WO2022170917A1 - 一种作为sos1抑制剂的多环嘧啶类衍生物、其制备方法及用途 - Google Patents

一种作为sos1抑制剂的多环嘧啶类衍生物、其制备方法及用途 Download PDF

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WO2022170917A1
WO2022170917A1 PCT/CN2022/072055 CN2022072055W WO2022170917A1 WO 2022170917 A1 WO2022170917 A1 WO 2022170917A1 CN 2022072055 W CN2022072055 W CN 2022072055W WO 2022170917 A1 WO2022170917 A1 WO 2022170917A1
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compound
reaction
mmol
membered
cancer
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PCT/CN2022/072055
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English (en)
French (fr)
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郑苏欣
谢成英
陆晓杰
郑明月
乔刚
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苏州阿尔脉生物科技有限公司
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Priority to CN202280007413.5A priority Critical patent/CN116568689A/zh
Publication of WO2022170917A1 publication Critical patent/WO2022170917A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of polycyclic pyrimidine derivatives, in particular to a polycyclic pyrimidine derivative as an SOS1 inhibitor, a preparation method and uses thereof.
  • the RAS family proteins belong to a small GTPase that includes three subfamilies, KRAS, NRAS, and HRAS.
  • the mutated RAS gene is an important oncogene, and RAS gene mutations are found in 20-30% of human tumors, especially pancreatic, colorectal, and lung cancers.
  • Various isoforms of RAS proteins have a balance between the activated state of GTP binding and the inactive state of GDP binding.
  • GTPase-activating proteins GAPs
  • GAPs can promote the conversion of GTP to GDP, thereby making RAS proteins inactive.
  • guanine nucleotide exchange factors can promote the release of GDP and the binding of GTP, thereby turning the RAS protein into the active state.
  • Activation of RAS protein can promote cell proliferation, apoptosis evasion and metabolic reorganization through the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT signaling pathways, thereby promoting the occurrence and development of tumors.
  • SOS1 (son of sevenless 1) is a key guanine nucleotide exchange factor (GEF) that can bind to RAS protein, promote the binding of RAS protein to GTP, and turn RAS protein into an active state.
  • GEF guanine nucleotide exchange factor
  • Recent studies have found that SOS1 inhibitors not only inhibit the growth of RAS mutant cells, but also synergize with MEK inhibitors, resulting in significant inhibition of KRAS-driven tumors 1-2 .
  • the development of SOS1 inhibitors has become a research hotspot.
  • SOS1 inhibitors with different structural types, such as WO2018172250, WO2019201848, WO2018115380, WO2019122129, WO2020173935, WO2020180768 and WO2020180770, etc.
  • the object of the present invention is to provide a polycyclic pyrimidine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, to screen out the effective Compounds used as SOS1 inhibitors with excellent properties in terms of safety, safety and selectivity.
  • Another object of the present invention is to provide a method for the preparation of the derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers.
  • the present invention provides a polycyclic pyrimidine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, wherein the structure of the polycyclic pyrimidine derivative is shown in formula ( I) shows:
  • R 1 is selected from hydrogen or C 1 -C 3 alkyl; preferably hydrogen or methyl;
  • a 1 is selected from N or CR 11 ;
  • R 11 is selected from H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • a 2 is selected from N or CR 2 ;
  • R 2 is selected from -OR 21 or cyano
  • R 21 is selected from H, C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C 1 -C 3 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkyl A membered heterocyclyl group is optionally substituted with 1-3 R 22 ;
  • R 22 is selected from halogen, C 1 -C 4 alkyl, cyano, hydroxyl;
  • L may be absent or selected from O, NH or NCH3 ;
  • R 3 is selected from 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered fused heterocyclyl, 6-10 membered bridged heterocyclyl, 6-10 membered spiro heterocyclyl, wherein 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, 6-10 membered fused heterocyclyl, 6-10 membered bridged heterocyclyl, 6-10 membered spiro heterocyclyl are optionally 1-3 R 31 substituted;
  • R 32 is selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-7 membered cycloalkyl or 4-7 membered heterocyclyl;
  • R 4 is -CH 3 ;
  • AR is selected from 6-10-membered aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R 5 ;
  • R 5 is selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 haloalkyl, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, -OR a , -NR a R b ;
  • R a is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 3-6 membered cycloalkyl or 4-7 membered heterocyclyl;
  • R b is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 3-6 membered cycloalkyl or 4-7 membered heterocyclyl;
  • a 1 is CR 11 ;
  • a 2 is C-OR 21 ;
  • heteroatoms in the heterocyclic group and the heteroaryl group in the formula (I) are 1-3 and are selected from one or more of oxygen, nitrogen or sulfur.
  • the phenyl group is optionally substituted by 1-4 R 5 , when the number of the R 5 is 2-4, the R 5 can be the same or different;
  • R 5 when the R 5 is a C 1 -C 4 haloalkyl group, the R 5 is 1-3, and when there are 2-3 R 5 , the R 5 can be the same or different;
  • the halogen atom therein is fluorine or chlorine
  • the R 5 when the R 5 is halogen, the R 5 is 1-3, and when there are 2-3 R 5 , the R 5 can be the same or different;
  • the halogen atom is fluorine or chlorine
  • R 5 when the R 5 is -NR a R b , the R 5 is 1-3, and when there are 2-3 R 5 , the R 5 can be the same or different;
  • R 5 when said R 5 is -NR a R b , said R a and R b may be the same or different.
  • R 3 is a 4-7 membered heterocyclic group optionally substituted by 1-3 R 31
  • the 4-7 membered heterocyclic group is 5-6 membered Heterocyclyl
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , the heterocyclic group contains 1-2 heteroatoms;
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , when the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different;
  • said R 21 is selected from H or C 1 -C 3 alkyl optionally substituted by 1-3 R 22 , said R 22 is selected from halogen, C 1 -C 4 alkyl, cyano base, hydroxyl;
  • R 31 and R 22 have the same limited ranges as above.
  • R3 is 3-7 membered cycloalkyl or 4-7 membered heterocyclyl optionally substituted with 1-3 R31 ;
  • the heteroatom in the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-7-membered heterocyclic group optionally substituted by 1-3 R 31 , the heteroatoms are 1-2;
  • R 31 has the same limited range as above.
  • polycyclic pyrimidine derivatives are selected from any one of the following structures:
  • Typical compounds of the present invention include, but are not limited to, the compounds in the following table:
  • the present invention provides a method for preparing a polycyclic pyrimidine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as described in the first aspect, which is selected from the group consisting of One of the following four options:
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-1) is subjected to metal-catalyzed cross-coupling to obtain the compound of general formula (I-2);
  • the compound of the general formula (I-2) is reacted under catalyst conditions to obtain a chiral sulfonimide compound of the general formula (I-3);
  • the compound of general formula (I-3) is reduced by a metal reducing agent to obtain a chiral compound of general formula (I-4);
  • the compound of general formula (I-4) is cleaved by sulfonamide under acidic conditions to obtain a chiral benzylamine compound of general formula (I-A).
  • the alcoholic hydroxyl group of the compound of the general formula (I-5) is oxidized to obtain the aldehyde compound of the general formula (I-6);
  • the alcoholic hydroxyl group of the compound of the general formula (I-7) is oxidized to obtain a chiral compound of the general formula (I-2);
  • Steps 4 to 6 are the same as above.
  • AR and R 4 have the same limited range as above.
  • the methyl group of the compound of the general formula (I-8) is oxidized to obtain the acid compound of the general formula (I-9);
  • the compound of the general formula (I-13) is formed into an amidine with a nitrile under acidic conditions, and then the ring is closed to obtain the compound of the general formula (I-B).
  • a 1 , A 2 , R 1 , R 3 and L have the same limited ranges as above; A 1 is preferably C; A 2 is preferably N; L is preferably absent; R 1 is preferably methyl.
  • the compound of general formula (I-9) is reacted with acyl chloride and ammonia to obtain the amide compound of general formula (I-14);
  • a 1 , A 2 , R 1 , R 3 and L have the same defined ranges as above; A 1 is preferably C; A 2 is preferably N; L is preferably absent or O; R 1 is preferably methyl.
  • the compound of the general formula (I-B) is subjected to halogenation to obtain the compound of the general formula (I-C).
  • a 1 is preferably C
  • a 2 is preferably N
  • L is preferably absent or O
  • R 1 is preferably methyl
  • the compound of general formula (I-11) and tert-butyl bromoacetate are subjected to substitution reaction under basic conditions to obtain the compound of general formula (I-17);
  • the compound of general formula (I-17) is removed tert-butyl under acidic conditions to obtain the compound of general formula (I-18);
  • the compound of the general formula (I-18) is esterified with an alcohol to obtain a compound of the general formula (I-19) under acidic conditions;
  • the 5th step the compound of general formula (I-21) obtains the compound of general formula (I-22) through halogenation reaction;
  • the seventh step, double bond oxidation in the compound of general formula (I-23) obtains the compound of general formula (I-24);
  • the compound of the general formula (I-25) is substituted with the hydroxyl group to obtain the compound of the general formula (I-C).
  • a 1 , A 2 , R 1 , R 3 , and L have the same limited range as above; A 1 is preferably N; A 2 is preferably CR 2 (R 2 is selected from -OR 21 ); L is preferably NH, R 1 Methyl is preferred.
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-B) and the compound of general formula (I-A) are reacted under condensation conditions to obtain the compound of general formula (I).
  • a 1 , A 2 , AR, R 1 , R 3 , R 4 and L have the same limited ranges as above.
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-C) and the compound of general formula (I-A) are reacted under basic conditions to obtain the compound of general formula (I).
  • a 1 , A 2 , AR, R 1 , R 3 , R 4 and L are as defined in general formula (I).
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-26) is demethylated under basic conditions to obtain the compound of general formula (I-27);
  • the protective group on the hydroxyl group of the compound of the general formula (I-28) obtains the compound of the general formula (I-29);
  • the compound of general formula (I-30) forms an amidine with nitrile under acidic conditions and then closes the ring to obtain the compound of general formula (I-31);
  • the hydroxyl group of the compound of the general formula (I-31) is halogenated to obtain the compound of the general formula (I-32);
  • the ninth step the compound of general formula (I-34) and trifluoromethanesulfonic anhydride react under basic conditions to obtain the compound of general formula (I-35);
  • the compound of the general formula (I-35) and the compound of the general formula (I-11) are obtained under basic conditions in the presence of a metal catalyst and a ligand to obtain the compound of the general formula (I).
  • PG is a protecting group, preferably benzyl;
  • a 1 , A 2 , AR, R 1 , R 3 , R 4 and L have the same limited range as above;
  • L is preferably NH;
  • a 1 is preferably C;
  • a 2 is preferably CR 2 (R 2 is preferably -OR 21 ).
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the methyl group of the compound of the general formula (I-36) is oxidized to obtain the acid compound of the general formula (I-37);
  • the compound of the general formula (I-37) is subjected to a nitration reaction to obtain the compound of the general formula (I-38);
  • the 4th step the compound of general formula (I-39) obtains the amide compound of general formula (I-40) through acid chloride and ammonia reaction;
  • the compound of the general formula (I-42) is subjected to halogenation to obtain the compound of the general formula (I-43);
  • the compound of the general formula (I-44) is reacted with zinc cyanide in the presence of a metal catalyst to obtain the compound of the general formula (I).
  • X 1 , X 2 and X 3 are halogen; X 1 is preferably fluorine; X 2 is preferably bromine; X 3 is preferably chlorine; A 1 , A 2 , AR, R 1 , R 3 , R 4 and L have the same as above A 1 is preferably C; A 2 is CR 2 (R 2 is preferably cyano); L is preferably O; R 1 is preferably methyl.
  • the reagents that provide alkaline conditions are selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, bismuth One or more of lithium trimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate , one or more of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;
  • the reagent for providing acidic conditions is one or more of hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrogen chloride solution in methanol, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;
  • the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphonium palladium dichloride (Pd(PPh) 3 ) one or more of Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 );
  • the ligands are 2-dicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthalene-2,2'-bisdiphenylphosphine (BINAP);
  • the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydrogen;
  • the oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;
  • the above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polycyclic pyrimidine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof Isomers; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
  • the term “comprising” means that the various ingredients can be used together in the mixture or composition of the present invention.
  • the terms “consisting essentially of” and “consisting of” are encompassed by the term “comprising”.
  • a "pharmaceutically acceptable” ingredient is one that is suitable for use in humans and/or animals without undue adverse side effects (eg, toxicity, irritation, and allergy), ie, with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to animals or humans.
  • the carrier can be liquid or solid.
  • the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight) of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.
  • a safe and effective amount such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight
  • a pharmaceutically acceptable carrier or excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition of the present invention contains 0.001-99.9 wt %, more preferably 0.01-99 wt %, more preferably 0.1-90 wt % of the total weight of the compound represented by formula (I) or its pharmacy an acceptable salt; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100% by weight.
  • the preferred ratio of the compound of formula (I) to a pharmaceutically acceptable carrier, excipient or sustained-release agent is that formula (I) as an active ingredient accounts for more than 65% of the total weight, and the rest accounts for The total weight ratio is 0.5-40%, or more preferably 1-20%, or more preferably 1-10%.
  • the unit dose of each dose comprises 0.05mg-500mg, preferably 0.5mg-200mg, more preferably 0.1mg-100mg of the compound of formula (I), enantiomer, external Racemates, pharmaceutically acceptable salts or mixtures thereof.
  • the amount of the active ingredients can generally be the conventional amount or lower in the prior art.
  • compositions of the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent middle.
  • the pharmaceutical compositions of the present invention may also be stored in a suitable sterile device for injection or instillation.
  • the pharmaceutical composition may also contain odorants, flavoring agents, and the like.
  • the compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be clinically used in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal routes of administration.
  • the preferred route of administration is oral.
  • the preferred daily dose is 0.5 mg to 200 mg/kg body weight, taken in one or divided doses. Regardless of the method of administration, the optimal dose for an individual should depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the effective dose of active ingredient employed may vary with the compound employed, the mode of administration, and the severity of the disease to be treated. Generally, however, satisfactory results are obtained when the compounds of the present invention are administered in doses of about 1-300 mg/kg of animal body weight per day, preferably in 1-3 divided doses per day, or in sustained release form Dosing. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg.
  • Dosage forms suitable for oral administration contain about 1-200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced, as dictated by the exigencies of the therapeutic situation.
  • the compounds or pharmaceutically acceptable salts and compositions thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously.
  • the preferred pharmaceutical compositions are solid compositions, especially tablets and solid- or liquid-filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: sterile water, polyethylene glycols, nonionic surfactants and edible oils (eg corn oil, peanut oil and sesame oil) as appropriate to the characteristics of the active ingredient and the particular mode of administration desired.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, such as flavors, colors, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • the active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds can also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, these forms must be sterile and must be fluid for easy syringe expelling. It must be stable under the conditions of manufacture and storage and must be resistant to the contaminating influence of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, alcohol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt and its composition can also be administered in combination with other active ingredients or drugs for treating or preventing chronic pain diseases.
  • other active ingredients or drugs for treating or preventing chronic pain diseases.
  • two or more drugs are administered in combination, they generally have better effects than when the two drugs are administered separately.
  • the present invention provides a polycyclic pyrimidine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or as described in the third aspect
  • a MEK signaling pathway inhibitor in the preparation of a medicament for the treatment of cancer or in the preparation of an SOS1 inhibitor
  • the cancer includes but is not limited to astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophagus, stomach, head and neck, hepatocellular, laryngeal, pancreatic, lung, oral, ovarian, prostate, thyroid, sarcoma, kidney and Cholangiocarcinoma
  • the cancer includes, but is not limited to, pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, renal cancer, gastric cancer and bile duct cancer.
  • said MEK signaling pathway inhibitor such as RAF, K
  • the dosage of the polycyclic pyrimidine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof or the pharmaceutical composition as described in the third aspect is 10-100 mg/kg; and/or the dose range of the MEK inhibitor is selected from 0.1-0.2 mg/kg; preferably, the polycyclic pyrimidine derivatives, their pharmaceutically acceptable salts, their tautomers
  • the dosage range of the isomer, its stereoisomer or the pharmaceutical composition is 25-50 mg/kg; and/or the dosage range of the MEK inhibitor is selected from 0.125 mg/kg; and/or the MEK inhibitor is Trametinib.
  • the cancer is a RAS family related cancer; preferably a KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or NRAS G12S related cancer, KRAS, HRAS or NRAS G12A-related cancer, KRAS, HRAS or NRAS G12V-related cancer, KRAS, HRAS or NRAS G13D-related cancer, KRAS, HRAS or NRAS G13C-related cancer, KRAS, HRAS or NRAS Q61X-related cancer, KRAS, HRAS or NRAS A146T-related cancer, KRAS, HRAS or NRAS A146V-related cancers or KRAS, HRAS or NRAS A146P-related cancers.
  • a RAS family related cancer preferably a KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or
  • a method of treating cancer comprising providing to a cancer patient a therapeutically effective amount of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.
  • the cancer is a RAS family associated cancer.
  • the cancer is a SOS-L associated cancer.
  • compositions and methods provided by the present invention can be used to treat a variety of cancers, including prostate, breast, brain, skin, cervical cancer, testicular cancer, and the like. More specifically, cancers treatable by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, cephalic Neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, cephalic Neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers and sarcomas.
  • Heart sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcoma), myxomas, rhabdomyomas, fibroids, lipomas and teratomas; lung: bronchial carcinoma (squamous squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma) , adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glu
  • the cancer is a RAS family related cancer, such as a KRAS, NRAS or HRAS related cancer.
  • the RAS family-related cancer is non-small cell lung cancer or pancreatic cancer.
  • the cancer is a cancer associated with SOS 1.
  • the SOS 1-related cancer is lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granulosa cell tumor of the skin.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer or bile duct cancer.
  • KRAS G12C refers to a mutated form of the mammalian KRAS protein containing the amino acid at amino acid position 12 replaced by cysteine for glycine.
  • KRAS G12D refers to a mutant form of the mammalian KRAS protein containing an amino acid with aspartic acid substituted for glycine at position 12.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence determined by UniProtKB/Swi-prot P01116: Variant P.Gly 12 Asp.
