hz, 2H) , 0.64(t, J=10.1Hz, 1H), 0.57(s, 2H), 0.37(s, 2H), 0.22(d, J=3.8Hz, 1H).
实施例51： 1H NMR(500MHz,DMSO)δ10.03(s,1H),9.34(d,J＝9.9Hz,1H),9.10(s,1H),8.88(s,1H),7.94(d,J＝8.6Hz,1H),7.82(d,J＝8.3Hz,1H),7.45(t,J＝7.5Hz,1H),7.36(t,J＝7.4Hz,2H),7.29-7.23(m,2H),7.09(d,J＝2.3Hz,1H),4.46(dd,J＝20.3,14.2Hz,2H),4.36(q,J＝11.6Hz,2H),4.22(d,J＝11.7Hz,4H),3.76(t,J＝15.2Hz,2H),3.16(d,J＝5.6Hz,2H),2.02(dt,J＝17.3,9.4Hz,4H),1.75-1.66(m,4H),1.23(s,4H),0.89-0.83(m,2H),0.81(d,J＝3.7Hz,2H)。 Example 51: 1 H NMR (500MHz, DMSO) δ 10.03(s, 1H), 9.34(d, J=9.9Hz, 1H), 9.10(s, 1H), 8.88(s, 1H), 7.94(d ,J=8.6Hz,1H),7.82(d,J=8.3Hz,1H),7.45(t,J=7.5Hz,1H),7.36(t,J=7.4Hz,2H),7.29-7.23(m ,2H),7.09(d,J＝2.3Hz,1H),4.46(dd,J＝20.3,14.2Hz,2H),4.36(q,J＝11.6Hz,2H),4.22(d,J＝11.7Hz ,4H),3.76(t,J＝15.2Hz,2H),3.16(d,J＝5.6Hz,2H),2.02(dt,J＝17.3,9.4Hz,4H),1.75-1.66(m,4H) , 1.23(s, 4H), 0.89-0.83(m, 2H), 0.81(d, J=3.7Hz, 2H).
实施例52： 1H NMR(500MHz,MeOD)δ7.76(d,J＝8.6Hz,1H),7.71(d,J＝8.2Hz,1H),7.45-7.35(m,2H),7.21(d,J＝2.1Hz,1H),7.17(dd,J＝14.4,6.1Hz,2H),7.08(s,1H), 4.54-4.42(m,3H),4.33(dd,J＝21.2,9.9Hz,2H),3.68-3.52(m,4H),3.16(dt,J＝11.3,5.8Hz,1H),2.90(dd,J＝10.8,3.7Hz,1H),2.77(dd,J＝13.2,7.0Hz,1H),2.66(dd,J＝15.5,9.5Hz,2H),2.51(t,J＝13.0Hz,1H),2.45-2.35(m,1H),2.11(ddd,J＝18.0,8.5,4.8Hz,1H),1.85(s,4H),0.73-0.62(m,2H),0.48(s,2H)。 Example 52: 1 H NMR (500 MHz, MeOD) δ 7.76 (d, J=8.6 Hz, 1 H), 7.71 (d, J=8.2 Hz, 1 H), 7.45-7.35 (m, 2H), 7.21 (d , J＝2.1Hz, 1H), 7.17(dd, J＝14.4, 6.1Hz, 2H), 7.08(s, 1H), 4.54-4.42(m, 3H), 4.33(dd, J＝21.2, 9.9Hz, 2H),3.68-3.52(m,4H),3.16(dt,J=11.3,5.8Hz,1H),2.90(dd,J=10.8,3.7Hz,1H),2.77(dd,J=13.2,7.0Hz ,1H),2.66(dd,J＝15.5,9.5Hz,2H),2.51(t,J＝13.0Hz,1H),2.45-2.35(m,1H),2.11(ddd,J＝18.0,8.5,4.8 Hz, 1H), 1.85 (s, 4H), 0.73-0.62 (m, 2H), 0.48 (s, 2H).