  • KRAS G12V refers to a mutant form of mammalian KRAS protein containing the amino acid valine in place of glycine at position 12.
  • the amino acid codons and residue positions of human KRAS were determined according to the amino acid sequence determined by UniProtKB/Swi-prot P01116: Variant P.Gly 12 Val.
  • KRAS G12S refers to a mutant form of a mammalian KRAS protein containing the amino acid at amino acid position 12 with serine substituted for glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01116: variant p.Gly 12Ser.
  • KRAS G12A refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid position 12 with alanine in place of glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.Gly 12Ala.
  • KRAS G13D refers to a mutant form of a mammalian KRAS protein containing the amino acid at amino acid position 13 aspartic acid in place of glycine.
  • the determination of amino acid codons and residue positions of human KRAS is based on the amino acid sequence determined by UniProtKB/SwissProt P01116: variant p.gly 13Asp.
  • KRAS G13C refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid 13 replaced by cysteine for glycine.
  • the amino acid codons and residue positions of human KRAS were determined according to the amino acid sequence determined by UniProtKB/SwissProt-Prot P01116: Variant P.Gly 13Cys.
  • KRAS Q61L refers to a mutant form of the mammalian KRAS protein containing the amino acid leucine in place of glutamine at amino acid 61.
  • the determination of amino acid codons and residue positions of human KRAS is based on the amino acid sequence of UniProtKB/SwissProt P 01116: variant p.Gln61Leu.
  • KRAS A146T refers to a mutant form of the mammalian KRAS protein containing the amino acid at amino acid position 146 with threonine in place of alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01116: variant p.al46Thr.
  • KRAS A146V refers to a mutant form of the mammalian KRAS protein containing an amino acid at amino acid position 146 with a valine in place of alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.al46Val.
  • KRAS A146P refers to a mutated form of the mammalian KRAS protein containing the amino acid at amino acid position 146 in which a proline is substituted for alanine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01116: variant p.Al46Pro.
  • HRAS G12C refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 12 replaced by cysteine for glycine. Based on the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Gly 12 Cys, the amino acid codons and residue positions of human HRAs were determined.
  • HRAS G12D refers to a mutant of a mammalian HRAS protein containing aspartic acid in place of glycine at amino acid position 12.
  • the amino acid codons and residue positions of human HRAs were determined based on UniProtKB/SwissProt P01112: Amino acid sequence of variant P.Gly 12Asp.
  • HRAS G12S refers to a mutant form of a mammalian HRAS protein containing 12 amino acids with serines substituted for glycines.
  • the amino acid codons and residue positions of human HRAS were determined according to the amino acid sequence determined by UniProtKB/SwissProt P01112: Variant P.Gly 12Ser.
  • HRAS G12A refers to a mutant form of a mammalian HRAS protein that replaces the amino acid at 12 with alanine for glycine.
  • the amino acid codons and residue positions of human KRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P01112: variant P.Gly 12Ala.
  • HRAS G13D refers to a mutant form of a mammalian HRAS protein containing an amino acid with aspartic acid substituted for glycine at position 13.
  • the amino acid codons and residue positions of human HRAS were determined according to the amino acid sequence determined by UniProtKB/Swi-prot P01112: variant p.gly 13Asp.
  • HRAS G13C is a mutant of mammalian HRAS protein, which contains cysteine in place of the amino acid of glycine at the 13th amino acid.
  • the determination of amino acid codons and residue positions of human HRAS was based on the amino acid sequence of UniProtKB/SwissProt-Prot P01112: variant P.Gly 13Cys.
  • HRAS Q61L refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 61 in place of leucine in place of glutamine. Based on the amino acid sequence identified by UniProtKB/SwissProt P 01112 variant p.Gln61Leu, the amino acid codons and residue positions of human HRAs were determined.
  • HRAS A146T refers to a mutated form of a mammalian HRAS protein containing the amino acid at amino acid position 146 with a threonine substituted for alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Al46Thr.
  • HRAS A146V refers to a mutant form of a mammalian HRAS protein containing the amino acid valine at amino acid position 146 in place of alanine. One amino acid replaces the alanine at amino acid position 146.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.al46Val.
  • HRAS A146P refers to a mutated form of the mammalian HRAS protein containing the amino acid at amino acid position 146 where a proline is substituted for alanine. Amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01112: variant p.Al46Pro.
  • NRAS G12C refers to a mutant form of the mammalian NRAS protein containing the amino acid glycine at amino acid 12 replaced by cysteine. Amino acid codons and residue positions of human NRAS were determined according to UniProtKB/SwissProt-Prot P01111: variant P.Gly12Cys.
  • NRAS G12D refers to a mutant form of the mammalian NRAS protein that contains an amino acid with aspartic acid substituted for glycine at position 12.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence determined by UniProtKB/Swi-prot P01111: Variant P.Gly 12 Asp.
  • NRAS G12S refers to a mutant form of the mammalian NRAS protein containing the amino acid serine substituted for glycine at amino acid 12.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P01111: variant p.Gly 12Ser.
  • NRAS G12A refers to a mutant form of the mammalian NRAS protein containing the amino acid at amino acid 12 where alanine is substituted for glycine.
  • the determination of amino acid codons and residue positions of human KRAS was based on the amino acid sequence of UniProtKB/SwissProt P01111: variant p.Gly 12Ala.
  • NRAS G13D refers to a mutated form of the mammalian NRAS protein that contains an amino acid substitution of aspartic acid at amino acid 13 for glycine at the amino acid position.
  • the determination of amino acid codons and residue positions of human NRAS is based on the amino acid sequence determined by UniProtKB/SwissProt P 01111: variant p.Gly 13 Asp.
  • HNRas G13C refers to a mutant form of the mammalian NRAS protein containing the amino acid cysteine in place of glycine at amino acid 13.
  • the determination of amino acid codons and residue positions of human NRAS was based on the amino acid sequence of UniProtKB/SwissProt P01111: variant P.Gly 13Cys.
  • HRAS Q61L refers to a mutated form of a mammalian HRAS protein containing a leucine at amino acid position 61 in place of glutamine at amino acid position 61. Based on the amino acid sequence identified by UniProtKB/SwissProt P 01112 variant p.Gln61Leu, the amino acid codons and residue positions of human HRAs were determined.
  • NRAS A146T refers to a mutant form of the mammalian NRAS protein containing the amino acid threonine at amino acid 146 in place of alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified in UniProtKB/SwissProt P 01111: variant p.Al46Thr.
  • NRAS A146V refers to a mutant form of a mammalian NRAS protein containing the amino acid valine at amino acid 146 in place of alanine.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01111: variant p.al46Val.
  • NRAS A146P refers to a mutated form of the mammalian NRAS protein containing an amino acid with a proline in place of alanine at amino acid 146.
  • the amino acid codons and residue positions of human NRAS were determined from the amino acid sequence identified by UniProtKB/SwissProt P 01111: variant p.Al46Pro.
  • RAS family member or “RAS family” refers to KRAS, HRAS, NRAS and activating mutants thereof, including positions G12, G13, Q61 and A146.
  • 'RAS family associated disease or disorder' refers to a disease or disorder associated with, mediated by, or having an activating RAS mutation, such as RAS at positions G12, G13, Q61 or A146.
  • RAS family related diseases or diseases are KRAS, HRAS or NRAS G12C related cancer, KRAS, HRAS or NRAS G12D related cancer, KRAS, HRAS or NRAS G12V related cancer, KRAS, HRAS or NRAS G12S related cancer, KRAS, HRAS or NRAS G12A-related cancer, KRAS, HRAS or NRAS G13D-related cancer, KRAS, HRAS or NRAS G13C-related cancer, KRAS, HRAS or NRAS Q61L-related cancer, KRAS, HRAS or NRAS A146T-related cancer, KRAS, HRAS or NRAS A146V-related cancer Cancer or KRAS, HRAS or NRAS 146P-related cancer.
  • SOS1-related disease or disorder refers to a disease or disorder associated with, mediated by, or having an activating SOS1 mutation.
  • activating SOS1 mutations include the SOS1N233S and SOS1N233Y mutations.
  • SOS1N233S refers to a mutant form of the mammalian SOS1 protein containing an amino acid substitution of serine for glutamine at amino acid position 233.
  • the determination of amino acid codons and residue positions for human SOS 1 was based on the amino acid sequence identified in UniProtKB/SwissProt Q 07889: variant p.Gln233Ser.
  • SOS1N233Y refers to a mutant form of the mammalian SOS1 protein in which amino acid 233 is replaced by an amino acid containing tyrosine in place of glutamine.
  • the determination of amino acid codons and residue positions of human SOS 1 was based on the amino acid sequence identified in UniProtKB/SwissProt Q 07889: variant p.Gln233Tyr.
  • SOS 1 inhibitor refers to a compound of the present invention, as described herein, represented by formula (I). These compounds negatively inhibit all or part of the interaction of SOS 1 with RAS family mutants or SOS 1 activating mutations, thereby reducing and/or modulating the nucleotide exchange activity of the RAS family member-SOS 1 complex.
  • KRAS inhibitor refers to inhibitors known in the art against various KRAS mutations. Inhibitors such as KRAS G12C, KRAS G12D, KRAS G12V can be targeted.
  • MEK signaling pathway inhibitors refer to inhibitors of RAF, MEK and ERK1/2 known in the art.
  • NF-1/NF-2-related disease or disorder refers to a disease or disorder caused by a loss-of-function mutation in the neurocellulase (NF-1) gene or the neurocellulase 2 (NF-2) gene.
  • loss-of-function mutation refers to any point mutation, splice site mutation, fusion, nonsense mutation (amino acid mutation to a stop codon), in-frame mutation or in-frame transfer mutation, including insertions and deletions, and the target cell Or homozygous deletion of a protein-encoding gene in a cancer cell, resulting in partial or complete loss of presence, activity, and/or function of the encoded protein.
  • Alkyl refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 - Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is sp 2 double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl and alkene Butyl and so on. Alkenyl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application, and are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic groups, wherein at least one ring atom atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl.
  • Heterocyclyl groups can be optionally substituted or unsubstituted.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to:
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, a heterocyclyl or a cycloalkyl, wherein the parent structure is linked together by an aryl ring, non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur.
  • heteroaryl include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-diazolyl Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindo
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the terms "subject,” “individual,” or “patient” are used interchangeably to refer to any animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates animals and humans.
  • the patient is a human.
  • the subject has experienced and/or displayed at least one symptom of the disease or disease to be treated and/or prevented.
  • the subject has been identified or diagnosed with cancer with a KRAS G12 or G13 mutation (eg, as determined by an FDA-approved regulatory agency, such as an FDA-approved assay or kit).
  • the subject has a tumor that is positive for a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12S mutation, a KRAS G12V mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, as approved by a regulatory agency-approved test or kit determination).
  • the subject can be a person with a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (e.g., an approved regulatory agency-such as an FDA-approved assay or reagent) Box) positive tumor patients.
  • a KRAS G12C mutation e.g., an approved regulatory agency-such as an FDA-approved assay or reagent
  • the subject can be a subject whose tumor has a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (eg, the tumor was approved by an FDA-approved regulatory agency, kit or assay).
  • the subject is suspected of having a KRAS G12 or G13 gene-related cancer.
  • the subject has a clinical record indicating that the subject has a tumor with a KRAS G12C mutation (and an optional clinical record indicating that the subject should be treated with any of the compositions provided herein).
  • the term "pediatric patient” as used herein refers to a patient under the age of 16 at the time of diagnosis or treatment.
  • the term "child” can also be divided into the following subcategories: neonatal (from birth to first month of life); infant (1 month to two years); child (2 to 12 years); adolescent (12 years) Age to 21 (until but not including 22nd birthday).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st ed. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to negatively modulate or inhibit SOS 1 enzymatic activity.
  • a "therapeutically effective dose” of a compound refers to an amount sufficient to ameliorate or somehow reduce symptoms, halt or reverse disease progression, or negatively modulate or inhibit SOS 1 activity. This dose can be given as a single dose or in a regimen to be effective.
  • treating means in any way ameliorating or otherwise altering the symptoms or pathology of a patient's condition, disorder, or disease.
  • improving the symptoms of a particular disease by use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with use of the composition Sexual, permanent or temporary.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation on the basis of their physicochemical differences.
  • Enantiomers can be separated by converting a chiral mixture into a diastereomeric mixture by reaction with an appropriate optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride , the diastereomers are separated, and the individual diastereomers are converted to the corresponding pure enantiomers.
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory.
  • the atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their steric structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • Tautomer or "tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • Valence (valence) tautomers include interconversions that recombine bond electrons.
  • the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention which are safe and effective when used in humans or animals.
  • the salts of the compounds can be obtained by using a sufficient amount of base or acid in neat solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, rice butenedioic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, among others (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • the present invention provides an SOS1 inhibitor with a new structure, and the test results show that the polycyclic pyrimidine derivative exhibits excellent SOS1 inhibitory activity, as well as excellent safety and selectivity, and can be used to prepare and treat cancer, especially It is a drug for diseases such as pancreatic cancer, colorectal cancer, lung cancer, hepatocellular cancer, kidney cancer, stomach cancer and bile duct cancer.
  • Fig. 1 is a graph showing the effect of the compounds involved in the present invention on the KRAS/ERK1/2 signal transduction pathway of K-562 cells.
  • Figure 2 is a graph showing the in vivo anti-tumor effect of the SOS1 inhibitor of the present invention alone on the KRAS G12D mutant PANC-1 pancreatic xenograft tumor nude mouse model.
  • Figure 3 is a graph showing the effect of single use of the SOS1 inhibitor of the present invention on the body weight of KRAS G12D mutant PANC-1 pancreatic xenograft nude mice model.
  • Figure 4 is a graph showing the in vivo antitumor effect of the SOS1 inhibitor of the present invention and Trametinib alone or in combination on the KRAS G12C mutant MIAPaCa-2 pancreatic xenograft nude mouse model.
  • Figure 5 is a graph showing the effect of the SOS1 inhibitor of the present invention and Trametinib alone or in combination on the body weight of KRAS G12C mutant MIAPaCa-2 pancreatic xenograft nude mice model.
  • the mass spectrum was measured by LC/MS, and the ionization mode was ESI.
  • HPLC model Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); Mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound or the developing solvent system of the thin layer chromatography method includes: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added Adjustments such as acetic acid or triethylamine, etc.
  • TLC thin layer chromatography
  • reaction solution was cooled to room temperature, hydrochloric acid (15 mL, 3N) was added, stirred for 30 minutes, filtered through a pad of celite, the filtrate was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through silica gel Column chromatography gave the title compound IN-1b (1.25 g, 72% yield) as a yellow oil.
  • reaction solution was cooled to room temperature, poured into ice water (60 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN- 1c (1.01 g, 56% yield).
  • reaction solution was quenched by dropwise addition of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-1d (150 mg, yield 58) as a white solid %).
  • reaction solution was cooled to room temperature, diluted hydrochloric acid (14.4 mL, 72.0 mmol, 5 M) was added, and the mixture was stirred at room temperature for 1 hour. TLC showed that the reaction of the starting materials was complete.
  • the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-2c (5.6 g, yield 83%) as a yellow liquid. .
  • reaction solution was cooled to room temperature, poured into vigorously stirred ice water, stirred continuously for 10 minutes, filtered, the filter cake was repeatedly washed with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration gave the title compound IN-2e as a yellow oil (9.0 g, crude), which was used directly in the next step.
  • reaction solution was poured into ice water and quenched, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound IN-2f (2.8 g, two step yield 21%).
  • reaction solution was poured into ice water to quench, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3b (2.9 g) as a yellow oil. , the two-step yield is 33%).
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-4b (29.8 g, crude product, containing a small amount of triphenylene) as a white solid. oxyphosphorus).
  • reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-4d (5.5 g, yield 80%) as a yellow oil.
  • reaction solution was cooled to 0°C, quenched by dropwise addition of methanol until no gas was produced, concentrated, the residue was dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound IN-5c as a pale yellow solid ( 14.5g, crude product), used directly in the next step.
  • reaction solution was quenched with water, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-5g (19.2 g, crude product) as a yellow solid, which was directly used for next reaction.
  • the seventh step (3-acetyl-5-(difluoromethyl)-4-fluorophenyl) tert-butyl carbamate IN-5h
  • reaction solution was added with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-5h as a yellow solid (9.1 g, yield 52% in seven steps) .
  • reaction solution was cooled to room temperature, quenched by adding water, filtered to remove insoluble matter, the filtrate was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN- 5i (4.60 g, 62% yield).
  • the ninth step (3-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-(difluoromethyl)-4-fluorophenyl)carbamic acid tertiary Butyl ester IN-5j
  • reaction solution was added with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-6b (2.2 g, two-step yield 67%) as a yellow solid. .
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with brine, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound 11 (56 mg, yield 49%) as a yellow solid.
  • the eleventh step N 4 ((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-N 6 -(( S)-Tetrahydrofuran-3-yl)quinazoline-4,6-diamine 1
  • 4,6-Dichloro-2-methylpyrimidine 2a (15.2 g, 93.25 mmol) was added to aqueous ammonia solution (150 mL, 25%), the temperature was raised to 65° C. and reacted for 3 hours. TLC showed that the reaction of the starting materials was completed. The reaction solution was concentrated to give the title compound 2b (11.9 g, crude product) as a white solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, adjusted to neutrality by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, washed with aqueous sodium sulfite solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white
  • the solid title compound 2c (11.82 g, crude) was used directly in the next step.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 2d (6.1 g, three-step yield 25 %).
  • the fourth step 4-amino-6-chloro-2-methylpyrimidine-5-carbaldehyde 2e
  • reaction solution was quenched by adding citric acid, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 2f (1.0 g, yield 24) as a pale yellow solid %).
  • reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 3c (8.5 g, crude product) as a yellow solid, which was used directly in the next step.
  • reaction solution was cooled to room temperature, filtered through a pad of celite, the filter cake was washed with ethanol, the filtrate was concentrated, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 3e (1.38 g) as a yellow solid. g, crude product), used directly in the next step.
  • reaction solution was cooled to 0°C, quenched by dropwise addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title as a pale yellow solid Compound 3g (150 mg, 3-step yield 29%).
  • 3-Fluoro-4-bromotoluene 4a (5.0 g, 26.45 mmol) was dissolved in pyridine (20 mL) and water (20 mL), heated to 90 °C, and potassium permanganate (16.7 g, 105.68 mmol) was added in portions, about The addition was completed in 1 hour, and the reaction was continued for 2 hours. TLC detected that the reaction was basically complete.
  • reaction solution was diluted with water, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 4e (3.6 g, four-step yield 41%) as an off-white solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain a yellow solid mixture (raw material and product) of the title compound 4j (50 mg, crude product), used directly in the next step.
  • the tenth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran- 3-yl)oxy)quinazoline-7-carbonitrile 4
  • reaction solution was cooled to room temperature, diluted hydrochloric acid (20 mL, 1N) was added, stirred at room temperature for 0.5 hours, extracted with ethyl acetate, the organic phase was discarded, the aqueous phase was neutralized with sodium carbonate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, It was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5c (1.7 g, 48% yield for three steps) as a yellow solid.
  • reaction solution was diluted with hydrochloric acid (1N), extracted with ethyl acetate, the organic phase was discarded, the aqueous phase was neutralized with sodium carbonate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was Prep -TLC purification gave the title compound 6a as a yellow-brown solid (330 mg, 63% yield).
  • reaction solution was cooled to room temperature, diluted with dilute hydrochloric acid (10 mL, 1N) dropwise, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 6b (350 mg, crude product) as a brown solid, used directly in the next step.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7b (2.28 g, crude product) as a yellow solid, which was directly used in the next step.
  • reaction solution was cooled to 0°C, quenched by dropwise addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 7e (200 mg, crude product) as a pale yellow solid, used directly in the next step.
  • the sixth step N 4 ((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-N 6 -((S)- Tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-4,6-diamine7
  • 2-Amino-4-methoxybenzoic acid 8a (15.0 g, 89.7 mmol) was dissolved in N,N-dimethylformamide (100 mL), cooled to 0 °C, and N-bromosuccinimide was added (17.6 g, 98.7 mmol), the reaction was naturally raised to room temperature for 2 hours, and the reaction was complete as detected by TLC.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 8h (290 mg, yield 56.4%) as a yellow solid.
  • the ninth step (3-((R)-1-((7-methoxy-2-methyl-6-(((S)-pyrrolidin-3-yl)amino)quinazolin-4-yl )amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate tert-butyl ester 8k
  • reaction solution was cooled to room temperature, concentrated, the residue was neutralized with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound as a yellow solid 9b (73 mg, 23% yield).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 9d (54 mg, yield 71%) as a yellow solid.
  • reaction solution was cooled to room temperature, filtered through a pad of celite, the filtrate was added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 10a (680 mg, crude product) as a yellow-brown solid, which was directly used in the next step. .
  • reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound 10c (710 mg, two-step yield 45%) as a yellow solid. .
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound 10f (95 mg, yield 57%) as a yellow solid.
  • the first step (3-((R)-1-((7-bromo-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-yl)amino )ethyl)-5-(difluoromethyl)-4-fluorophenyl)carbamate tert-butyl ester 12a
  • the third step 4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(((S )-tetrahydrofuran-3-yl)oxy)quinazoline-7-carbonitrile 12
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13a (1.01 g, yield 87%) as a pale yellow solid ).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 13b (70 mg, yield 69%) as a yellow solid.
  • the third step N 4 ((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-N 6 -((S)-Tetrahydrofuran-3-yl)quinazoline-4,6-diamine 13
  • reaction solution was filtered, the filtrate was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 14c (1.2 g, two-step yield 70%) as a transparent oil. .
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14e (270 mg, crude product) as a brown solid, which was used directly in the next step.
  • the reaction solution was filtered through a hot pad of celite, the filter cake was washed with ethanol, the filtrate was concentrated, water was added, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain The title compound 14f (230 mg, 75% yield over three steps) was a yellow solid.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14h (126 mg, crude product) as a yellow solid, which was directly used in the next step.
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 16b as a brown solid (1.0 g, yield 94%) .
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 16e (122 mg, yield 58%) as a yellow solid.
  • the sixth step (3-((R)-1-((6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-methylpyridine Isopropyl [3,4-d]pyrimidin)-4-yl)amino)ethyl)-5-(difluoromethyl)-4-fluorophenyl)carbamate 16g
  • the seventh step (3-(difluoromethyl)-4-fluoro-5-((R)-1-((2-methyl-6-((1S,4S)-5-methyl-2,5 - Diazabicyclo[2.2.1]heptan-2-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)ethyl)phenyl)carbamate 16h
  • reaction solution was filtered through a pad of celite while hot, the filter cake was washed, the filtrate was concentrated, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 17b as a yellow solid ( 87 mg, two-step yield 94%).
  • reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 18b (1.7 g, yield 94%) as a yellow solid.
  • reaction solution was filtered while hot, the filter cake was washed with ethanol, the filtrate was concentrated, water was added, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound as a yellow solid 18c (1.4 g, 90% yield).
  • reaction solution was cooled to room temperature, ice water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 18e (54 mg, yield 50%) as a yellow solid.
  • the sixth step (3-((1R)-1-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methylpyrido[3,4- d] Isopropyl pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-4-fluorophenyl)carbamate 18g
  • the seventh step (3-(difluoromethyl)-4-fluoro-5-((1R)-1-((2-methyl-6-(6-methyl-3,6-diazabicyclo[ 3.1.1] Heptan-3-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)ethyl)phenyl)isopropylcarbamate 18h
  • the human chronic myelogenous leukemia cell K-562 (CCL-243) used in the present invention was purchased from American Type Culture Collection (ATCC). Cells were grown in RPMI 1640 medium with 10% fetal bovine serum (FBS) and 1% dual antibodies at 37°C, 5% CO 2 .
  • FBS fetal bovine serum
  • Inhibition rate (control well OD570nm-OD690nm - administration well OD570nm-OD690nm )/control well OD570nm-OD690nm ⁇ 100%
  • IC50 values were calculated from compound concentrations and corresponding inhibition ratios using Graphpad prism 5.0 software. The test results are shown in Table 1.
  • the compounds in the examples of the present invention can inhibit the proliferation of K-562 cells, and the activities of several compounds are comparable to BI-3402.
  • Protein sample preparation collect the cell suspension, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and use 1 ⁇ SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 ⁇ L of lysed cells. Cell lysates were denatured by heating at 100°C for 10 minutes.
  • 1 ⁇ SDS gel loading buffer 50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue
  • the compounds of the examples of the present invention have obvious inhibitory effect on the phosphorylation of ERK1/2 in K-562 cells, and the inhibitory activity is concentration gradient dependent.
  • Compounds with a final concentration of 400 times are prepared.
  • the final concentration of the detection is 5uM
  • the compounds are prepared at a concentration of 400 times, that is, 2 mM.
  • the compound was serially diluted to the set number of concentration points using an automatic micropipette.
  • the fluorescence signal value (Ex665/Em615) was read with a microplate reader Envision.
  • Inhibition rate (%) (maximum value-sample value)/(maximum value-minimum value) ⁇ 100%.
  • liver microsomes (20 mg protein/mL) from the -80°C refrigerator, place them on a 37°C water bath constant temperature shaker for pre-incubation for 3 minutes, and thaw them for use.
  • Control group (without ⁇ -NADPH): respectively take 25 ⁇ L of PB solution into 75 ⁇ L of the incubation system mixture described in (2), vortex for 30 s, mix well, the total reaction volume is 100 ⁇ L, and replicate. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min and 60min.
  • Sample group respectively add 25 ⁇ L of ⁇ -NADPH solution (4mM) to 75 ⁇ L of the reaction system described in (2), vortex for 30 s, mix well, the total reaction volume is 100 ⁇ L, and repeat. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min, 5min, 15min, 30min, and 60min.
  • CLint(liver) CLint(mic) ⁇ liver weight to body weight ratio ⁇ liver microsomal protein concentration per gram of liver
  • Example Compound 1 had no obvious effect on the body weight of mice under the single and combined doses, showing good safety.
  • Example compound 1 alone has a certain inhibitory activity on PANC-1 (KRAS G12D) nude mice xenograft tumor, and the tumor growth inhibition rate is 40.6% (P ⁇ 0.01);
  • Mice xenografts had a certain inhibitory activity, the tumor growth inhibition rate was 65.4% (P ⁇ 0.01), and the tumor inhibition rate in the combined group with MEK inhibitor Trametinib was 105.6%.
  • the tumors of all mice in the combined group regressed. The activity was significantly enhanced (P ⁇ 0.001).
  • the present invention is to illustrate a polycyclic pyrimidine derivative of the present invention as an SOS1 inhibitor and its preparation method and application through the above-mentioned examples, but the present invention is not limited to the above-mentioned examples, that is, it does not mean that The present invention must rely on the above-described embodiments to be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

属于多环嘧啶类衍生物技术领域，具体涉及一种作为SOS1抑制剂的多环嘧啶类衍生物、其制备方法及用途。所述多环嘧啶类衍生物的结构如式(I)所示，其具有显著的抑制RAS信号通路和治疗癌症的作用，所述癌症为胰腺癌、结直肠癌、肺癌、肝细胞癌、肾癌、胃癌和胆管癌等。

Description

一种作为SOS1抑制剂的多环嘧啶类衍生物、其制备方法及用途 技术领域
本发明属于多环嘧啶类衍生物技术领域，具体涉及一种作为SOS1抑制剂的多环嘧啶类衍生物、其制备方法及用途。
背景技术
RAS家族蛋白属于一种小GTP酶，包含了KRAS、NRAS和HRAS三种亚家族。突变的RAS基因是一种重要的致癌基因，RAS基因突变的发现存在于20-30％的人类肿瘤中，特别是胰腺癌、结直肠癌和肺癌。各种亚型的RAS蛋白都存在着GTP结合的激活态和GDP结合的失活态的平衡，GTP酶活化蛋白(GTPase-activating proteins,GAPs)可以促使GTP转为GDP，从而使RAS蛋白向失活态转变，而鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factor,GEFs)能够促使GDP的释放和GTP的结合，从而使RAS蛋白转向激活态。RAS蛋白的激活会通过RAS-RAF-MEK-ERK和RAS-PI3K-PDK1-AKT的信号通路促进细胞的增殖，凋亡逃避和代谢重组等从而促进肿瘤的发生和发展。
SOS1(son of sevenless 1)是一种关键的鸟嘌呤核苷酸交换因子(GEF)能够与RAS蛋白结合，促进RAS蛋白与GTP的结合，使RAS蛋白转向激活态。最近的研究发现SOS1的抑制剂不单能够抑制RAS突变细胞的生长，还可以和MEK抑制剂产生协同效应，对KRAS驱动的肿瘤产生显著的抑制作用 1-2。SOS1抑制剂的开发成为了研究的热点，多篇专利中报道了不同结构类型的SOS1抑制剂，比如WO2018172250，WO2019201848，WO2018115380，WO2019122129，WO2020173935，WO2020180768和WO2020180770等。
但这些现有技术中公开的化合物以及试验药物在有效性、安全性或选择性等方面依然存在不确定性，因此有必要研究和开发新的选择性的SOS1抑制剂。
参考文献：
1、Hillig et al.Discovery of poetent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.PNAS.116,2251-2560(2019).
2、Hofmann et al.BI-3406,a potent and selective SOS1::KRAS interaction inhibitor,is effective in KRAS-driven cancers through combined MEK inhibition.Cancer Discov.CD-20-0142(2020).
发明内容
为了解决现有技术的上述问题，本发明的目的在于提供一种多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，以筛选出在有效性、安全性和选择性等性能方面均具有优异性能的用作SOS1抑制剂的化合物。
本发明的另一个目的是提供所述衍生物、其药学上可接受的盐、其互变异构体或其立体异构体的制备方法。
为达到此发明目的，本发明采用以下技术方案：
第一方面，本发明提供一种多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，所述多环嘧啶类衍生物的结构如式(I)所示：
Figure PCTCN2022072055-appb-000001
其中：R 1选自氢或C 1-C 3烷基；优选为氢或甲基；
A 1选自N或C-R 11；