实施例53： 1H NMR(500MHz,CDCl 3)δ7.62(d,J＝8.3Hz,1H),7.44(d,J＝8.5Hz,2H),7.29(dd,J＝15.3,7.7Hz,1H),7.19(d,J＝1.6Hz,1H),7.11(dd,J＝13.7,7.1Hz,2H),7.03-6.95(m,1H),5.07(d,J＝55.9Hz,1H),4.47-4.18(m,5H),3.59(s,2H),3.55-3.49(m,1H),3.43(d,J＝12.3Hz,1H),2.80(ddd,J＝22.3,16.5,8.6Hz,3H),2.60(dd,J＝36.1,12.5Hz,1H),2.52-2.36(m,2H),2.12-1.84(m,2H),1.74(s,4H),0.63(s,2H),0.44(d,J＝20.3Hz,2H)。 Example 53: 1 H NMR (500 MHz, CDCl 3 ) δ 7.62 (d, J=8.3 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.29 (dd, J=15.3, 7.7 Hz, 1H), 7.19(d, J＝1.6Hz, 1H), 7.11(dd, J＝13.7, 7.1Hz, 2H), 7.03-6.95(m, 1H), 5.07(d, J＝55.9Hz, 1H), 4.47-4.18(m, 5H), 3.59(s, 2H), 3.55-3.49(m, 1H), 3.43(d, J=12.3Hz, 1H), 2.80(ddd, J=22.3, 16.5, 8.6Hz, 3H), 2.60(dd, J＝36.1, 12.5Hz, 1H), 2.52-2.36(m, 2H), 2.12-1.84(m, 2H), 1.74(s, 4H), 0.63(s, 2H), 0.44 (d, J=20.3 Hz, 2H).
实施例54： 1H NMR(500MHz,DMSO)δ9.97(s,1H),7.86(d,J＝8.6Hz,1H),7.80(d,J＝8.2Hz,1H),7.46-7.37(m,2H),7.27-7.19(m,3H),7.09(d,J＝2.2Hz,1H),4.38-4.23(m,3H),4.17(d,J＝10.9Hz,1H),3.57-3.41(m,4H),3.02(d,J＝8.7Hz,1H),2.77(t,J＝9.2Hz,1H),2.65-2.52(m,4H),2.32(d,J＝12.3Hz,1H),1.97(d,J＝5.7Hz,1H),1.79-1.61(m,5H),1.24(s,1H),0.63(s,2H),0.43(s,2H)。 Example 54: 1 H NMR (500MHz, DMSO) δ 9.97 (s, 1H), 7.86 (d, J=8.6Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.46-7.37 (m ,2H),7.27-7.19(m,3H),7.09(d,J=2.2Hz,1H),4.38-4.23(m,3H),4.17(d,J=10.9Hz,1H),3.57-3.41( m, 4H), 3.02(d, J=8.7Hz, 1H), 2.77(t, J=9.2Hz, 1H), 2.65-2.52(m, 4H), 2.32(d, J=12.3Hz, 1H), 1.97(d, J=5.7Hz, 1H), 1.79-1.61(m, 5H), 1.24(s, 1H), 0.63(s, 2H), 0.43(s, 2H).
实施例55： 1H NMR(500MHz,MeOD)δ7.86(d,J＝8.6Hz,1H),7.74(d,J＝8.2Hz,1H),7.50-7.36(m,2H),7.29(dd,J＝8.4,6.8Hz,1H),7.25-7.16(m,2H),7.09(d,J＝2.4Hz,1H),4.63-4.49(m,2H),4.42(s,2H),3.86(s,2H),3.74-3.58(m,6H),2.63-2.38(m,6H),2.05-1.93(m,4H),0.71(t,J＝5.1Hz,2H),0.50(t,J＝5.0Hz,2H)。 Example 55: 1 H NMR (500 MHz, MeOD) δ 7.86 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.50-7.36 (m, 2H), 7.29 (dd , J=8.4, 6.8Hz, 1H), 7.25-7.16(m, 2H), 7.09(d, J=2.4Hz, 1H), 4.63-4.49(m, 2H), 4.42(s, 2H), 3.86( s, 2H), 3.74-3.58(m, 6H), 2.63-2.38(m, 6H), 2.05-1.93(m, 4H), 0.71(t, J=5.1Hz, 2H), 0.50(t, J= 5.0Hz, 2H).
实施例56： 1H NMR(500MHz,MeOD)δ7.95(d,J＝8.7Hz,1H),7.76(d,J＝8.6Hz,1H),7.47-7.38(m,3H),7.26(d,J＝2.3Hz,1H),7.24-7.18(m,1H),7.10(d,J＝2.4Hz,1H),4.78-4.62(m,2H),4.59-4.40(m,2H),4.29-4.16(m,3H),4.15-4.00(m,2H),3.98-3.80(m,4H),3.69-3.52(m,1H),3.50-3.34(m,1H),3.28-3.17(m,1H),2.86-2.66(m,1H),2.25-2.11(m,4H),1.37(s,3H),1.16-1.01(m,2H),1.00-0.87(m,1H),0.78(s,1H)。 Example 56: 1 H NMR (500 MHz, MeOD) δ 7.95 (d, J=8.7 Hz, 1 H), 7.76 (d, J=8.6 Hz, 1 H), 7.47-7.38 (m, 3H), 7.26 (d , J=2.3Hz, 1H), 7.24-7.18(m, 1H), 7.10(d, J=2.4Hz, 1H), 4.78-4.62(m, 2H), 4.59-4.40(m, 2H), 4.29- 4.16(m,3H),4.15-4.00(m,2H),3.98-3.80(m,4H),3.69-3.52(m,1H),3.50-3.34(m,1H),3.28-3.17(m,1H) ), 2.86-2.66(m, 1H), 2.25-2.11(m, 4H), 1.37(s, 3H), 1.16-1.01(m, 2H), 1.00-0.87(m, 1H), 0.78(s, 1H) ).