R 11选自H、C 1-C 3烷基或C 1-C 3卤代烷基；
A 2选自N或C-R 2；
R 2选自-OR 21或氰基；
R 21选自H、C 1-C 3烷基、3-7元环烷基、4-7元杂环基，其中C 1-C 3烷基、3-7元环烷基、4-7元杂环基任选地被1-3个R 22所取代；
R 22选自卤素、C 1-C 4烷基、氰基、羟基；
L可以不存在或选自O、NH或NCH 3；
R 3选自3-7元环烷基、4-7元杂环基、6-10元的稠杂环基、6-10元的桥杂环基、6-10元的螺杂环基，其中3-7元环烷基、4-7元杂环基、6-10元的稠杂环基、6-10元的桥杂环基、6-10元的螺杂环基任选地被1-3个R 31所取代；
R 31选自C 1-C 3烷基、C 1-C 3卤代烷基、羟基、卤素、氰基、-NR aR b、C 1-C 3烷氧基、＝O、-NHCOR 32或-COR 32；
R 32选自C 1-C 3烷基、C 1-C 3卤代烷基、3-7元环烷基或4-7元杂环基；
R 4为-CH 3；
AR选自6-10元的芳基或5-10元的杂芳基，其中的芳基或杂芳基任选被1-4个R 5所取代；
R 5选自卤素、C 1-C 4烷基、C 1-C 4卤代烷基、羟基-C 1-C 4烷基、羟基-C 1-C 4卤代烷基、3-6元环烷基、4-7元杂环基、-OR a、-NR aR b；
R a选自H、C 1-C 4烷基、C 1-C 4卤代烷基、3-6元环烷基或4-7元杂环基；
R b选自H、C 1-C 4烷基、C 1-C 4卤代烷基、3-6元环烷基或4-7元杂环基；
上述定义中，如下条件不能同时出现：
1)A 1为C-R 11；
2)A 2为C-OR 21；
3)L为O或不存在；
所述式(I)中的杂环基、杂芳基中的杂原子为1-3个并选自氧、氮或硫中的一种或多种。
优选地，所述多环嘧啶类衍生物的结构如式(Ⅱ)所示：
Figure PCTCN2022072055-appb-000002
其中，R 1、L、R 3和R 5具有与上述相同的限定范围；n＝1-4(例如n＝1、n＝2、n＝3、n＝4)；
优选地，对于式(II)化合物，所述的苯基任选被1-4个R 5所取代，当所述R 5的个数为2-4个时，所述的R 5可相同或不同；
和/或，当所述R 5为C 1-C 4卤代烷基时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
和/或，当所述R 5为C 1-C 4卤代烷基时，其中的卤原子为氟或氯；
和/或，当所述R 5为卤素时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
和/或，当所述R 5为卤素时，其中的卤原子为氟或氯；
和/或，当所述R 5为-NR aR b时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
和/或，当所述R 5为-NR aR b时，所述的R a和R b可相同或不同。
优选地，所述多环嘧啶类衍生物的结构如式(III)所示：
Figure PCTCN2022072055-appb-000003
其中，R 1、R 21、R 3和R 5具有与上述相同的限定范围；n＝1-4(例如n＝1、n＝2、n＝3、n＝4)；
优选地，对于式(III)化合物，R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的4-7元杂环基为5-6元杂环基；
和/或，R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基含有1-2个杂原子；
和/或，所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基的杂原子为氮和/或氧；
和/或，所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基的杂原子为两个时，两个杂原子相同或不同；
和/或，所述R 21选自H或任选地被1-3个R 22所取代的C 1-C 3烷基，所述R 22选自卤素、C 1-C 4烷基、氰基、羟基；
其中，R 31和R 22具有与上述相同的限定范围。
优选地，所述多环嘧啶类衍生物的结构如式(IV)所示：
Figure PCTCN2022072055-appb-000004
其中，R 1、L、R 3和R 5具有与上述相同的限定范围；n＝1-4(例如n＝1、n＝2、n＝3、n＝4)；
优选地，对于式(IV)化合物，当L不存在或为O时，R 3为任选地被1-3个R 31所取代的3-7元环烷基或4-7元杂环基；
和/或，当所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的杂环基中杂原子为氮和/或氧；
和/或，当所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的杂原子为1-2个；
其中，R 31具有与上述相同的限定范围。
优选地，所述多环嘧啶类衍生物的结构如式(V)所示：
Figure PCTCN2022072055-appb-000005
其中，R 1、A 2、L、R 3和R 5具有与上述相同的限定范围；n＝1-4(例如n＝1、n＝2、n＝3、n＝4)。
进一步优选地，所述多环嘧啶类衍生物选自如下结构的任意一种：
Figure PCTCN2022072055-appb-000006
Figure PCTCN2022072055-appb-000007
Figure PCTCN2022072055-appb-000008
Figure PCTCN2022072055-appb-000009
Figure PCTCN2022072055-appb-000010
本发明的典型化合物包括但不限于如下表格中的化合物：
第二方面，本发明提供一种如第一方面所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体的制备方法，其选自如下四种方案中的一种：
方案一
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其药用盐的制备方法，包括以下步骤：
关键中间体(I-A)的制备，方法一：
Figure PCTCN2022072055-appb-000011
第一步，通式(I-1)的化合物经金属催化交叉偶联得到通式(I-2)的化合物；
第二步，通式(I-2)的化合物在催化剂条件下反应得到通式(I-3)的手性磺酰亚胺化合物；
第三步，通式(I-3)的化合物经金属还原剂还原得到通式(I-4)的手性化合物；
第四步，通式(I-4)的化合物在酸性条件下磺酰胺裂解得到通式(I-A)的手性苄胺化合物。
关键中间体(I-A)的制备，方法二：
Figure PCTCN2022072055-appb-000012
第一步，通式(I-5)的化合物的醇羟基经氧化得到通式(I-6)的醛类化合物；
第二步，通式(I-6)的化合物经格式反应得到通式(I-7)的化合物；
第三步，通式(I-7)的化合物醇羟基经氧化得到通式(I-2)的手性化合物；
第四步至第六步同上。
其中，AR、R 4具有与上述相同的限定范围。
关键中间体(I-B)的制备，方法一：
Figure PCTCN2022072055-appb-000013
第一步，通式(I-8)的化合物甲基经氧化得到通式(I-9)的酸类化合物；
第二步，通式(I-9)的化合物经酯化反应得到通式(I-10)的化合物；
第三步，通式(I-10)的化合物和通式(I-11)的化合物在碱性条件下反应得到通式(I-12)的化合物；
第四步，通式(I-12)的化合物硝基经还原得到通式(I-13)的化合物；
第五步，通式(I-13)的化合物在酸性条件下与腈成脒再闭环得到通式(I-B)的化合物。
其中，A 1、A 2、R 1、R 3和L具有与上述相同的限定范围；A 1优选C；A 2优选N；L优选不存在；R 1优选甲基。
关键中间体(I-B)的制备，方法二：
Figure PCTCN2022072055-appb-000014
第一步，通式(I-9)的化合物经酰氯化和氨水反应得到通式(I-14)的酰胺类化合物；
第二步，通式(I-14)的化合物和通式(I-11)的化合物在碱性条件下反应得到通式(I-15)的化合物；
第三步，通式(I-15)的化合物硝基经还原得到通式(I-16)的化合物；
第四步，通式(I-16)的化合物和原乙酸三乙酯反应得到通式(I-B)的化合物(R 1＝甲基)；通式(I-16)的化合物和原甲酸三乙酯反应得到通式(I-B)的化合物(R 1＝H)。
其中，A 1、A 2、R 1、R 3和L具有与上述相同的限定范围；A 1优选C；A 2优选N；L优选不存在或O；R 1优选甲基。
关键中间体(I-C)的制备，方法一：
Figure PCTCN2022072055-appb-000015
第一步，通式(I-B)的化合物经卤代反应得到通式(I-C)的化合物。
其中，A 1优选C，A 2优选N，L优选不存在或O，R 1优选甲基。
关键中间体(I-C)的制备，方法二：
Figure PCTCN2022072055-appb-000016
第一步，通式(I-11)的化合物和溴乙酸叔丁酯在碱性条件下经取代反应得到通式(I-17)的化合物；
第二步，通式(I-17)的化合物在酸性条件下脱叔丁基得到通式(I-18)的化合物；
第三步，通式(I-18)的化合物在酸性条件下和醇经酯化反应得到通式(I-19)的化合物；
第四步，通式(I-20)的化合物和氨水反应得到通式(I-21)的化合物；
第五步，通式(I-21)的化合物经卤代反应得到通式(I-22)的化合物；
第六步，通式(I-22)的化合物和乙烯基三氟硼酸钾在碱性条件下，在金属催化剂和配体的存在下，经Suzuki反应得到通式(I-23)的化合物；
第七步，通式(I-23)的化合物中双键氧化得到通式(I-24)的化合物；
第八步，通式(I-24)的化合物和通式(I-19)的化合物在碱性条件下反应得到通式(I-25)的化合物；
第九步，通式(I-25)的化合物羟基取代得到通式(I-C)的化合物。
其中，A 1，A 2，R 1，R 3，和L具有与上述相同的限定范围；A 1优选N；A 2优选CR 2(R 2选自-OR 21)；L优选NH，R 1优选甲基。
通式(I)的制备：
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其药用盐的制备方法，包括以下步骤：
Figure PCTCN2022072055-appb-000017
第一步，通式(I-B)的化合物和通式(I-A)的化合物在缩合条件下反应得到通式(I)的化合物。
其中，A 1、A 2、AR、R 1、R 3、R 4和L具有与上述相同的限定范围。
方案二
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其药用盐的制备方法，包括以下步骤：
Figure PCTCN2022072055-appb-000018
第一步，通式(I-C)的化合物和通式(I-A)的化合物在碱性条件下反应得到通式(I)的化合物。
其中，A 1、A 2、AR、R 1、R 3、R 4和L如通式(I)中所定义。
方案三
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其药用盐的制备方法，包括以下步骤：
Figure PCTCN2022072055-appb-000019
第一步，通式(I-26)的化合物在碱性条件下脱甲基得到通式(I-27)的化合物；
第二步，通式(I-27)的化合物经酯化反应得到通式(I-28)的化合物；
第三步，通式(I-28)的化合物羟基上保护基得到通式(I-29)的化合物；
第四步，通式(I-29)的化合物硝基经还原得到通式(I-30)的化合物；
第五步，通式(I-30)的化合物酸性条件下与腈成脒再闭环得到通式(I-31)的化合物；
第六步，通式(I-31)的化合物羟基经卤代得到通式(I-32)的化合物；
第七步，通式(I-32)的化合物和通式(I-A)的化合物在碱性条件下反应得到通式(I-33)的化合物；
第八步，通式(I-33)的化合物在酸性条件下脱保护基得到通式(I-34)的化合物；
第九步，通式(I-34)的化合物和三氟甲磺酸酐在碱性条件下反应得到通式(I-35)的化合物；
第十步，通式(I-35)的化合物和通式(I-11)的化合物在碱性条件下，金属催化剂和配体存在下，得到通式(I)的化合物。
其中，PG为保护基，优选为苄基；A 1、A 2、AR、R 1、R 3、R 4和L具有与上述相同的限定范围；L优选NH；A 1优选C；A 2优选CR 2(R 2优选-OR 21)。
方案四
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其药用盐的制备方法，包括以下步骤：
Figure PCTCN2022072055-appb-000020
第一步，通式(I-36)的化合物甲基经氧化得到通式(I-37)的酸类化合物；
第二步，通式(I-37)的化合物经硝化反应得到通式(I-38)的化合物；
第三步，通式(I-38)的化合物和通式(I-11)的化合物在碱性条件下反应得到通式(I-39)的化合物；
第四步，通式(I-39)的化合物经酰氯化和氨水反应得到通式(I-40)的酰胺类化合物；
第五步，通式(I-40)的化合物硝基经还原得到通式(I-41)的化合物；
第六步，通式(I-41)的化合物和甲酸三乙酯反应得到通式(I-42)的化合物(R 1＝H)；
第七步，通式(I-42)的化合物经卤代反应得到通式(I-43)的化合物；
第八步，通式(I-43)的化合物和通式(I-A)的化合物在碱性条件下反应得到通式(I-44)的化合物；
第九步，通式(I-44)的化合物和氰化锌在金属催化剂存在下反应得到通式(I)的化合物。
其中，X 1、X 2和X 3为卤素；X 1优选氟；X 2优选溴；X 3优选氯；A 1、A 2、AR、R 1、R 3、R 4和L具有与上述相同的限定范围；A 1优选C；A 2为CR 2(R 2优选氰基)；L优选O；R 1优选甲基。
对于上述制备方法中，
提供碱性条件的试剂选自有机碱或无机碱类，所述的有机碱类为三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、叔丁醇钠、甲醇钠和叔丁醇钾中的一种或多种，所述的无机碱类为氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠、氢氧化钾、碳酸氢钠和氢氧化锂中的一种或多种；
提供酸性条件的试剂为氯化氢、氯化氢的1,4-二氧六环溶液、氯化氢的甲醇溶液、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸和磷酸中的一种或多种；
金属催化剂为钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物、双三苯基磷二氯化钯(Pd(PPh 3)Cl 2)和三(二亚苄基丙酮)二钯(Pd 2(dba) 3)中的一种或多种；
配体为2-双环己基膦-2,6'-二甲氧基联苯(SPhos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(XantPhos)、2-二环己基磷-2,4,6-三异丙基联苯(XPhos)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(DavePhos)、1,1'-双(二苯基膦)二茂铁(Dppf)和1,1'-联萘-2,2'-双二苯膦(BINAP)中的一种或多种，优选为1,1'-联萘-2,2'-双二苯膦(BINAP)；
还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠、三乙酰氧基硼氢化钠、四氢铝锂中的一种或多种；
氧化剂为高锰酸钾、二氧化锰、重铬酸钾、重铬酸钠和锇酸钾中的一种或多种；
上述反应优选在溶剂中进行，所用溶剂为N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、1,4-二氧六环、水、四氢呋喃、二氯甲烷、1,2-二氯乙烷、甲醇、乙醇、甲苯、石油醚、乙酸乙酯、正己烷和丙酮中的一种或多种。
第三方面，本发明提供一种药物组合物，所述药物组合物包括如第一方面所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体；优选地，所述药物组合物还包括可药用载体和/或赋形剂。
本发明中，术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中，“药学上可接受的载体”是用于将本发明的活性物质或其生理上可接受的盐传送给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
在本发明中，所述的药物组合物含有安全有效量(如0.001-99.9重量份，更佳地，0.01-99重量份，更优选0.1-90重量份)的式(I)所示的化合物或其药学上可接受的盐；以及药学上可接受的载体或赋形剂，其中组合物的总重量为100重量份。
或者，本发明所述的药物组合物含有0.001-99.9wt％，更佳地，0.01-99重量％，更优选占总重量0.1- 90重量％的式(I)所示的化合物或其药学上可接受的盐；以及药学上可接受的载体或赋形剂，其中组合物的总重量为100重量％。
在另一优选例中，式(I)化合物与药学上可接受的载体、赋形剂或缓释剂的优选比例是，式(I)作为活性成分占总重量比65％以上，其余部分占总重量比0.5-40％，或更好为1-20％，或最好为1-10％。
本发明药物组合物的各种制剂形式，其单位剂量每剂包含0.05mg-500mg，优选0.5mg-200mg，更优选0.1mg-100mg所述的式(I)化合物、对映异构体、外消旋体、药学上可接受的盐或它们的混合物。
当所述的药物组合物中含有额外的治疗或预防癌症的药物活性成分时，该活性成分的用量通常可以是现有技术中的常规用量或更低。
本发明的药物组合物可以是多种形式，如片剂、胶囊、粉末、糖浆、溶液状、悬浮液和气雾剂等，其中式(I)化合物可以存在于适宜的固体或液体载体或稀释液中。本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。该药物组合物中还可包含气味剂、香味剂等。
本发明的式(I)化合物或包含式(I)化合物的药物组合物可通过口、鼻、皮肤、肺或胃肠道等给药途径对哺乳动物(包括人)临床使用。优选的给药途径为口服。优选的每日剂量为0.5mg-200mg/kg体重，一次或分次服用。不管用何种服用方法，个人的最佳剂量应根据具体治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最合适的剂量。
所用的活性成分的有效剂量可随所用的化合物、给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物每天以约1-300mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以1-3次分开的剂量给予，或以缓释形式给药。对大部分大型哺乳动物而言，每天的总剂量约为5-1000mg，较佳地约为10-500mg。适用于内服的剂量形式，包含与固态或液态药学上可接受的载体密切混合的约1-200mg的活性化合物。可调节此剂量方案以提供最佳治疗应答。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
所述化合物或其药学上可接受的盐及其组合物可通过口服以及静脉内、肌内或皮下等途径给药。从易于制备和给药的立场看，优选的药物组合物是固态组合物，尤其是片剂和固体填充或液体填充的胶囊。药物组合物的口服给药是优选的。
固态载体包括：淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土，而液态载体包括：无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油)，只要适合活性成分的特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括，例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
所述活性化合物或其药学上可接受的盐及其组合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下，这些制剂中含有防腐剂以防止微生物的生长。
适应于注射的药物形式包括：无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况中，这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的，且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质，其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。
式(I)所示的化合物或其药学上可接受的盐及其组合物还可与其它治疗或预防慢性疼痛类疾病的活性成分或药物联合给药。当两种或两种以上的药物联合给药时，一般具有优于两种药物分别单独给药的效果。
第四方面，本发明提供一种如第一方面所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或如第三方面所述的药物组合物单用或联合MEK信号通路抑制剂在制备用于治疗癌症的药物或在制备SOS1抑制剂中的用途；优选地，所述癌症包括但不限于星形细胞癌、乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、食道癌、胃癌、头颈部癌、肝细胞癌、喉癌、胰腺癌、肺癌、口腔癌、卵巢癌、前列腺癌、甲状腺癌、肉瘤、肾癌和胆管癌；进一步优选地，所述癌症包括但不限于：胰腺癌、结直肠癌、肺癌、肝细胞癌、肾癌、胃癌和胆管癌。和/或所述MEK信号通路抑制剂如RAF、KRAS、MEK或ERK1/2抑制剂。
优选地，如第一方面所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或如第三方面所述的药物组合物的剂量范围为10-100mg/kg；和/或MEK抑制剂的剂量范围选自0.1-0.2mg/kg；优选地，所述多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或药物组合物的剂量范围为25-50mg/kg；和/或MEK抑制剂的剂量范围选自0.125mg/kg；和/或所述MEK抑制剂为Trametinib。
如第四方面所述的用途，其中癌症是RAS家族相关的癌症；优选KRAS、HRAS或NRAS G12C相关癌，KRAS、HRAS或NRAS G12D相关癌，KRAS、HRAS或NRAS G12S相关癌，KRAS、HRAS或NRAS G12A相关癌，KRAS、HRAS或NRAS G12V相关癌，KRAS、HRAS或NRAS G13D相关癌，KRAS、HRAS或NRAS G13C相关癌，KRAS、HRAS或NRAS Q61X相关癌，KRAS、HRAS或NRAS A146T相关癌，KRAS、HRAS或NRAS A146V相关癌或KRAS、HRAS或NRAS A146P等相关癌。
在另一方面，提供了治疗癌症的方法，包括向癌症患者提供公式(I)、其药学上可接受的盐或含有该化合物或其药学上可接受的盐的药物组合物的治疗有效量。在一个实施例中，癌症是RAS家族相关的癌症.在一个实施例中，癌症是与SOS-L相关的癌症。
本发明提供的组合物和方法可用于治疗多种癌症，包括前列腺、乳腺、脑、皮肤、宫颈癌、睾丸癌等。更具体地说，本发明的组合物和方法可治疗的癌症包括但不限于肿瘤类型，例如星形细胞癌、乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、食道癌、胃、头颈部、肝细胞癌、喉癌、肺癌、口腔癌、卵巢癌、前列腺癌和甲状腺癌及肉瘤。更具体地说，这些化合物可用于治疗：心脏：肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤；肺：支气管癌(鳞状细胞、未分化小细胞、未分化大细胞、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤、间皮瘤；胃肠道：食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素、胃泌素瘤、类癌、VIPoma)、小肠(腺癌、淋巴瘤、类癌、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛腺瘤、错构瘤、平滑肌瘤)；泌尿生殖道：肾(腺癌、肾母细胞瘤(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝：肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆道：胆囊癌、壶腹癌、胆管癌；骨：成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨慢性化瘤(骨软骨肉瘤)、良性肿瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤；神经系统：颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、骨炎)、脑膜(脑膜瘤、脑膜肉瘤、胶质瘤)、脑(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、胶质母细胞瘤多形性、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓纤维瘤、脑膜瘤、胶质瘤、肉瘤；妇科：子宫(子宫内膜癌)、子宫颈(宫颈癌、癌前宫颈发育不良)、卵巢(卵巢癌(浆液性囊腺癌、粘液性囊腺癌、未分类癌)、颗粒鞘细胞瘤、支持细胞瘤、生殖细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、类囊肉瘤(胚性横纹肌肉瘤)、输卵管(癌)；血液学：血液(急性和慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；皮肤：恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、痣样痣、脂肪瘤、血管瘤、皮肤纤维瘤、红斑狼疮、银屑病和肾上腺：神经母细胞瘤。在某些实施例中，癌症是弥漫性大B细胞淋巴瘤(DLBCL)。
在一个实施例中，癌症是RAS家族相关癌症，如KRAS、NRAS或HRAS相关癌。在某些实施例中，RAS家族相关的癌症是非小细胞肺癌或胰腺癌。在一个实施例中，癌症是与SOS 1相关的癌症。在某些实施例中，SOS 1相关癌是肺腺癌、胚胎横纹肌肉瘤、支持细胞睾丸肿瘤和皮肤颗粒细胞肿瘤。
优选地，所述癌症为胰腺癌、结直肠癌、肺癌、肝细胞癌、肾癌、胃癌或胆管癌。
术语解释
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
在此使用的“KRAS G12C”是指哺乳动物KRAS蛋白的一种突变形式，该蛋白含有在氨基酸位置12处用半胱氨酸取代甘氨酸的氨基酸。
人类KRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P 01116：变异型p.Gly 12 Cys的氨基酸序列。
“KRAS G12D”是指哺乳动物KRAS蛋白的一种突变型，它含有天冬氨酸在第12位取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/Swi-prot P01116：变异型P.Gly 12 Asp确定的氨基酸序列确定的。
“KRAS G12V”是指哺乳动物KRAS蛋白的一种突变型，它含有缬氨酸在第12位取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/Swi-prot P01116：变异型P.Gly 12 Val确定的氨基酸序列确定的。