实施例57： 1H NMR(500MHz,DMSO)δ9.60(s,1H),9.45(d,J＝9.6Hz,1H),9.28(s,1H),7.94(d,J＝8.6Hz,1H),7.82(d,J＝8.3Hz,1H),7.46(t,J＝7.5Hz,1H),7.36(t,J＝7.7Hz,3H),7.31-7.22(m,3H),7.11(s,1H),4.75(s,1H),4.68(s,1H),4.56-4.38(m,4H),4.25-4.16(m,4H),4.15(d,J＝9.7Hz,1H),3.84(d,J＝9.1Hz,1H),3.14(d,J＝10.6Hz,2H),2.31(d,J＝11.3Hz,1H),2.01(s,6H),0.95(d,J＝4.3Hz,1H),0.92-0.78(m,3H),0.74(d,J＝3.8Hz,1H)。 Example 57: 1 H NMR (500 MHz, DMSO) δ 9.60 (s, 1H), 9.45 (d, J=9.6 Hz, 1H), 9.28 (s, 1H), 7.94 (d, J=8.6 Hz, 1H) ),7.82(d,J＝8.3Hz,1H),7.46(t,J＝7.5Hz,1H),7.36(t,J＝7.7Hz,3H),7.31-7.22(m,3H),7.11(s ,1H),4.75(s,1H),4.68(s,1H),4.56-4.38(m,4H),4.25-4.16(m,4H),4.15(d,J＝9.7Hz,1H),3.84( d,J＝9.1Hz,1H),3.14(d,J＝10.6Hz,2H),2.31(d,J＝11.3Hz,1H),2.01(s,6H),0.95(d,J＝4.3Hz, 1H), 0.92-0.78 (m, 3H), 0.74 (d, J=3.8Hz, 1H).
实施例59： 1H NMR(500MHz,DMSO)δ9.96(s,1H),7.86(d,J＝8.6Hz,1H),7.80(d,J＝8.2Hz,1H),7.48-7.36(m,2H),7.23(dd,J＝14.8,6.8Hz,3H),7.09(d,J＝2.3Hz,1H),5.47(s, 1H),4.43(t,J＝6.8Hz,2H),4.31(dd,J＝37.8,11.9Hz,2H),3.49(dd,J＝32.9,15.5Hz,4H),3.30(s,3H),2.87(s,2H),2.42(t,J＝6.6Hz,3H),2.30(s,2H),2.11(s,2H),1.76-1.59(m,4H),1.24(s,2H),0.39(t,J＝4.7Hz,2H),0.21(t,J＝4.8Hz,2H)。 Example 59: 1 H NMR (500 MHz, DMSO) δ 9.96 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.48-7.36 (m ,2H),7.23(dd,J＝14.8,6.8Hz,3H),7.09(d,J＝2.3Hz,1H),5.47(s,1H),4.43(t,J＝6.8Hz,2H),4.31 (dd, J＝37.8, 11.9Hz, 2H), 3.49(dd, J＝32.9, 15.5Hz, 4H), 3.30(s, 3H), 2.87(s, 2H), 2.42(t, J＝6.6Hz, 3H), 2.30(s, 2H), 2.11(s, 2H), 1.76-1.59(m, 4H), 1.24(s, 2H), 0.39(t, J＝4.7Hz, 2H), 0.21(t, J =4.8Hz, 2H).