“KRAS G12S”是指一种哺乳动物KRAS蛋白的突变型，该蛋白含有氨基酸位置12处用丝氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01116：变异型p.Gly 12Ser鉴定的氨基酸序列确定的。
在此使用的“KRAS G12A”是指哺乳动物KRAS蛋白的一种突变形式，该蛋白含有氨基酸位置12处用丙氨酸替代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01116：变异型p.Gly 12Ala鉴定的氨基酸序列确定的。
“KRAS G13D”是指一种哺乳动物KRAS蛋白的突变型，该蛋白含有氨基酸位置13处天冬氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P01116：变体p.gly 13Asp所确定的氨基酸序列。
“KRAS G13C”是指一种哺乳动物KRAS蛋白的突变型，它含有氨基酸13处用半胱氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt-Prot P01116：变异型P.Gly 13Cys确定的氨基酸序列确定的。
在此使用的“KRAS Q61L”是指哺乳动物KRAS蛋白的一种突变形式，该蛋白含有氨基酸61处亮氨酸取代谷氨酰胺的氨基酸。人类KRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P 01116的氨基酸序列：变异型p.Gln61Leu。
在此使用的“KRAS A146T”是指哺乳动物KRAS蛋白的一种突变形式，它含有在氨基酸第146位以苏氨酸取代丙氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01116：变异型p.al46Thr鉴定的氨基酸序列确定的。
在此使用的“KRAS A146V”是指哺乳动物KRAS蛋白的一种突变形式，它含有一个氨基酸第146位以缬氨酸取代丙氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01116：变种p.al46Val鉴定的氨基酸序列确定的。
在此使用的“KRAS A146P”是指哺乳动物KRAS蛋白的一种突变形式，该蛋白含有在氨基酸位置146处的脯氨酸替代丙氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01116：变异型p.Al46Pro鉴定的氨基酸序列确定的。
在此使用的“HRAS G12C”是指哺乳动物HRAS蛋白的一种突变形式，其中含有在氨基酸位置12处用半胱氨酸取代甘氨酸的氨基酸。根据UniProtKB/SwissProt P 01112：变体p.Gly 12 Cys鉴定的氨基酸序列，确定了人HRAs的氨基酸密码子和残基位置。
“HRAS G12D”是指一种哺乳动物HRAS蛋白的突变体，该蛋白含有天冬氨酸取代甘氨酸的氨基酸取代氨基酸第12位，人类HRAs的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P01112：变异型P.Gly 12Asp的氨基酸序列。
“HRAS G12S”是指一种哺乳动物HRAS蛋白的突变型，该蛋白含有12处用丝氨酸取代甘氨酸的氨基酸。人类HRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P01112：变异型P.Gly 12Ser确定的氨基酸序列确定的。
“HRAS G12A”是指一种哺乳动物HRAS蛋白的突变型，该蛋白12处用丙氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P01112：变异型P.Gly 12Ala鉴定的氨基酸序列确定的。
“HRAS G13D”是指一种哺乳动物HRAS蛋白的突变型，其中含有天冬氨酸在第13位取代甘氨酸的氨基酸。人类HRAS的氨基酸密码子和残基位置是根据UniProtKB/Swi-prot P01112：变异型p.gly 13Asp确定的氨基酸序列确定的。
“HRAS G13C”是一种哺乳动物HRAS蛋白的突变体，其中含有半胱氨酸在第13位氨基酸酸取代甘氨酸的氨基酸。人类HRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt-Prot P01112：变异型P.Gly 13Cys的氨基酸序列。
在此使用的“HRAS Q61L”是指一种哺乳动物HRAS蛋白的突变形式，该蛋白含有氨基酸位置61处的亮氨酸取代谷氨酰胺的氨基酸，其氨基酸位置为61。根据UniProtKB/SwissProt P 01112变异型p.Gln61Leu鉴定的氨基酸序列，确定了人HRAs的氨基酸密码子和残基位置。
在此使用的“HRAS A146T”是指哺乳动物HRAS蛋白的一种突变形式，该蛋白含有在氨基酸位置146处的苏氨酸取代丙氨酸的氨基酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01112：变异型p.Al46Thr鉴定的氨基酸序列确定的。
在此使用的“HRAS A146V”是指哺乳动物HRAS蛋白的一种突变形式，该蛋白含有氨基酸位置146处的缬氨酸取代丙氨酸的氨基酸。一个氨基酸替代氨基酸位置146处的丙氨酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01112：变体p.al46Val鉴定的氨基酸序列确定的。
在此使用的“HRAS A146P”是指哺乳动物HRAS蛋白的一种突变形式，其中含有在氨基酸位置146处的脯氨酸替代丙氨酸的氨基酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01112：变体p.Al46Pro鉴定的氨基酸序列确定的。
“NRAS G12C”是指哺乳动物NRAS蛋白的一种突变形式，它含有氨基酸12处半胱氨酸取代甘氨酸的氨基酸。人类NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt-Prot P01111：变异型P.Gly12Cys确定的。
“NRAS G12D”是指哺乳动物NRAS蛋白的一种突变型，它含有天冬氨酸在第12位取代甘氨酸的氨基酸。人类NRAS的氨基酸密码子和残基位置是根据UniProtKB/Swi-prot P01111：变异型P.Gly 12 Asp确定的氨基酸序列确定的。
“NRAS G12S”是指哺乳动物NRAS蛋白的一种突变型，该蛋白含有氨基酸12处丝氨酸取代甘氨酸的氨基酸。人类NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P01111：变异型p.Gly 12Ser鉴定的氨基酸序列确定的。
“NRAS G12A”是指哺乳动物NRAS蛋白的一种突变型，它含有氨基酸12处丙氨酸取代甘氨酸的氨基酸。人类KRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P01111：变异型p.Gly 12Ala的氨基酸序列。
在这里使用的“NRAS G13D”是指哺乳动物NRAS蛋白的一种突变形式，它含有氨基酸13处天冬氨酸在氨基酸位置取代甘氨酸的氨基酸替代物。人类NRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P 01111：变异型p.Gly 13 Asp所确定的氨基酸序列。
“HNRas G13C”是指哺乳动物NRAS蛋白的一种突变形式，该蛋白含有氨基酸13处半胱氨酸取代甘氨酸的氨基酸。人类NRAS的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt P01111：变异型P.Gly 13Cys的氨基酸序列。
在此使用的“HRAS Q61L”是指一种哺乳动物HRAS蛋白的突变形式，该蛋白含有氨基酸61处亮氨酸取代谷氨酰胺，其氨基酸位置为61。根据UniProtKB/SwissProt P 01112变异型p.Gln61Leu鉴定的氨基酸序列，确定了人HRAs的氨基酸密码子和残基位置。
在此使用的“NRAS A146T”是指哺乳动物NRAS蛋白的一种突变形式，该蛋白含有在氨基酸第146处的苏氨酸取代丙氨酸的氨基酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01111：变体p.Al46Thr鉴定的氨基酸序列确定的。
在此使用的“NRAS A146V”是指哺乳动物NRAS蛋白的一种突变形式，该蛋白含有在氨基酸第146处的缬氨酸取代丙氨酸的氨基酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01111：变异型p.al46Val鉴定的氨基酸序列确定的。
如本文所用，“NRAS A146P”是指哺乳动物NRAS蛋白的一种突变形式，其中含有一种氨基酸146处脯氨酸替代丙氨酸的氨基酸。人NRAS的氨基酸密码子和残基位置是根据UniProtKB/SwissProt P 01111：变异型p.Al46Pro鉴定的氨基酸序列确定的。
如此处所用，“RAS家族成员”或“RAS家族”是指KRAS、HRAS、NRAS及其激活突变体，包括在G12、G13、Q61和A 146位置。
这里使用的‘RAS家族相关疾病或紊乱’是指与激活的RAS突变相关、由其介导或具有激活RAS突变的疾病或疾病，例如位于G12、G13、Q61或A 146位置的RAS。RAS家族相关疾病或疾病的非限制性例子有KRAS、HRAS或NRAS G12C相关癌、KRAS、HRAS或NRAS G12D相关癌、KRAS、HRAS或NRAS G12V相关癌、KRAS、HRAS或NRAS G12S相关癌、KRAS、HRAS或NRAS G12A相关癌、KRAS、HRAS或NRAS G13D相关癌、KRAS、HRAS或NRAS G13C相关癌、KRAS、HRAS或NRAS Q61L相关癌、KRAS、HRAS或NRAS A146T相关癌、KRAS、HRAS或NRAS A146V相关癌或KRAS、HRAS或NRAS 146P相关癌症。
这里使用的“SOS1相关疾病或紊乱”是指与激活的SOS 1突变相关的、由其介导的或具有激活的SOS1突变的疾病或疾病。激活SOS 1突变的例子包括SOS1N233S和SOS1N233Y突变。
在此，“SOS1N233S”是指哺乳动物SOS 1蛋白的一种突变形式，其中含有丝氨酸取代谷氨酰胺在233号氨基酸位置的氨基酸替代物。人类SOS 1的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt Q 07889：变体p.Gln233Ser鉴定的氨基酸序列。
在此，“SOS1N233Y”是指哺乳动物SOS 1蛋白的一种突变形式，其中含有酪氨酸取代谷氨酰胺的氨基酸替代氨基酸233位。人类SOS 1的氨基酸密码子和残基位置的确定是基于UniProtKB/SwissProt Q 07889：变体p.Gln233Tyr鉴定的氨基酸序列。
在这里使用的，“SOS 1抑制剂”是指本发明的化合物，如本文所述，由公式(I)表示。这些化合物能负抑制SOS 1与RAS家族突变体或SOS 1激活突变的全部或部分相互作用，从而降低和/或调控RAS家族成员-SOS 1复合物的核苷酸交换活性。
在这里使用的，“KRAS抑制剂”是指本领域已知的针对各种KRAS突变的抑制剂。可以针对如KRAS G12C、KRAS G12D、KRAS G12V的抑制剂。
在这里使用的，“MEK信号通路”抑制剂是指本领域已知的针对RAF、MEK和ERK1/2的抑制剂。
“NF-1/NF-2相关疾病或紊乱”是指由神经纤维素酶(NF-1)基因或神经纤维素酶2(NF-2)基因中的功能缺失突变引起的疾病或疾病。
在此使用的“功能缺失突变”是指任何点突变、剪接位点突变、融合、无义突变(氨基酸突变为终止密码子)、帧内突变或框架转移突变，包括插入和缺失，以及目标细胞或癌细胞中编码蛋白质的基因的纯合性缺失，导致编码蛋白的部分或完全丧失存在、活动和/或功能。
“烷基”指饱和脂肪族烃基团，包括1-20个碳原子，或1-10个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子，或1-2个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述地取代基所取代。烷基基团更近一步地实例包括，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是任选取代或未取代的。
“烯基”指2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子直链或支链的一价烃基，其中至少一个C-C为sp 2双键，其中烯基的基团可以独立任选地被1个或多个本发明所描述的取代基所取代，其中具体的实例包括，但并不限于乙烯基、烯丙基和烯丁基等等。烯基可以是任选取代或未取代的。
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包括3至20个碳原子，优选包括3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实施例包括，但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000021
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000022
“桥环烷基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000023
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，本申请中可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基，其中至少一个环原子原子是杂原子，如氧、氮、硫原子等。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1，1-二氧代-硫代吗啉基，哌啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、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。杂环基可以是任选取代的或未取代的。
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O) m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非 限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000024
“稠杂环基”指含有两个或两个以上环状结构彼此公用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O) m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000025
“桥杂环基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O) m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000026
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000027
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、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，非限制性实施例包括但不限于：
Figure PCTCN2022072055-appb-000028
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”指具有一个或者多个卤素取代基的烷基，其中烷基基团具有如本发明所述的含义。卤代烷基的实例包括，但并不限于氟甲基、二氟甲基、三氟甲基、全氟乙基、1,1-二氯乙基、1,2-二氯丙基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“苄基”指-CH 2-苯基。
“羧基”指-C(O)OH。
“乙酰基”指-C(O)CH 3或Ac。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“任选”意味着其所描述的事件可以但不必发生。例如，“AR任选被1到多个R c取代”该说明包含着AR基团可以被1到多个R c取代或者不被R c取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)R b、-OC(O)R b、-NR bR b、-C(O)NR bR b、-NR bC(O)R b、-S(O)NR bR b或-S(O) 2NR bR b，其中，R b的定义如通式(I)中所述。
如此处所用，“主体”、“个体”或“病人”一词交替使用，指任何动物，包括老鼠、老鼠、其他啮齿动物、兔子、狗、猫、猪、牛、羊、马、灵长类动物和人类。在一些实施例中，病人是人类。在一些实施例中，被试已经经历和/或显示了要治疗和/或预防的疾病或疾病的至少一个症状。在一些实施例中，该研究对象已被确定或诊断为具有KRAS G12或G13突变的癌症(例如，由经FDA批准的监管机构确定，如FDA批准的、化验或试剂盒)。在一些实施例，所述对象具有对KRAS G12C突变、KRAS G12D突变、KRAS G12S突变、KRAS G12V突变、KRAS G12A突变、KRAS G13D突变或KRAS G13C突变呈阳性的肿瘤(例如，由监管机构-批准的检测或试剂盒确定)。该研究对象可以是具有KRAS G12C突变、KRAS G12D突变、KRAS G12V突变、KRAS G12S突变、KRAS G12A突变、KRAS G13D突变或KRAS G13C突变(例如，经批准的监管机构-如FDA批准的、分析或试剂盒)阳性的肿瘤患者。该对象可以是其肿瘤具有KRAS G12C突变、KRAS G12D突变、KRAS G12V突变、KRAS G12S突变、KRAS G12A突变、KRAS G13D突变或KRAS G13C突变的对象(例如，该肿瘤是通过经FDA批准的监管机构、试剂盒或化验确定的)。在一些实施例中，被试被怀疑患有KRAS G12或G13基因相关的癌症。在一些实施例中，被试具有临床记录，表明 被试具有具有KRAS G12C突变的肿瘤(以及可选的临床记录表明应使用本文提供的任何组合物治疗该对象)。
此处使用的“儿科病人”一词是指在诊断或治疗时未满16岁的病人。“儿童”一词还可分为以下几个亚类：新生儿(从出生到出生第一个月)；婴儿(1个月至两岁)；儿童(2岁至12岁)；青少年(12岁至21岁(直到但不包括22岁生日))。Berhman RE，Kliegman R，Arvin AM，Nelson we.尼尔森儿科教科书，第15版。费城：W.B.Saunders公司，1996年；Rudolph AM，等人。鲁道夫的儿科，第21版。纽约：McGrow-Hill，2002年；和Avery MD，第一LR。儿科医学，第二版。巴尔的摩：Williams&Wilkins；1994。
如本文所用，化合物的“有效量”是指足以负调节或抑制SOS 1酶活性的量。
如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或负调节或抑制SOS 1活性的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。
如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。
本发明中立体化学的定义和惯例的使用通常参考以下文献：
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。非对映异构体可以以其物理化学差异为基础，通过层析、结晶、蒸馏或升华等方法被分离为个别非对映异构体。对映异构体可以通过分离，使手性异构混合物转化为非对映异构混合物，其方式是与适当光学活性化合物(例如手性辅助剂，譬如手性醇或Mosher氏酰氯)的反应，分离非对映异构体，且使个别非对映异构体转化为相应的纯对映异构体。本发明的中间体与化合物也可以不同互变异构形式存在，且所有此种形式被包含在本发明的范围内。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的原子或原子团互相连接次序相同，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体的混合物都属于本发明的范围。
“药学上可接受的盐”指本发明化合物的盐，这类盐用于人或动物体内时具有安全性和有效性。化合物的盐可以通过在纯的溶液或合适的惰性溶解中用足量的碱或酸获得相应的加成盐。可药用的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐等，可药用的酸加成盐包括无机酸盐和有机酸盐，所述的无机酸和有机酸包括盐酸、氢溴酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸一氢根、乙酸、马来酸、丙二酸、琥珀酸、饭丁烯二酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸和甲磺酸等(参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science 66:1-19(1977))。
本发明提供了一种新结构的SOS1抑制剂，试验结果表明，该多环嘧啶类衍生物表现出优异的SOS1抑制活性，同时表现出优异的安全性和选择性，可用于制备治疗癌症，尤其是胰腺癌、结直肠癌、肺癌、肝细胞癌、肾癌、胃癌和胆管癌等疾病的药物。
附图说明
图1是本发明所涉及化合物对K-562细胞KRAS/ERK1/2信号转导通路的影响结果图。
图2是单用本发明所涉及SOS1抑制剂对KRAS G12D突变体PANC-1胰腺异种移植瘤裸小鼠模型的体内抗肿瘤作用图。
图3是单用本发明所涉及SOS1抑制剂对KRAS G12D突变体PANC-1胰腺异种移植瘤裸小鼠模型的小鼠体重影响图。
图4是单用或者组合的本发明所涉及SOS1抑制剂和曲美替尼(Trametinib)对KRAS G12C突变体MIAPaCa-2胰腺异种移植瘤裸小鼠模型的体内抗肿瘤作用图。
图5是单用或者组合的本发明所涉及SOS1抑制剂和曲美替尼(Trametinib)对KRAS G12C突变体MIAPaCa-2胰腺异种移植瘤裸小鼠模型的小鼠体重影响图。
具体实施方式
下面通过具体实施例对本发明的方法进行说明，以使本发明技术方案更易于理解、掌握，但本发明并不局限于此。下述实施例中 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式为ESI。
高效液相色谱仪型号：安捷伦1260、赛默飞U3000；色谱柱型号：Waters xbrige C18(4.6*150mm,3.5μm)；流动相：A:ACN,B:Water(0.1％H 3PO 4)；流速：1.0mL/min；梯度：5％A for 1min,increase to 20％A within 4min,increase to 80％A within 8min,80％A for 2min,back to 5％A within 0.1min；波长：220nm；柱温箱：35℃。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2mm-0.3mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于国药集团，百灵威科技有限公司，梯希爱(上海)化成工业发展有限公司，上海毕得医药科技有限公司和上海迈瑞尔化学科技有限公司等。
CD 3OD：氘代甲醇
CDCl 3：氘代氯仿
DMSO-d 6：氘代二甲基亚砜
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯
XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽
XPhos：2-二环己基磷-2,4,6-三异丙基联苯
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
TLC：薄层色谱法
HPLC：高效液相色谱法
purity：纯度
&：和
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系或薄层色谱法的展开剂体系包括：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：正己烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性 试剂进行调节，如醋酸或三乙胺等。
中间体的制备
中间体1
(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺IN-1
Figure PCTCN2022072055-appb-000029
第一步1-(3-硝基-5-(三氟甲基)苯基)乙-1-酮IN-1b
3-溴-5-硝基三氟甲苯IN-1a(2.0g,7.41mmol)，三丁基(1-乙氧基乙烯)锡(3.5g,9.69mmol)和Pd(PPh 3) 2Cl 2(520mg,0.74mmol)依次加入到甲苯(25mL)中，氮气保护下，加热至100℃反应过夜，TLC显示反应完全。反应液冷却至室温，加入盐酸(15mL,3N)，搅拌30分钟，垫硅藻土过滤，滤液分液，水相乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色油状标题化合物IN-1b(1.25g,收率72％)。
1H NMR(400MHz,CDCl 3)δ8.94(s,1H),8.68(s,1H),8.53(s,1H),2.75(s,3H).
第二步(R,Z)-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)亚乙基)丙烷-2-亚磺酰胺IN-1c
化合物IN-1b(1.25g,5.36mmol)、(R)-(+)-叔丁基亚磺酰胺(974mg,8.04mmol)和钛酸四乙酯(10mL,47.70mmol)的混合物加热至80℃反应3小时，TLC显示有少量原料剩余。反应液冷却至室温，倒入冰水(60mL)中，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得到黄色油状标题化合物IN-1c(1.01g,收率56％)。
第三步(R)-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺IN-1d
化合物IN-1c(260mg,0.77mmol)溶于四氢呋喃(2.5mL)和水(0.05mL)中，降温至-60℃，分批加入硼氢化钠(74mg,1.95mmol)，加毕，保持-60℃继续搅拌1小时，TLC显示反应完全。反应液中滴加水淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得到白色固体标题化合物IN-1d(150mg,收率58％)。
1H NMR(400MHz,CDCl 3)δ8.43-8.42(m,2H),7.95(s,1H),4.75-4.69(m,1H),3.55(d,J＝4.4Hz,1H),1.61(d,J＝6.8Hz,3H),1.25(s,9H).