实施例60： 1H NMR(500MHz,MeOD)δ7.13(s,1H),7.34-7.19(m,1H),7.52-7.40(m,1H),7.90(d,J＝8.55Hz,1H),7.84(d,J＝8.20Hz,1H),2.42(s,1H),1.92(t,J＝13.60,13.60Hz,1H),1.83-1.62(m,1H),0.69(s,1H),0.46(s,1H),3.68-3.06(m,1H),4.47-4.21(m,1H),1.23(dd,J＝18.38,11.34Hz,1H)。 Example 60: 1 H NMR (500 MHz, MeOD) δ 7.13 (s, 1H), 7.34-7.19 (m, 1H), 7.52-7.40 (m, 1H), 7.90 (d, J=8.55Hz, 1H) ,7.84(d,J＝8.20Hz,1H),2.42(s,1H),1.92(t,J＝13.60,13.60Hz,1H),1.83-1.62(m,1H),0.69(s,1H), 0.46 (s, 1H), 3.68-3.06 (m, 1H), 4.47-4.21 (m, 1H), 1.23 (dd, J=18.38, 11.34 Hz, 1H).
实施例62： 1H NMR(500MHz,CDCl 3)δ7.64(d,J＝8.1Hz,1H),7.44(s,2H),7.35-7.28(m,1H),7.19(s,1H),7.06(t,J＝26.8Hz,3H),4.34(dd,J＝45.6,27.8Hz,4H),3.59(d,J＝33.8Hz,2H),3.51-3.44(m,3H),3.42-3.33(m,1H),3.01(d,J＝18.1Hz,3H),2.47(d,J＝58.6Hz,2H),1.62(dd,J＝46.8,34.2Hz,9H),0.82(d,J＝45.2Hz,3H),0.67(s,2H),0.46(s,2H)。 Example 62: 1 H NMR (500 MHz, CDCl 3 ) δ 7.64 (d, J=8.1 Hz, 1H), 7.44 (s, 2H), 7.35-7.28 (m, 1H), 7.19 (s, 1H), 7.06(t,J＝26.8Hz,3H),4.34(dd,J＝45.6,27.8Hz,4H),3.59(d,J＝33.8Hz,2H),3.51-3.44(m,3H),3.42-3.33 (m,1H),3.01(d,J=18.1Hz,3H),2.47(d,J=58.6Hz,2H),1.62(dd,J=46.8,34.2Hz,9H),0.82(d,J= 45.2Hz, 3H), 0.67(s, 2H), 0.46(s, 2H).
实施例63： 1H NMR(500MHz,DMSO)δ8.18(s,1H),7.89(d,J＝8.6Hz,1H),7.81(d,J＝8.3Hz,1H),7.45(t,J＝7.5Hz,1H),7.39(d,J＝8.2Hz,1H),7.34-7.26(m,2H),7.26-7.21(m,1H),7.10(d,J＝1.9Hz,1H),6.06-5.77(m,1H),4.43(dd,J＝28.1,13.0Hz,2H),4.30(dd,J＝24.4,10.6Hz,2H),4.10(s,2H),3.76-3.67(m,2H),2.88-2.75(m,2H),2.35(dd,J＝23.9,14.6Hz,2H),1.97(s,7H),1.62(t,J＝10.6Hz,2H),1.40(d,J＝10.5Hz,1H),1.14(dd,J＝17.8,7.0Hz,1H),0.66(s,2H),0.42(s,2H)。 Example 63: 1 H NMR (500 MHz, DMSO) δ 8.18 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.45 (t, J =7.5Hz,1H),7.39(d,J=8.2Hz,1H),7.34-7.26(m,2H),7.26-7.21(m,1H),7.10(d,J=1.9Hz,1H),6.06 -5.77(m,1H),4.43(dd,J=28.1,13.0Hz,2H),4.30(dd,J=24.4,10.6Hz,2H),4.10(s,2H),3.76-3.67(m,2H) ), 2.88-2.75(m, 2H), 2.35(dd, J=23.9, 14.6Hz, 2H), 1.97(s, 7H), 1.62(t, J=10.6Hz, 2H), 1.40(d, J= 10.5Hz, 1H), 1.14 (dd, J=17.8, 7.0Hz, 1H), 0.66 (s, 2H), 0.42 (s, 2H).
实施例64： 1H NMR(500MHz,DMSO)δ9.96(s,1H),7.86(d,J＝8.6Hz,1H),7.80(d,J＝8.2Hz,1H),7.46-7.38(m,2H),7.23(dd,J＝16.3,9.4Hz,3H),7.09(d,J＝2.2Hz,1H),4.38-4.23(m,4H),3.48(dd,J＝30.6,17.5Hz,4H),2.71(s,2H),2.31(s,2H),2.20(s,2H),2.06(d,J＝12.5Hz,2H),1.83(d,J＝9.5Hz,2H),1.69(d,J＝9.9Hz,4H),1.24(s,2H),0.63(s,2H),0.39(s,2H)。 Example 64: 1 H NMR (500MHz, DMSO) δ 9.96 (s, 1H), 7.86 (d, J=8.6Hz, 1H), 7.80 (d, J=8.2Hz, 1H), 7.46-7.38 (m ,2H),7.23(dd,J＝16.3,9.4Hz,3H),7.09(d,J＝2.2Hz,1H),4.38-4.23(m,4H),3.48(dd,J＝30.6,17.5Hz, 4H), 2.71(s, 2H), 2.31(s, 2H), 2.20(s, 2H), 2.06(d, J=12.5Hz, 2H), 1.83(d, J=9.5Hz, 2H), 1.69( d, J=9.9Hz, 4H), 1.24 (s, 2H), 0.63 (s, 2H), 0.39 (s, 2H).