第四步(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺IN-1
化合物IN-1d(164mg,0.48mmol)溶于四氢呋喃(3mL)中，滴加浓盐酸(0.5mL)，滴毕，室温反应1小时，TLC显示反应完全。反应液滴加饱和碳酸钠水溶液调节pH＝8，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色油状标题化合物IN-1(105mg,收率92％)。
LC-MS:m/z＝235.1[M+H] +
中间体2
(R)-3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯胺IN-2
Figure PCTCN2022072055-appb-000030
第一步1-溴-3-二氟甲基-2-氟苯IN-2b
2-氟-3-溴苯甲醛IN-2a(10.0g,49.26mmol)溶于二氯甲烷(200mL)中，冷却至0℃，慢慢滴加二乙胺基 三氟化硫(15.9g,98.64mmol)，滴毕，缓慢升至室温搅拌1小时，TLC显示原料反应完全。反应液倒入饱和碳酸氢钠水溶液中淬灭，二氯甲烷萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色液体标题化合物IN-2b(8.1g,收率73％)。
1H NMR(400MHz,CDCl 3)δ7.68(t,J＝7.2Hz,1H),7.55(t,J＝7.2Hz,1H),7.14(t,J＝8.0Hz,1H),6.89(t,J＝54.8Hz,1H).
第二步1-(3-(二氟甲基)-2-氟苯乙酮IN-2c
化合物IN-2b(8.1g,36.00mmol)溶于1,4-二氧六环(80mL)中，室温下依次加入三乙胺(9.1g,89.93mmol)和三丁基(1-乙氧基乙烯)锡(15.6g,43.20mmol)，氮气鼓泡15分钟，加入Pd(PPh 3) 2Cl 2(250mg,0.36mmol)，氮气置换多次，升温至100℃搅拌1小时，TLC显示反应完全。反应液冷却至室温，加入稀盐酸(14.4mL,72.0mmol,5M)，室温搅拌1小时，TLC显示原料反应完全。反应液加水稀释，乙酸乙酯萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色液体标题化合物IN-2c(5.6g,收率83％)。
1H NMR(400MHz,CDCl 3)δ8.00(t,J＝7.2Hz,1H),7.79(t,J＝6.8Hz,1H),7.34(t,J＝7.6Hz,1H),6.94(t,J＝54.8Hz,1H),2.67(d,J＝5.2Hz,3H).
第三步1-(3-(二氟甲基)-2-氟-5-硝基苯基)乙-1-酮IN-2d
硝酸钾(45.6g,0.45mmol)溶于浓硫酸(100mL)中，室温搅拌30分钟，冷却至0℃左右，缓慢滴加化合物IN-2c(8.5g,45.18mmol)，0℃搅拌5分钟，TLC显示反应完全。反应液慢慢加入冰水中，乙酸乙酯萃取，合并有机相，饱和碳酸氢钠水溶液洗，饱和盐水洗，浓缩，粗品经硅胶柱纯化得淡黄色液体标题化合物IN-2d(9.0g,收率86％)。
1H NMR(400MHz,CDCl 3)δ8.88-8.86(m,1H),8.66-8.64(m,1H),7.12-6.85(m,1H),2.73(d,J＝4.8Hz,3H).
第四步(R,Z)-N-(1-(3-(二氟甲基)-2-氟-5-硝基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺IN-2e
化合物IN-2d(9.0g,38.60mmol)分散在钛酸四乙脂(90mL)中，室温下加入(R)-(+)-叔丁基亚磺酰胺(7.0g,57.76mmol)，缓慢升温至100℃搅拌1小时，TLC显示原料反应完全。反应液冷却至室温，倒入剧烈搅拌的冰水中，持续搅拌10分钟，过滤，滤饼反复用乙酸乙酯洗涤，滤液乙酸乙酯萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩得黄色油状标题化合物IN-2e(9.0g,粗品)，直接用于下一步。
LC-MS:m/z＝337.1[M+H] +
第五步(R)-N-(1-(3-(二氟甲基)-2-氟-5-硝基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺IN-2f
化合物IN-2e(9.0g,粗品)溶于四氢呋喃(150mL)和水(2mL)中，降温至-60℃左右，分批加入硼氢化钠(3.1g,81.95mmol)，加毕，缓慢升温至室温继续反应2小时，TLC显示原料被耗尽。反应液倒入冰水淬灭，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱纯化得棕色油状标题化合物IN-2f(2.8g,两步收率21％)。
LC-MS:m/z＝339.1[M+H] +
第六步(R)-1-(3-(二氟甲基)-2-氟-5-硝基苯基)乙-1-胺IN-2g
化合物IN-2f(2.8g,8.28mmol)溶于四氢呋喃(30mL)中，加入浓盐酸(1.4mL,16.52mmol)，室温搅拌1小时，TLC显示原料被耗尽。反应液冷却至室温，倒入饱和碳酸氢钠水溶液调节pH为碱性，乙酸乙酯萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩得棕色液体，放置固化成棕色固体标题化合物IN-2g(1.8g,收率95％)。
LC-MS:m/z＝235.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.76-8.74(m,1H),8.41-8.39(m,1H),7.52-7.25(m,1H),4.42(q,J＝6.4Hz,1H),2.48-2.24(m,2H),1.35(d,J＝6.8Hz,3H).
第七步(R)-3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯胺2e
化合物IN-2g(300mg,1.28mmol)溶于乙醇和水(6mL/2mL)中，室温下加入还原铁粉(358mg,6.41mmol)和氯化铵(346mg,6.69mmol)，加热至90℃反应2小时，TLC检测显示反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩得到标题化合物IN-2(350mg,粗品)，直接用于下一步。
中间体3
(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺IN-3
Figure PCTCN2022072055-appb-000031
第一步(R,Z)-N-(1-(3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺IN-3a
化合物IN-2c(5.6g,29.76mmol)溶于钛酸四乙脂(50mL)中，室温下加入(R)-(+)-叔丁基亚磺酰胺(10.8g,89.11mmol)，缓慢升温至100℃搅拌1小时，TLC显示原料反应完全。反应液冷却至室温，倒入剧烈搅拌的冰水中，持续搅拌10分钟，过滤，滤饼反复用乙酸乙酯洗涤，滤液乙酸乙酯萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩得黄色油状标题化合物IN-3a(9.5g,粗品)，直接用于下一步。
LC-MS:m/z＝292.1[M+H] +
第二步(R)-N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺IN-3b
化合物IN-3a(9.5g,粗品)溶于四氢呋喃(100mL)和水(2mL)中，降温至-60℃左右，分批加入硼氢化钠(3.7g,97.80mmol)，加毕，缓慢升温至室温继续反应2小时，TLC显示原料被耗尽。反应液倒入冰水淬灭，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色油状标题化合物IN-3b(2.9g,两步收率33％)。
LC-MS:m/z＝294.1[M+H] +
第三步(R)-1-(3-(二氟甲基)-2-氟苯乙胺IN-3
化合物IN-3b(2.9g,9.88mmol)溶于四氢呋喃(50mL)中，室温下加入浓盐酸(720mg,19.8mmol,12N)，升温至80℃搅拌1小时，TLC显示原料被耗尽。反应液冷却至室温，倒入饱和碳酸氢钠水溶液调节pH为碱性，乙酸乙酯萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，浓缩得棕色液体标题化合物IN-3(2.0g,粗品)，直接用于下一步。
LC-MS:m/z＝190.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.58(t,J＝7.4Hz,1H),7.47(t,J＝6.8Hz,1H),7.23(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),4.45(q,J＝6.8Hz,1H),1.80(s,2H),1.43(d,J＝6.4Hz,3H).
中间体4
(S)-2-((四氢呋喃-3-基)氧基)乙酸乙酯IN-4
Figure PCTCN2022072055-appb-000032
第一步(S)-四氢呋喃-3-基4-硝基苯甲酸酯IN-4b
氮气保护下，(R)-(-)-3-羟基四氢呋喃IN-4a(10.0g,0.113mol)溶于四氢呋喃(130mL)中，室温下加入硝基苯甲酸(18.9g,0.113mol)和三苯基磷(35.6g,0.136mol)，降温至0℃，滴加偶氮二甲酸二异丙酯(27.8g,0.137mol)的四氢呋喃(20mL)溶液，滴完室温反应2小时，TLC显示原料反应完。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得白色固体标题化合物IN-4b(29.8g,粗品，含有少量三苯氧磷)。
第二步(S)-3-羟基四氢呋喃IN-4c
化合物IN-4b(29.8g,粗品)溶于乙醇(300mL)中，再加入碳酸钠(25.0g,0.236mol)，加热至85℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，过滤，滤液浓缩，粗品经硅胶柱层析得油状标题化合物IN-4c(8.1g,两步收率81％)。
第三步(S)-2-((四氢呋喃-3-基)氧基)乙酸叔丁酯IN-4d
化合物IN-4c(3.0g,34.05mmol)溶于甲苯(40mL)中，加入四丁基溴化铵(3.0g,9.30mmol)和氢氧化钠水溶液(30mL,360mmol,12mol/L)，室温搅拌下加入溴乙酸叔丁酯(9.9g,50.75mmol)，加完20℃搅拌过夜，TLC显示反应完全。反应液乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得黄色油状标题化合物IN-4d(5.5g,收率80％)。
1H NMR(400MHz,CDCl 3)δ4.22-4.25(m,1H),3.97(s,2H),3.80-3.95(m,4H),1.96-2.09(m,2H),1.48(s,9H).
第四步(S)-2-((四氢呋喃-3-基)氧基)乙酸IN-4e
化合物IN-4d(5.5g,27.19mmol)溶于二氯甲烷(15mL)中，加入三氟乙酸(30mL)，加热至45℃反应2小时，TLC显示基本反应完全。反应液浓缩(二氯甲烷带3次)得到淡黄色油状标题化合物IN-4e(13.5g,粗品)，直接用于下一步。
第五步(S)-2-((四氢呋喃-3-基)氧基)乙酸乙酯IN-4
化合物IN-4e(13.5g,粗品)溶于乙醇(100mL)中，室温下加入浓硫酸(30mL)，加热至85℃反应5小时。反应液冷却至室温，倒入冰盐水中，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得微黄色油状标题化合物IN-4(2.1g,两步收率44％)。
1H NMR(400MHz,CDCl 3)δ4.29-4.18(m,3H),4.08(s,2H),3.96-3.79(m,4H),2.09-1.96(m,2H),1.29(t,J＝7.2Hz,3H).
中间体5
R)-(3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5
Figure PCTCN2022072055-appb-000033
第一步3-溴-2-氟-5-硝基苯甲酸IN-5b
浓硫酸(60mL)冷却至0℃，加入2-氟-5-硝基苯甲酸IN-5a(10.0g,54.0mmol)，溶解后加入二溴海因(9.30g,32.4mmol)，升至室温反应过夜，TLC检测原料反应完全。反应液倒入冰水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物IN-5b(15.0g,粗品)，直接用于下一步。
第二步(3-溴-2-氟-5-硝基苯基)甲醇IN-5c
化合物IN-5b(15.0g,粗品)溶于四氢呋喃(100mL)中，氮气保护下，冷却至0℃，滴加硼烷四氢呋喃溶液(85.3mL,85.3mmol,10M)，加完升至室温反应过夜，TLC检测反应完全。反应液冷却至0℃，滴加甲醇淬灭至无气体产生，浓缩，残余物溶于乙酸乙酯，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物IN-5c(14.5g,粗品)，直接用于下一步。
第三步(5-氨基-3-溴-2-氟苯基)甲醇IN-5d
化合物IN-5c(14.5g,粗品)和氯化亚锡(44.0g,232mmol)溶于乙酸乙酯(200mL)中，冷却至0℃，滴加浓盐酸(9.70mL,116mmol,12M)，加完自然升至室温搅拌3小时，TLC检测反应完全。反应液加冰水淬灭，氢氧化钠水溶液(2N)调节pH＝14，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物IN-5d(13.5g,粗品)，直接用于下一步。
LC-MS:m/z＝220.0[M+H] +
第四步(3-溴-4-氟-5-(羟甲基)苯基)氨基甲酸叔丁酯IN-5e
化合物IN-5d(12.8g,粗品)溶于N,N-二甲基甲酰胺(100mL)中，室温下加入二碳酸二叔丁酯(25.3g,116mmol)，升温至60℃搅拌3小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物IN-5e(18.6g,粗品)，直接用于下一步。
LC-MS:m/z＝318.0[M-H] -
第五步(3-溴-4-氟-5-甲酰基苯基)氨基甲酸叔丁酯IN-5f
化合物IN-5e(18.6g,粗品)溶于二氯甲烷(200mL)中，冷却至0℃，加入戴斯-马丁试剂(36.9g,87.0mmol)，室温反应2小时，TLC检测原料反应完全。反应液冷却至0℃，加饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物IN-5f(18.4g,粗品)，直接用于下一步。
第六步(3-溴-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5g
化合物IN-5f(18.4g,粗品)溶于二氯甲烷(200mL)中，冷却至0℃，滴加二乙胺基三氟化硫(19.6g,122mmol)，加完0℃继续反应1小时，再升至室温反应2小时，TLC检测反应完全。反应液加水淬灭，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品硅胶柱层析纯化得到黄色固体标题化合物IN-5g(19.2g,粗品)，直接用于下一步反应。
第七步(3-乙酰基-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5h
化合物IN-5g(19.2g,粗品)，三丁基(1-乙氧基乙烯)锡(20.1g,56.5mmol)和双三苯基磷二氯化钯(793mg,1.13mmol)依次加入到甲苯(100mL)中，氮气保护下升温至100℃搅拌过夜，TLC检测原料消失。反应液冷却至室温，加稀盐酸(50mL,2N)搅拌3小时，TLC检测反应完全。反应液加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物IN-5h(9.1g,七步收率52％)。
第八步(R,Z)-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5i
化合物IN-5h(5.50g,18.1mmol)和叔丁基亚磺酰胺(3.30g,27.2mmol)溶于四氢呋喃(80mL)中，室温下加入钛酸异丙酯(10.3g,36.3mmol)，升温至80℃搅拌过夜，TLC检测反应完全。反应液冷却至室温，加水淬灭，过滤除去不溶物，滤液乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物IN-5i(4.60g,收率62％)。
第九步(3-((R)-1-(((R)-叔丁基亚磺酰基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5j
化合物IN-5i(4.60g,11.3mmol)溶于四氢呋喃(50mL)和水(3mL)中，降温至-20℃，加入硼氢化钠(856mg,22.6mmol)，自然升至室温搅拌1小时，TLC检测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色油状标题化合物IN-5j(1.92g,收率42％)。
第十步(R)-(3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯IN-5
化合物IN-5j(1.92g,4.70mmol)溶于四氢呋喃(20mL)中，加入浓盐酸(0.80mL,9.40mmol,12N)，室温搅拌1小时，TLC检测反应完全。反应液加水淬灭，饱和碳酸氢钠水溶液中和，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色油状标题化合物IN-5(1.41g,收率99％)。
LC-MS:m/z＝305.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.64-7.57(m,1H),7.54-7.46(m,1H),6.83(t,J＝54.8Hz,1H),6.80(br,1H),4.43(q,J＝6.8Hz,1H),2.51(s,2H),1.50(s,9H),1.43(d,J＝6.8Hz,3H).
中间体6
(R)-(3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯IN-6
Figure PCTCN2022072055-appb-000034
第一步1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙烷-1-酮IN-6a
化合物IN-5h(3.0g,9.89mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(10mL)，室温反应3小时，TLC检测反应完全。反应液浓缩，剩余物用饱和碳酸钠水溶液中和，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得黄色油状标题化合物IN-6a(2.5g,粗品)，直接用于下一步。
第二步(3-乙酰基-5-(二氟甲基)-4-氟苯基)氨基甲酸苄酯IN-6b
化合物IN-6a(2.5g,粗品)溶于四氢呋喃(20mL)和水(8mL)中，加入碳酸钠(5.2g,49.06mmol)，滴加氯甲酸苄酯(2.0g,11.72mmol)，加毕，室温反应4小时，TLC检测基本反应完全。反应液加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄色固体标题化合物IN-6b(2.2g,两步收率67％)。
LC-MS:m/z＝393.1[M+H] +
第三步(R,Z)-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯IN-6c
化合物IN-6b(2.2g,6.52mmol)和(R)-(+)-叔丁基亚磺酰胺(870mg,7.18mmol)溶于四氢呋喃(20mL)中，室温下加入钛酸四异丙酯(9.2g,32.37mmol)，加热至70℃反应过夜，TLC检测基本反应完全。反应液冷却至室温，加入乙酸乙酯和水，剧烈搅拌半小时，过滤，滤液乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得淡黄色固体标题化合物IN-6c(1.4g,收率55％)。
第四步(3-((R)-1-(((R)-叔丁基亚磺酰基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯IN-6d
化合物IN-6c(1.4g,3.57mmol)分散在四氢呋喃(15mL)和水(1.5mL)中，降温至-60℃，分批加入硼氢化钠(675mg,17.85mmol)，加毕，缓慢升至室温反应2小时，TLC检测反应完全。反应液倒入冰水中淬灭，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得标题化合物淡黄色固体IN-6d(710mg,收率50％)。
第五步(R)-(3-(1-氨基乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯IN-6
化合物IN-6d(710mg,1.80mmol)溶于四氢呋喃(10mL)中，加入浓盐酸(0.2mL,2.36mmol,12N)，室温反应2小时，TLC检测反应完全。反应液加入饱和碳酸钠水溶液中和，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到白色固体标题化合物IN-6(495mg,收率95％)。
LC-MS:m/z＝291.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.68-7.53(m,2H),7.41-7.30(m,1H),6.83(t,J＝54.8Hz,1H),5.03-4.93(m,1H),4.47(q,J＝6.4Hz,1H),3.59(br,2H),1.45(d,J＝6.8Hz,3H),1.28(d,J＝6.4Hz,6H).
实施例1
N 4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-四氢呋喃-3-基)喹唑啉-4,6-二胺1
Figure PCTCN2022072055-appb-000035
第一步5-羟基-4-甲氧基-2-硝基苯甲酸1b
将2-硝基-4,5-二甲氧基苯甲酸1a(15.0g,66.03mmol)溶于氢氧化钠水溶液(60mL,6M)中，反应液升温至100℃搅拌3小时，TLC检测原料反应完全。反应液冷却至室温，用盐酸调节pH至2-3，用乙酸乙酯萃取，盐水洗涤，有机相干燥后浓缩得到黄色固体标题化合物1b(14.1g,粗品)，直接用于下一步。
1H NMR(400MHz,DMSO-d 6)δ13.44(s,1H),10.76(s,1H),7.56(s,1H),7.08(s,1H),3.90(s,3H).
第二步5-羟基-4-甲氧基-2-硝基苯甲酸甲酯1c
将化合物1b(14.1g,粗品)溶于甲醇(150mL)，滴加氯化亚砜(23.6g,198.37mmol)，反应液升温至80℃搅拌28小时，TLC检测反应完全。反应液冷却至室温，浓缩，残余物溶于乙酸乙酯，加水洗涤，饱和盐水洗涤，有机相干燥后浓缩得到黄色固体标题化合物1c(14.1g,粗品)，直接用于下一步。
第三步5-(苄氧基)-4-甲氧基-2-硝基苯甲酸甲酯1d
将化合物1c(14.1g,粗品)和溴化苄(12.7g,74.26mmol)溶于二甲基亚砜(100mL)，加入碳酸铯(40.4g,123.99mmol)，室温搅拌过夜，TLC检测反应完全。反应液加水，用乙酸乙酯萃取，盐水洗涤，有机相干燥后浓缩得到黄色油状标题化合物1d(18.4g,粗品)，直接用于下一步。
第四步2-氨基-5-(苄氧基)-4-甲氧基苯甲酸甲酯1e
将化合物1d(18.4g,粗品)溶于乙醇(200mL)和水(40mL)中，加入铁粉(16.2g,0.29mol)和氯化铵(15.5g,0.29mol)，反应液升温至90℃搅拌2小时，TLC检测反应完全。反应液垫硅藻土趁热过滤，滤液浓缩，残余物溶于乙酸乙酯，用盐水洗涤，有机相干燥后浓缩，剩余物经硅胶柱层析纯化得到黄色油状标题化合物1e(14.6g,四步收率77％)。
第五步6-(苄氧基)-7-甲氧基-2-甲基喹唑啉-4(3H)-酮1f
将化合物1e(1.0g,3.48mmol)溶于乙腈(10mL)，加入4M盐酸/1,4-二氧六环溶液(20mL,4M)，反应液升温至90℃搅拌过夜。反应液冷却至室温，将析出的沉淀过滤，收集固体。将固体溶于水中，用饱和碳酸氢钠水溶液调节pH至8，有固体析出，过滤收集固体，将固体干燥得到黄色固体标题化合物1f(930mg,粗品)，直接用于下一步。
LC-MS:m/z＝297.1[M+H] +
第六步6-(苄氧基)-4-氯-7-甲氧基-2-甲基喹唑啉1g
将化合物1f(930mg,粗品)溶于三氯氧磷(20mL)中，加入N,N-二异丙基乙胺(1.2g,9.29mmol)，反应液升温至100℃搅拌8小时，TLC检测反应完全。反应液冷却至室温，浓缩，残余物溶于二氯甲烷，滴入冷却的碳酸氢钠水溶液中淬灭，用盐水洗涤，有机相浓缩后柱层析纯化得棕色固体标题化合物1g(400mg,两步收率36％)。
LC-MS:m/z＝315.1[M+H] +
第七步(R)-6-(苄氧基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺1h
将化合物1g(400mg,1.27mmol)和化合物IN-1(328mg,1.40mmol)溶于二甲基亚砜(10mL)中，加入N,N-二异丙基乙胺(493mg,3.81mmol)，反应液升温至80℃搅拌过夜，TLC检测反应完全。反应液冷却至室温，加入水，用乙酸乙酯萃取，盐水洗涤，有机相干燥后浓缩得到黄色固体标题化合物1h(700mg,粗品)，直接用于下一步。
第八步(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-醇1i
将化合物1h(700mg,粗品)溶于三氟乙酸(6mL)中，反应液升温至80℃搅拌2小时，TLC检测反应完全。反应液冷却至室温，浓缩，残余物溶于二氯甲烷，加水洗涤，有机相干燥后浓缩得到黄色固体标题化合物1i(577mg,粗品)，直接用于下一步。
LC-MS:m/z＝423.2[M+H] +
第九步(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基三氟甲磺酸酯1j
将化合物1i(577mg,粗品)溶于二氯甲烷(20mL)中，加入吡啶(216mg,2.73mmol)和三氟甲磺酸酐(578mg,2.05mmol)，反应液室温搅拌3小时，TLC检测反应完全。反应液加水用二氯甲烷萃取，盐水洗涤，有机相浓缩后硅胶柱层析纯化得到黄色油状标题化合物1j(460mg,三步收率65％)。
LC-MS:m/z＝555.2[M+H] +
第十步7-甲氧基-2-甲基-N 4-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-N 6-((S)-四氢呋喃-3-基)喹唑啉-4,6-二胺5l
将化合物1j(130mg,0.23mmol)和(S)-3-氨基四氢呋喃1k(61mg,0.70mmol)溶于甲苯(20mL)中，加入Pd 2(dba) 3(43mg,0.047mmol)、BINAP(59mg,0.095mmol)和碳酸铯(152mg,0.47mmol)，氮气保护下反应液升温至100℃搅拌5小时，TLC检测原料基本反应完全。反应液冷却至室温，加水，用乙酸乙酯萃取，盐水洗涤，有机相干燥后浓缩，残余物经硅胶柱层析纯化得到黄色固体标题化合物1l(56mg,收率49％)。
LC-MS:m/z＝492.2[M+H] +
第十一步N 4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-四氢呋喃-3-基)喹唑啉-4,6-二胺1
将化合物1k(56mg,0.11mmol)溶于乙醇(6mL)和水(1mL)中，加入铁粉(32mg,0.57mmol)和氯化铵(30mg,0.56mmol)，反应液升温至90℃搅拌2小时，TLC检测反应完全。反应液垫硅藻土趁热过滤，滤液浓缩，残余物经Prep-TLC纯化得到淡黄色固体标题化合物1(26mg,收率49％)。
LC-MS:m/z＝462.3[M+H] +
1H NMR(400MHz,CD 3OD)δ7.20(s,1H),6.98(s,1H),6.97(s,1H),6.94(s,1H),6.80(s,1H),5.66(q,J＝7.2Hz,1H),4.35-4.29(m,1H),4.07-3.96(m,5H),3.91-3.85(m,1H),3.75-3.72(m,1H),2.47(s,3H),2.44-2.35(m,1H),1.99-1.92(m,1H),1.65(d,J＝7.2Hz,3H).(96.49％purity by HPLC)
实施例2
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺2
Figure PCTCN2022072055-appb-000036
第一步6-氯-2-甲基-4-嘧啶胺2b
4,6-二氯-2-甲基嘧啶2a(15.2g,93.25mmol)加入氨水溶液(150mL,25％)中，升温至65℃反应3小时，TLC显示原料反应完。反应液浓缩得到白色固体标题化合物2b(11.9g,粗品)，直接用于下一步。
LC-MS:m/z＝144.1[M+H] +
第二步6-氯-5-碘-2-甲基-4-嘧啶胺2c
化合物2b(11.9g,粗品)加入醋酸(120mL)中，室温下分批加入N-碘代丁二酰亚胺(18.64g,82.85mmol)，加热至70℃反应4小时，TLC显示原料反应完。反应液冷却至室温，加入饱和碳酸氢钠水溶液调节至中性，乙酸乙酯萃取，合并有机相，饱和碳酸氢钠水溶液洗，亚硫酸钠水溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得到白色固体标题化合物2c(11.82g,粗品)，直接用于下一步。
LC-MS:m/z＝270.0[M+H] +
第三步6-氯-2-甲基-5-乙烯基-4-嘧啶胺2d
化合物6c(18.0g,粗品)溶于乙二醇二甲醚(180mL)中，室温下依次加入乙烯基三氟硼酸钾(17.89g,0.13mol)，磷酸钾(35.9g,0.17mol)和Pd(dppf)Cl 2二氯甲烷络合物(1.64g,2.01mmol)，氮气置换3次，升温至80℃反应3小时，TLC显示原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得到白色固体标题化合物2d(6.1g,三步收率25％)。
第四步4-氨基-6-氯-2-甲基嘧啶-5-甲醛2e
化合物2d(5.00g,29.48mmol)溶于丙酮和水(120mL/30mL)中，加入高碘酸钠(14.32g,66.95mmol)和锇酸钾水溶液(催化量)，室温反应2小时，TLC显示原料反应完全。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得到类白色固体标题化合物2e(2.5g,收率49％)。
LC-MS:m/z＝172.1[M+H] +
第五步(S)-4-氯-2-甲基-6-((四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-7(8H)-酮2f
氮气保护下，化合物2e(2.50g,14.57mmol)溶于四氢呋喃(500mL)中，室温下加入中间体IN-4(3.30g,18.94mmol)，冷却至-60℃，滴加二异丙基氨基锂(22mL,43.86mmol,2.0M)，滴完-60℃反应1小时，缓慢升至室温反应过夜。反应液加入柠檬酸淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得得到淡黄色固体标题化合物2f(1.0g,收率24％)。
LC-MS:m/z＝282.1[M+H] +
第六步(S)-4-氯-7-甲氧基-2-甲基-6-((四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶2g
化合物2f(70mg,0.25mmol)溶于氯仿(5mL)中，室温下加入碳酸银(102mg,0.37mmol)和碘甲烷(705mg,4.97mmol)，加热至65℃反应过夜，TLC显示原料还有部分剩余。反应液冷却至室温，过滤，滤饼二氯甲烷洗涤，滤液浓缩，粗品经Prep-TLC纯化得到白色固体标题化合物2g(56mg,收率77％)。
LC-MS:m/z＝296.1[M+H] +
1H NMR(400MHz,CDCl 3)δ7.34(s,1H),5.06-5.01(m,1H),4.17(s,3H),4.17-3.97(m,3H),3.93-3.87(m,1H),2.77(s,3H),2.37-2.26(m,1H),2.23-2.15(m,1H).
第七步7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺2h
化合物2g(44mg,0.15mmol)溶于二甲基亚砜(3mL)中，室温下加入N,N-二异丙基乙胺(58mg,0.45mmol)和化合物IN-1(38mg,0.16mmol)，加热至100℃反应10小时，TLC显示原料反应完。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物2h(55mg,收率75％)。
LC-MS:m/z＝494.2[M+H] +
第八步N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺2
化合物2h(55mg,0.11mmol)溶于乙醇(10mL)水(3mL)中，室温下加入还原铁粉(31mg,0.56mmol)和氯化铵(28mg,0.52mmol)，加热至90℃反应3小时，TLC显示原料反应完。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得白色固体标题 化合物2(35mg,收率67％)。
LC-MS:m/z＝464.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.01-6.95(m,2H),6.81(s,1H),5.68(q,J＝7.2Hz,1H),5.20-5.15(m,1H),4.11(s,3H),4.06-3.95(m,3H),3.94-3.90(m,1H),2.55(s,3H),2.41-2.31(m,1H),2.23-2.16(m,1H),1.68(d,J＝7.2Hz,3H).(99.74％purity by HPLC)
实施例3
N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[3,4-d]嘧啶-4-胺3
Figure PCTCN2022072055-appb-000037
第一步2-氯-5-硝基异烟酸3b
2-氯-5-硝基-4-甲基吡啶3a(20g,115.9mmol)溶于浓硫酸(150mL)中，室温下分批加入三氧化铬(28.97g,289.7mmol)，室温反应过夜，TLC显示反应完全。反应液倒入冰水中，搅拌1小时，过滤，滤饼水洗干燥得固体类白色固体标题化合物3b(21.6g,粗品)，直接用于下一步。
第二步2-氯-5-硝基异烟酰胺3c
化合物3b(10.0g,49.37mmol)在氯化亚砜(100mL)中加热回流反应3小时，TLC检测反应完全。反应液冷却至室温，浓缩，剩余物用四氢呋喃(50mL)溶解，缓慢滴加入冷却至0℃左右的氨水(100mL)中，加毕，0℃反应0.5小时，TLC检测反应完全。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物3c(8.5g,粗品)，直接用于下一步。
第三步(S)-5-硝基-2-((四氢呋喃-3-基)氧基)异烟酰胺3d
化合物3c(3.0g,粗品)溶于乙腈(30mL)中，室温下加入碳酸铯(9.69g,29.74mmol)和S-3-羟基四氢呋喃IN-4c(3.27g,37.11mmol)，升温至30℃反应过夜，TLC显示少量原料未反应完。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物3d(1.67g,三步收率35％)。
LC-MS:m/z＝254.1[M+H] +
第四步(S)-5-氨基-2-((四氢呋喃-3-基)氧基)异烟酰胺3e
化合物3d(1.67g,6.60mmol)溶于乙醇(30mL)和水(10mL)中，室温下加入还原铁粉(1.84g,32.95mmol)和氯化铵(1.69g,31.59mmol)，加热至90℃反应3小时，TLC显示原料反应完。反应液冷却至室温，垫硅藻土过滤，滤饼乙醇洗，滤液浓缩，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物3e(1.38g,粗品)，直接用于下一步。
LC-MS:m/z＝224.2[M+H] +
第五步(S)-2-甲基-6-((四氢呋喃-3-基)氧基)吡啶并[3,4-d]嘧啶-4-醇3f
化合物3e(300mg,粗品)溶于原乙酸三乙酯(6mL)中，升温120℃反应20小时，TLC显示原料反应完。反应液冷却至室温，过滤，滤饼甲基叔丁基醚洗涤，烘干得到白色固体标题化合物3f(170mg,粗品)，直接用于下一步。
LC-MS:m/z＝248.1[M+H] +
第六步(S)-4-氯-2-甲基-6-((四氢呋喃-3-基)氧基)吡啶并[3,4-d]嘧啶3g
化合物3f(170mg,粗品)悬浮于1,4-二氧六环(10mL)中，室温下加入N,N-二异丙基乙胺(355mg,2.75mmol)和三氯氧磷(421mg,2.75mmol)，加热至100℃反应4小时，TLC显示原料反应完。反应液冷却至0℃，滴加饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到淡黄色固体标题化合物3g(150mg,三步收率29％)。
第七步N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[3,4-d]嘧啶-4-胺3
化合物3g(65mg,0.26mmol)溶于二甲基亚砜(3mL)中，室温下加入N,N-二异丙基乙胺(100mg,0.77mmol)和中间体IN-2(53mg,0.26mmol)，加热至80℃反应1.5小时，TLC显示原料反应完。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体，再经Prep-HPLC纯化得到淡黄色固体标题化合物3(21mg,收率19％)。
LC-MS:m/z＝434.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.66(s,1H),7.58(s,1H),7.02-6.81(m,2H),6.78-5.68(m,1H),5.73(q,J＝7.2Hz,1H),5.65-5.657(m,1H),4.08-3.87(m,4H),2.43(s,3H),2.39-2.27(m,1H),2.22-2.13(m,1H),1.63(d,J＝7.2Hz,3H).(99.46％purity by HPLC)
实施例4
4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈4
Figure PCTCN2022072055-appb-000038
第一步4-溴-3-氟苯甲酸4b
3-氟-4-溴甲苯4a(5.0g,26.45mmol)溶于吡啶(20mL)和水(20mL)中，加热至90℃，分批加入高锰酸钾(16.7g,105.68mmol)，约1小时加毕，继续反应2小时，TLC检测基本反应完全。反应液垫硅藻土热过滤，滤液冷却后，用浓盐酸调至pH＝3左右，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到白色固体标题化合物4b(3.2g,粗品)，直接用于下一步。
第二步4-溴-5-氟-2-硝基苯甲酸4c
化合物4b(3.2g,粗品)溶于浓硫酸(30mL)中，分批加入硝酸钾(1.7g,16.82mmol)，加毕，室温反应2小时，TLC检测基本反应完全。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物4c(3.8g,粗品)，直接用于下一步。
第三步(S)-4-溴-2-硝基-5-((四氢呋喃-3-基)氧基)苯甲酸4d
化合物4c(3.8g,粗品)和化合物IN-4c(3.8g,43.13mmol)溶于N,N-二异丙基乙胺(30mL)中，室温下加 入碳酸铯(14.0g,42.97mmol)，加热至100℃反应4小时，TLC检测基本反应完全。反应液冷却至室温，稀盐酸(3N)调节至pH＝3左右，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物4d(5.2g,粗品)，直接用于下一步。
LC-MS:m/z＝330.0[M-H] -
第四步(S)-4-溴-2-硝基-5-((四氢呋喃-3-基)氧基)苯甲酰胺4e
化合物4d(5.2g,粗品)溶于氯化亚砜(30mL)中，加热至80℃反应3小时。反应液冷却至室温，浓缩，剩余物用四氢呋喃(50mL)溶解，滴加入冷却至0℃左右的氨水(80mL)中，加毕，0℃反应0.5小时，TLC检测反应完全。反应液加水稀释，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到类白色固体标题化合物4e(3.6g,四步收率41％)。
LC-MS:m/z＝331.1[M+H] +
第五步(S)-2-氨基-4-溴-5-((四氢呋喃-3-基)氧基)苯甲酰胺4f
化合物4e(1.0g,3.02mmol)溶于乙醇(20mL)和水(4mL)中，室温下加入铁粉(676mg,12.10mmol)和氯化铵(808mg,15.11mmol)，加热至80℃反应3小时，LCMS检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物4f(830mg,粗品)，直接用于下一步。
LC-MS:m/z＝301.1[M+H] +
第六步(S)-7-溴-2-甲基-6-((四氢呋喃-3-基)氧基)喹唑啉-4(3H)-酮4g
化合物4f(830mg,粗品)溶于原甲酸三乙酯(15mL)中，加热至150℃反应5小时，TLC检测反应完全。反应液冷却至室温，析出固体，过滤，得到固体粗品经硅胶柱层析纯化得到类白色固体标题化合物4g(490mg,两步收率50％)。
LC-MS:m/z＝325.0[M+H] +
第七步(S)-7-溴-4-氯-2-甲基-6-((四氢呋喃-3-基)氧基)喹唑啉4h
化合物4g(490mg,1.51mmol)分散在1,4-二氧六环(5mL)中，室温下加入吡啶(73mg,0.92mmol)和三氯氧磷(143mg,0.93mmol)，加热至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，碳酸氢钠中和，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物4h(510mg,粗品)，直接用于下一步。
第八步7-溴-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-胺4i
化合物4h(80mg,粗品)和中间体IN-1(41mg,0.18mmol)溶于二甲基亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(46mg,0.36mmol)，加热至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物4i(70mg,两步收率74％)。
LC-MS:m/z＝541.1[M+H] +
第九步2-甲基-4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈4j
化合物4i(70mg,0.13mmol)溶于N,N-二异丙基乙胺(3mL)中，室温下加入氰化锌(30mg,0.26mmol)和四三苯基膦钯(30mg,0.026mmol)，氮气置换3次，加热至120℃反应过夜，LCMS检测原料部分剩余。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体混合物(原料和产品)标题化合物4j(50mg,粗品)，直接用于下一步。
第十步4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈4