实施例66： 1H NMR(500MHz,MeOD)δ8.11(d,J＝8.3Hz,1H),8.01(d,J＝7.3Hz,1H),7.95(d,J＝8.3Hz,1H),7.70-7.63(m,1H),7.59(dd,J＝7.4,1.1Hz,1H),7.54-7.43(m,3H),4.85-4.69(m,2H),4.58(t,J＝14.4Hz,1H),4.49-4.36(m,1H),4.28(s,2H),3.93(dd,J＝40.3,28.2Hz,4H),3.49-3.35(m,1H),3.32(d,J＝3.4Hz,1H),3.15(s,2H),2.14(d,J＝24.8Hz,6H),1.97(d,J＝38.6Hz,2H),1.01-0.84(m,4H)。 Example 66: 1 H NMR (500 MHz, MeOD) δ 8.11 (d, J=8.3 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.70-7.63(m, 1H), 7.59(dd, J=7.4, 1.1Hz, 1H), 7.54-7.43(m, 3H), 4.85-4.69(m, 2H), 4.58(t, J=14.4Hz, 1H), 4.49-4.36(m, 1H), 4.28(s, 2H), 3.93(dd, J=40.3, 28.2Hz, 4H), 3.49-3.35(m, 1H), 3.32(d, J=3.4Hz) , 1H), 3.15 (s, 2H), 2.14 (d, J=24.8Hz, 6H), 1.97 (d, J=38.6Hz, 2H), 1.01-0.84 (m, 4H).
实施例68： 1H NMR(500MHz,CDCl 3)δ7.48(dd,J＝20.2,8.4Hz,2H),7.30-7.27(m,2H),7.12-7.04(m,2H),6.85-6.76(m,1H),4.45(d,J＝12.2Hz,1H),4.36-4.24(m,3H),3.69(d,J＝10.9Hz,2H),3.61(d,J＝12.1Hz,1H),3.52(s,1H),3.08(d,J＝8.2Hz,2H),2.52(s,2H),2.43 -2.31(m,2H),1.83(s,3H),1.30-1.22(m,3H),0.70-0.53(m,3H),0.41(s,2H),0.25(d,J＝4.0Hz,1H)。 Example 68: 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 (dd, J=20.2, 8.4 Hz, 2H), 7.30-7.27 (m, 2H), 7.12-7.04 (m, 2H), 6.85-6.76 (m, 1H), 4.45 (d, J=12.2Hz, 1H), 4.36-4.24 (m, 3H), 3.69 (d, J=10.9Hz, 2H), 3.61 (d, J=12.1Hz, 1H) ,3.52(s,1H),3.08(d,J=8.2Hz,2H),2.52(s,2H),2.43-2.31(m,2H),1.83(s,3H),1.30-1.22(m,3H) ), 0.70-0.53 (m, 3H), 0.41 (s, 2H), 0.25 (d, J=4.0Hz, 1H).
药理实验Pharmacological experiments
实施例1:细胞p-ERK检测试验Example 1: Cell p-ERK detection test
将两种KRas-G12D突变型肿瘤细胞AGS(
Figure PCTCN2022080545-appb-000029
CRL-1739 TM)或Panc 04.03(
Figure PCTCN2022080545-appb-000030
CRL-2555 TM)按5×10 4/孔的细胞密度铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度10000nM、3333nM、1111nM、370.4nM、123.4nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM、0.1％DMSO加入96孔板中，培养3h后，利用MSD(Meso Scale Discovery)电化学发光免疫检测试剂盒中的lysis buffer(50μL)提取96孔板中各处理细胞样品的蛋白裂解液，利用BCA方法对蛋白裂解液进行定量，并利用lysis buffer将蛋白样品浓度稀释为0.1μg/μL。向MSD检测96孔板中加入25ul/孔的蛋白稀释液，室温孵育3h后加入25μL detection antibody solution，继续室温孵育1h，洗板后加入150μL 1×read buffer T。在SECTOR Imager上进行孔板读值，采集原始数据。 Two KRas-G12D mutant tumor cells AGS (
Figure PCTCN2022080545-appb-000029
CRL- 1739TM ) or Panc 04.03 (
Figure PCTCN2022080545-appb-000030
CRL-2555 ™ ) was plated in a 96-well plate at a cell density of 5×10 4 /well, and cultured overnight in a cell incubator. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and cultured. After 3h, the lysis buffer (50 μL) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit was used to extract the protein lysate of each treated cell sample in the 96-well plate, and the protein lysate was quantified by BCA method. lysis buffer to dilute the protein sample concentration to 0.1 μg/μL. Add 25ul/well of protein diluent to MSD detection 96-well plate, incubate at room temperature for 3h, add 25μL detection antibody solution, continue to incubate at room temperature for 1h, and add 150μL 1×read buffer T after washing the plate. Plate readings were performed on the SECTOR Imager and raw data was collected.
根据MSD检测方法中的公式，将读值转化为p-ERK％值：The readings were converted to p-ERK % values according to the formula in the MSD detection method:
p-ERK％值＝((2×磷酸化信号值)/(磷酸化信号值+总信号值))×100p-ERK% value=((2×phosphorylation signal value)/(phosphorylation signal value+total signal value))×100
根据以下公式，计算p-ERK抑制百分数：The percent p-ERK inhibition was calculated according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (Maximum value - Measured value) / (Maximum value - Blank) × 100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Max" is from 0.1% DMSO control wells, "Blank" is from blank control wells, "Measured" is from compound treated wells).
利用GraphPad Prism软件进行曲线拟合并获取IC 50值。 Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
表1Table 1
Figure PCTCN2022080545-appb-000031
Figure PCTCN2022080545-appb-000031
实施例2：细胞增殖实验(AGS)Example 2: Cell proliferation assay (AGS)
将KRas-G12D突变型肿瘤细胞AGS(
Figure PCTCN2022080545-appb-000032
CRL-1739 TM)按1×10 3/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数： KRas-G12D mutant tumor cells AGS (
Figure PCTCN2022080545-appb-000032
CRL-1739 ™ ) was plated in a low-adsorption 96-well plate at a cell density of 1×10 3 /well, and cultured in a cell incubator overnight. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 μL of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (Maximum value - Measured value) / (Maximum value - Blank) × 100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Max" is from 0.1% DMSO control wells, "Blank" is from blank control wells, "Measured" is from compound treated wells).
利用GraphPad Prism软件进行曲线拟合并获取IC 50值。 Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
表2Table 2
Figure PCTCN2022080545-appb-000033
Figure PCTCN2022080545-appb-000033
实施例3：细胞增殖实验(NCI-H1975)Example 3: Cell proliferation assay (NCI-H1975)
将KRas-WT肿瘤细胞NCI-H1975(
Figure PCTCN2022080545-appb-000034
CRL-5908 TM)按1×10 3/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度20000、6666.67、2222.22、740.74、246.91、82.30、27.43、9.14、3.05、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数： KRas-WT tumor cells NCI-H1975 (
Figure PCTCN2022080545-appb-000034
CRL-5908 ™ ) was plated in a low-adsorption 96-well plate at a cell density of 1×10 3 /well, and placed in a cell incubator for overnight culture. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 μL of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (Maximum value-Measured value)/(Maximum value-Blank)×100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Max" is from 0.1% DMSO control wells, "Blank" is from blank control wells, "Measured" is from compound treated wells).
利用GraphPad Prism软件进行曲线拟合并获取IC 50值。 Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
本发明的化合物具有良好选择性。并且化合物2/50和65/51之间的选择性高于10倍，表明通式(I)中R 3为任选地被1-2个R 3a取代
Figure PCTCN2022080545-appb-000035
时，X为炔基或卤素具有更好选择性。 The compounds of the present invention have good selectivity. And the selectivity between compounds 2/50 and 65/51 is higher than 10 times, indicating that R 3 in general formula (I) is optionally substituted by 1-2 R 3a
Figure PCTCN2022080545-appb-000035
When X is alkynyl or halogen, it has better selectivity.
表3table 3
Figure PCTCN2022080545-appb-000036
Figure PCTCN2022080545-appb-000036
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims of the present invention.

Claims (17)

  1. 一种通式(I)所示的化合物、其互变异构体、氘代物或药用盐：A compound shown in general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
    Figure PCTCN2022080545-appb-100001
    Figure PCTCN2022080545-appb-100001
    其中，in,
    环A选自C 3-6环烷基或3-6元杂环基； Ring A is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
    L 1选自-O-(CH 2) 0-3、-S-(CH 2) 0-3、-NH-(CH 2) 0-3或C 1-3亚烷基； L 1 is selected from -O-(CH 2 ) 0-3 , -S-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene;
    L 2选自键或C 1-3亚烷基； L 2 is selected from a bond or a C 1-3 alkylene group;
    R 1独立地选自H、卤素、烷基、烷氧基、卤代烷基、羟基和羟烷基； R 1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
    R 2选自C 3-14环烷基、3-14元杂环基、C 6-14芳基和5-14元杂芳基，所述C 3-14环烷基、3-14元杂环基、C 6-14芳基和5-14元杂芳基任选进一步被1-4个选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、氰基、氨基、硝基、羟基、C 1-6羟烷基、-C 0-3亚烷基-N(R a) 2、环烷基、杂坏基、芳基和杂芳基的取代基所取代，所述R a独立地选自H或C 1-6烷基； R 2 is selected from C 3-14 cycloalkyl, 3-14-membered heterocyclyl, C 6-14 aryl and 5-14-membered heteroaryl, the C 3-14 cycloalkyl, 3-14-membered heteroaryl Cyclic, C 6-14 aryl and 5-14 membered heteroaryl are optionally further 1-4 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heterocortyl, aryl and heteroaryl Substituents are substituted, and the R a is independently selected from H or C 1-6 alkyl;
    R 3选自H、卤素、C 1-6烷基或-OR 2a，所述R 2a选自C 1-6烷基、C 3-8环烷基或卤代烷基； R 3 is selected from H, halogen, C 1-6 alkyl or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
    R 4选自环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选地进一步被一个或多个R 3a取代；R 3a独立地选自H、＝O、＝S、酰基、羟基、氰基、卤素、硝基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、-C 0-3亚烷基-OR b、-OC(＝O)C 1-6烷基、-C 0-3亚烷基-SR b、-C 0-3亚烷基-N(R b) 2、-C 0-3亚烷基-S(＝O)R b、-C 0-3亚烷基-S(＝O) 2R b、-C 0-3亚烷基-SR b、-C 0-3亚烷基-S(R b) 5、-C 0-3亚烷基-C(＝O)R b、-C 0-3亚烷基-C(＝O)OR b、-C 0-3亚烷基-C(＝O)N(R b) 2、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基、取代或未取代的-C 0-3亚烷基-C 3-14环烷基、取代或未取代的-C 0-3亚烷基-(3-14元杂环烷基)、取代或未取代的-C 0-3亚烷基-C 6-14芳基或取代或未取代的-C 0-3亚烷基-(5-14元杂芳基)，每个R b独立地为H、C 1-6烷基、C 3-6环烷基或C 1-6卤代烷基； R4 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with one or more R3a ; R3a independently selected from H, =O, =S, acyl, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -C 0- 3 alkylene-OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene-SR b , -C 0-3 alkylene-N(R b ) 2 , - C 0-3 alkylene-S(=O)R b , -C 0-3 alkylene-S(=O) 2 R b , -C 0-3 alkylene-SR b , -C 0- 3 alkylene-S(R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0- 3 alkylene-C(=O)N(R b ) 2 , substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted -C 0- 3 alkylene-C 3-14 cycloalkyl, substituted or unsubstituted-C 0-3 alkylene-(3-14 membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene base-C 6-14 aryl or substituted or unsubstituted-C 0-3 alkylene-(5-14-membered heteroaryl ) , each R is independently H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
    R 5选自H、氨基、取代的氨基、C 1-6烷基、取代的C 1-6烷基、卤素、C 2-6烯基、取代的C 2-6烯基、C 3-6环烷基或取代的C 3-6环烷基； R 5 is selected from H, amino, substituted amino, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
    R 6选自H、卤素或C 1-6烷基； R 6 is selected from H, halogen or C 1-6 alkyl;
    m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，环A选自C 3-6环烷基；优选为环丙基； The compound according to claim 1, its tautomer, deuterated product or pharmaceutically acceptable salt, wherein ring A is selected from C 3-6 cycloalkyl; preferably cyclopropyl;
  3. 根据权利要求1或2所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，L 1选自-O-(CH 2) 0-3、-NH-(CH 2) 0-3或C 1-3亚烷基；优选为-O-(CH 2) 0-3； The compound, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L 1 is selected from -O-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene; preferably -O-(CH 2 ) 0-3 ;
  4. 根据权利要求1-3任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，L 2选自C 1-3亚烷基； The compound, tautomer, deuterated substance or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein L 2 is selected from C 1-3 alkylene;
  5. 根据权利要求1-4任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 1选自H、卤素或烷基；优选为H； The compound according to any one of claims 1-4, its tautomer, deuterated product or pharmaceutically acceptable salt, wherein R 1 is selected from H, halogen or alkyl; preferably H;
  6. 根据权利要求1-5任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 2选自C 3-14环烷基或3-14元杂环基；所述C 3-14环烷基或3-14元杂环基任选进一步被1-4个选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、氰基、氨基、硝基、羟基、C 1-6羟烷基、-C 0-3亚烷基-N(R a) 2、环烷基、杂坏基、芳基和杂芳基的取代基所取代，所述R a独立地选自H或C 1-6烷基； The compound, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 2 is selected from C 3-14 cycloalkyl or 3-14 membered heterocycle base; the C 3-14 cycloalkyl or 3-14 membered heterocyclic group is optionally further 1-4 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Haloalkyl, cyano, amino, nitro, hydroxy, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heteroalkyi, aryl and heteroaryl is substituted by the substituent of the base, and the R is independently selected from H or C 1-6 alkyl ;
  7. 根据权利要求1-6任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 2选自 The compound, tautomer, deuterated substance or pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R 2 is selected from
    Figure PCTCN2022080545-appb-100002
    Figure PCTCN2022080545-appb-100002
  8. 根据权利要求1-7任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 3选自H、卤素或-OR 2a，所述R 2a选自C 1-6烷基、C 3-8环烷基或卤代烷基； The compound, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 3 is selected from H, halogen or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
  9. 根据权利要求1-8任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 4选自芳基或杂芳基，所述芳基或杂芳基任选地进一步被一个或多个R 3a取代；所述R 3a独立地选自H、羟基、氰基、卤素、硝基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、取代或未取代的C 2-6烯基或取代或未取代的C 2-6炔基； The compound, tautomer, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R 4 is selected from aryl or heteroaryl, and said aryl or heteroaryl group is optionally further substituted with one or more R 3a ; said R 3a is independently selected from H, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl;
  10. 根据权利要求1-9任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 4选自 The compound, tautomer, deuterated substance or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R 4 is selected from
    Figure PCTCN2022080545-appb-100003
    Figure PCTCN2022080545-appb-100003
  11. 根据权利要求1-10任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 5选自H、C 1-6烷基、环丙基、卤素、C 1-6卤代烷基、C 2-6烯基。 The compound according to any one of claims 1-10, its tautomer, deuterated product or pharmaceutically acceptable salt, wherein R 5 is selected from H, C 1-6 alkyl, cyclopropyl, halogen , C 1-6 haloalkyl, C 2-6 alkenyl.
  12. 根据权利要求1-11任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 6选自H。 The compound, tautomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein R 6 is selected from H.
  13. 根据权利要求1-12任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，式(I)所示的化合物、其互变异构体、氘代物或药用盐选自式(IA)所示的化合物The compound, tautomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, characterized in that the compound represented by formula (I), its tautomer, deuterated compound Or the pharmaceutically acceptable salt is selected from the compound represented by formula (IA)
    Figure PCTCN2022080545-appb-100004
    Figure PCTCN2022080545-appb-100004
    其中，in,
    L 1选自-O-(CH 2) 0-3； L 1 is selected from -O-(CH 2 ) 0-3 ;
    L 2选自C 1-3亚烷基； L 2 is selected from C 1-3 alkylene;
    R 2、R 3、R 4、R 5、R 6的定义同权利要求1中式(I)所示。 The definitions of R 2 , R 3 , R 4 , R 5 and R 6 are the same as those shown in formula (I) in claim 1 .
  14. 一种化合物、其互变异构体、氘代物或药用盐，其中，所述化合物选自：A compound, its tautomer, deuterated substance or a pharmaceutically acceptable salt, wherein the compound is selected from:
    Figure PCTCN2022080545-appb-100005
    Figure PCTCN2022080545-appb-100005
  15. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-14中任一项所述的化合物和至少一种药学上可接受的辅料。A pharmaceutical composition, characterized in that, the pharmaceutical composition contains a therapeutically effective amount of the compound described in any one of claims 1-14 and at least one pharmaceutically acceptable excipient.
  16. 权利要求1-14中任一项所述的化合物或权利要求15所述的药物组合物在制备药物中的应用。Use of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15 in the preparation of a medicament.
  17. 一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的权利要求1-14中任一项所述的化合物或权利要求15所述的药物组合物。A method of treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.
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