化合物4j(50mg,粗品)溶于乙醇(5mL)和水(1mL)，室温下依次加入氯化铵(30mg,0.56mmol)和铁粉(30mg,0.54mmol)，加热至80℃反应3小时，TLC检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，剩余物加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物4(8mg,两步收率14％)。
LC-MS:m/z＝458.2[M+H] +
1H NMR(400MHz,CD 3OD)δ7.91(s,1H),7.86(s,1H),7.01-6.95(m,2H),6.81(s,1H),5.65(q,J＝7.2Hz,1H),5.33-5.27(m,1H),4.19-4.00(m,3H),3.99-3.93(m,1H),2.48(s,3H),2.43-2.31(m,1H),2.28-2.19(m,1H),1.67(d,J＝7.2Hz,3H).(96.53％purity by HPLC)
实施例5
N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((S)-2-甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺5
Figure PCTCN2022072055-appb-000039
第一步(S)-4-(4-氨基甲酰基-5-硝基吡啶-2-基)-3-甲基哌嗪-1-羧酸叔丁酯5a
化合物3c(2.0g,9.92mmol)溶于二甲基亚砜(10mL)中，室温下加入(S)-4-N-叔丁氧羰基-2-甲基哌嗪(2.2g,10.98mmol)和N,N-二异丙基乙胺(2.6g,20.12mmol)，升温至80℃反应5小时，TLC检测反应完全。反应液冷却至室温，加水，析出固体，过滤，滤饼洗涤干燥得到黄色固体标题化合物5a(4.2g,粗品)，直接用于下一步。
LC-MS:m/z＝388.2[M+Na] +
第二步(S)-4-(5-氨基-4-氨基甲酰基吡啶-2-基)-3-甲基哌嗪-1-羧酸叔丁酯5b
化合物5a(4.2g,粗品)溶于乙醇(80mL)和水(15mL)中，室温下加入氯化铵(2.6g,48.61mmol)和还原铁粉(2.2g,39.39mmol)，加热至80℃反应3小时，TLC检测基本反应完全。反应液垫硅藻土趁热过滤，滤液浓缩，剩余物加入水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物5b(3.5g,粗品)，直接用于下一步。
LC-MS:m/z＝336.3[M+H] +
第三步(S)-4-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯5c
化合物5b(3.5g,粗品)和对甲苯磺酸(30mg,0.17mmol)溶于原乙酸三乙酯(30mL)中，加热至150℃反应5小时，TLC检测反应完全。反应液冷却至室温，加入稀盐酸(20mL,1N)，室温搅拌0.5小时，乙酸乙酯萃取，丢弃有机相，水相用碳酸钠中和，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物5c(1.7g,三步收率48％)。
第四步(S)-4-(4-氯-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯5d
化合物5c(1.0g,2.78mmol)溶于1,4-二氧六环(10mL)中，室温下加入三乙胺(845mg,8.35mmol)，滴加三氯氧磷(1.28g,8.35mmol)，滴毕加热至100℃反应2小时，TLC检测原料基本反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到棕色标题化合物5d(1.0g,粗品)，直接用于下一步。
LC-MS:m/z＝378.3[M+H] +
第五步(S)-4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯5e
化合物5d(123mg,粗品)和中间体IN-3(50mg,0.26mmol)溶于二甲基亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(67mg，0.52mmol)，加热至90℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色 固体标题化合物5e(120mg,两步收率66％)。
LC-MS:m/z＝531.3[M+H] +
第六步N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((S)-2-甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺5
化合物5e(120mg,0.23mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温反应2小时，TLC检测反应完全。反应液浓缩，加饱和碳酸氢钠溶液中和，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物5(90mg,收率91％)。
LC-MS:m/z＝431.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.67(s,1H),7.59(t,J＝7.2Hz,1H),7.47(t,J＝7.2Hz,1H),7.30(s,1H),7.22(t,J＝7.6Hz,1H),7.14-6.87(m,1H),5.81(q,J＝7.2Hz,1H),4.71-4.57(m,1H),4.00(dd,J＝12.8,2.4Hz,1H),3.18-3.03(m,3H),3.01-2.95(m,1H),2.92-2.80(m,1H),2.38(s,3H),1.69(d,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,3H).(99.64％purity by HPLC)
实施例6
N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺6
Figure PCTCN2022072055-appb-000040
第一步(S)-4-(4-羟基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯6a
化合物5b(510mg,1.52mmol)溶于原甲酸三乙酯(15mL)中，室温下加入对甲苯磺酸(10mg,0.058mmol)，加热至150℃反应3小时，TLC显示反应完全。反应液加入盐酸(1N)稀释，乙酸乙酯萃取，丢弃有机相，水相用碳酸钠中和，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品Prep-TLC纯化得到黄棕色固体标题化合物6a(330mg,收率63％)。
第二步(S)-4-(4-氯吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯6b
化合物6a(330mg,0.96mmol)溶于1,4-二氧六环(5mL)中，室温下加入吡啶(440mg,5.56mmol)，滴加三氯氧磷(377mg,2.46mmol)，滴毕加热至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，滴加稀盐酸(10mL,1N)稀释，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得棕色固体标题化合物6b(350mg,粗品)，直接用于下一步。
第三步(S)-4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯6c
化合物6b(130mg,粗品)和中间体IN-3(31mg,0.16mmol)溶于二甲基亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(42mg,0.32mmol)，加热至100℃反应2小时，TLC显示原料剩余，补加中间体IN-3(31mg,016mmol)，继续反应2小时，TLC检测反应完全。反应液冷却至室温，加水，析出固体，过滤，滤饼经Prep-TLC纯化得到黄色固体标题化合物6c(20mg,收率12％)。
LC-MS:m/z＝517.3[M+H] +
第四步N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-6-((S)-2-甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺6d
化合物6c(20mg,0.039mmol)溶于二氯甲烷(2mL)中，室温下加入三氟乙酸(0.5mL)，加热至35℃反应2小时，TLC检测反应完全。反应液冷却至室温，加饱和碳酸氢钠水溶液调至碱性，二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物6d(20mg,粗品)，直接用于下一步。
第五步N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺6
化合物6d(20mg,粗品)溶于甲醇(5mL)中，室温下加入甲醛水溶液(20mg,0.25mmol,37％)和钯/碳(10mg,10％)，氢气氛围下升温至30℃反应3小时，TLC显示反应完全。反应液冷却至室温，过滤，滤饼洗涤，滤液浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物6(10mg,两步收率59％)。
LC-MS:m/z＝431.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.80(s,1H),8.28(s,1H),7.59(t,J＝7.6Hz,1H),7.49-7.47(m,2H),7.24(t,J＝8.0Hz,1H),7.14-6.89(m,1H),5.81(q,J＝6.8Hz,1H),5.06-4.97(m,1H),4.55-4.42(m,1H),3.60-3.34(m,4H),3.13-3.03(m,1H),2.89(s,3H),1.71(d,J＝6.8Hz,3H),1.36(d,J＝7.2Hz,3H).(98.88％purity by HPLC)
实施例7
N 4-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-N 6-((S)-四氢呋喃-3-基)吡啶并[3,4-d]嘧啶-4,6-二胺7
Figure PCTCN2022072055-appb-000041
第一步2-氯-5-硝基异烟酸甲酯7a
化合物3b(43.50g,0.21mol)溶于N,N-二甲基甲酰胺(300mL)中，室温下加入碳酸钾(60.00g,0.43mol)，滴加碘甲烷(45.91g,0.32mol)，加完室温反应2小时，TLC显示反应完全。反应液加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物7a(46.1g,收率99％)。
LC-MS:m/z＝217.1[M+H] +
第二步(S)-5-硝基-2-((四氢呋喃-3-基)氨基)异烟酸甲酯7b
化合物7a(1.92g,8.87mmol)溶于四氢呋喃(30mL)中，室温下加入碳酸铯(4.33g,13.29mmol)和(S)-3-胺基四氢呋喃1k(850mg,9.76mmol)，升温至30℃反应过夜，TLC显示少量原料未反应完。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物7b(2.28g,粗品)，直接用于下一步。
LC-MS:m/z＝268.1[M+H] +
第三步(S)-5-氨基-2-((四氢呋喃-3-基)氨基)异烟酸甲酯7c
化合物7b(2.28g,粗品)溶于甲醇(30mL)中，加入钯/碳(400mg,10％)，氢气氛围下升温至30℃反应5小时，TLC显示原料反应完。反应液冷却至室温，垫硅藻土过滤，滤饼甲醇洗涤，滤液浓缩，粗品经硅胶柱层析纯化得到黄棕色固体标题化合物7c(1.67g,两步收率80％)。
LC-MS:m/z＝238.2[M+H] +
第四步(S)-2-甲基-6-((四氢呋喃-3-基)氨基)吡啶并[3,4-d]嘧啶-4-醇7d
化合物7c(700mg,2.95mmol)溶于乙腈(30mL)中，冷却至0℃左右，通入氯化氢气体2小时，通完加热至80℃反应过夜，TLC显示原料反应完。反应液冷却至室温，加入碳酸氢钠调节至碱性，过滤，滤饼水洗涤，甲醇洗，滤饼加入甲苯中，浓缩得到黄色固体标题化合物7d(650mg,粗品)，直接用于下一步。
LC-MS:m/z＝247.1[M+H] +
第五步(S)-4-氯-2-甲基-N-(四氢呋喃-3-基)吡啶并[3,4-d]嘧啶-6-胺7e
化合物7d(500mg,粗品)悬浮于1,4-二氧六环(20mL)中，室温下加入N,N-二异丙基乙胺(1.05g,8.12mmol)和三氯氧磷(1.24g,8.09mmol)，加热至90℃反应4小时，TLC显示原料反应完。反应液冷却至0℃，滴加饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物7e(200mg,粗品)，直接用于下一步。
LC-MS:m/z＝265.1[M+H] +
第六步N 4-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-N 6-((S)-四氢呋喃-3-基)吡啶并[3,4-d]嘧啶-4,6-二胺7
化合物7e(78mg,粗品)溶于二甲基亚砜(3mL)中，室温下加入N,N-二异丙基乙胺(95mg,0.74mmol)和中间体IN-2(60mg,0.29mmol)，升温至80℃反应8小时，TLC显示原料反应完。反应液冷却至室温，加水，乙酸乙酯萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-HPLC纯化得到淡黄色固体标题化合物7(6mg,三步收率6％)。
LC-MS:m/z＝433.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.59(s,1H),7.06(s,1H),7.05-6.85(m,2H),6.80-6.77(m,1H),5.75(q,J＝7.2Hz,1H),4.45-4.37(m,1H),4.10-3.98(m,2H),3.94-3.87(m,1H),3.73(dd,J＝3.6,8.8Hz,1H),2.41(s,3H),2.41-2.33(m,1H),2.02-1.93(m,1H),1.67(d,J＝7.2Hz,3H).(97.91％purity by HPLC)
实施例8
N 4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-1-甲基吡咯烷-3-基)喹唑啉-4,6-二胺8
Figure PCTCN2022072055-appb-000042
第一步2-氨基-5-溴-4-甲氧基苯甲酸8b
2-氨基-4-甲氧基苯甲酸8a(15.0g,89.7mmol)溶于N,N-二甲基甲酰胺(100mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(17.6g,98.7mmol)，自然升至室温反应2小时，TLC检测反应完全。反应液加水，用稀盐酸(1N)调pH＝3，乙酸乙酯萃取，有机相饱和亚硫酸钠水溶液洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物8b(22.1g,粗品)，直接用于下一步。
第二步2-氨基-5-溴-4-甲氧基苯甲酸甲酯8c
化合物8b(22.1g,粗品)溶于甲醇(200mL)中，室温下滴加浓硫酸(10mL)，加完升温至80℃搅拌过夜，TLC检测原料基本反应完全。反应液冷却至室温，加饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物8c(19.5g,两步收率84％)。
第三步6-溴-7-甲氧基-2-甲基喹唑啉-4(3H)-酮8d
化合物8c(19.5g,75.0mmol)溶于乙腈(150mL)中，室温下加入甲烷磺酸(40mL)，升温至90℃搅拌过夜，TLC检测原料反应完全。反应液浓缩，加水稀释，用氢氧化钠水溶液(2N)调pH＝8-9，有固体析出，过滤，滤饼水洗干燥得到类白色固体标题化合物8d(10.5g,收率52％)。
第四步6-溴-4-氯-7-甲氧基-2-甲基喹唑啉8e
化合物8d(1.00g,3.72mmol)溶于三氯氧磷(6mL)中，室温下加入N,N-二甲基甲酰胺(0.1mL)，升温至90℃反应6小时，TLC检测反应完全。反应液冷却至室温，倒入冰水中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到淡黄色固体标题化合物8e(535mg,收率50％)。
LC-MS:m/z＝287.0[M+H] +
第五步(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺8f
化合物8e(500mg,1.74mmol)和中间体IN-1(407mg,1.74mmol)溶于二甲基亚砜(20mL)中，室温下加入N,N-二异丙基乙胺(674mg,5.22mmol)，升温至80℃搅拌过夜，TLC检测反应完全。反应液冷却至室温，加水淬灭，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物8f(810mg,粗品)，直接用于下一步。
LC-MS:m/z＝485.1[M+H] +
第六步N 6-((S)-1-苄基吡咯烷-3-基)-7-甲氧基-2-甲基-N 4-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4,6-二胺8h
化合物8f(430mg,0.89mmol)和(S)-1-苄基-3-氨基吡咯烷8g(312mg,1.77mmol)溶于甲苯(20mL)中，室温下加入三(二亚苄基丙酮)二钯(162mg,0.18mmol)，1,1'-联萘-2,2'-双二苯膦(220mg,0.35mmol)和碳酸铯(577mg,1.77mmol)，氮气保护下升温至100℃搅拌过夜，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物8h(290mg,收率56.4％)。
第七步N 4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-N 6-((S)-1-苄基吡咯烷-3-基)-7-甲氧基-2-甲基喹唑啉-4,6-二胺8i
化合物8h(290mg,0.50mmol)溶于乙醇(20mL)和水(4mL)中，室温下加入铁粉(140mg,2.50mmol)和氯化铵(134mg,2.50mmol)，升温至90℃搅拌2小时，TLC检测反应完全。反应液垫硅藻土趁热过滤，滤液浓缩，残余物溶于乙酸乙酯，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色油状标题化合物8i(275mg,粗品)，直接用于下一步。
第八步(3-((R)-1-((6-(((S)-1-苄基吡咯烷-3-基)氨基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯8j
化合物8i(275mg,粗品)溶于四氢呋喃(32mL)中，加入碳酸钠(159mg,1.50mmol)和二碳酸二叔丁酯(218mg,1.00mmol)，室温反应过夜，TLC检测基本反应完全。反应液加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到淡黄色固体标题化合物8j(70mg,两步收率22％)。
LC-MS:m/z＝651.3[M+H] +
第九步(3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-吡咯烷-3-基)氨基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯8k
化合物8j(70mg,0.11mmol)溶于乙醇(10mL)中，加入钯碳(20mg,10％)，氢气氛围下室温反应2小时，TLC检测原料反应完全。反应液垫硅藻土过滤，滤液浓缩得到淡黄色油状标题化合物8k(50mg,粗品)，直接用于下一步。
第十步(3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯烷-3-基)氨基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸叔丁酯8l
化合物8k(50mg,粗品)和甲醛水溶液(26mg,0.32mmol,37％)溶于乙醇(10mL)中，加入钯碳(20mg,10％)，氢气氛围下室温反应3小时，TLC检测原料反应完全。反应液过滤，滤液浓缩，粗品经Prep-TLC纯化得到淡黄色固体标题化合物8l(37mg,两步收率60％)。
第十一步N 4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-1-甲基吡咯烷-3-基)喹唑啉-4,6-二胺8
化合物8l(37mg,0.06mmol)溶于甲醇(1mL)中，加入盐酸甲醇溶液(3mL,4M)，室温反应2小时，TLC检测原料反应完全。反应液加氨甲醇溶液(4M)中和，过滤除去不溶物，滤液浓缩，粗品经Prep-TLC纯化得到淡黄色固体标题化合物8(20mg,收率66％)。
LC-MS:m/z＝475.3[M+H] +
1H NMR(400MHz,CD 3OD)δ7.11(s,1H),6.99(s,1H),6.97(s,1H),6.94(s,1H),6.80(s,1H),5.64(q,J＝6.8Hz,1H),4.32-4.25(m,1H),3.98(s,3H),3.00-2.86(m,2H),2.70-2.66(m,1H),2.63-2.55(m,1H),2.55-2.47(m,1H),2.45(s,6H),1.82-1.74(m,1H),1.64(d,J＝6.8Hz,3H).
实施例9
4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈9
Figure PCTCN2022072055-appb-000043
第一步(S)-7-溴-6-((四氢呋喃-3-基)氧基)喹唑啉-4(3H)-酮9a
化合物4f(1.0g,3.32mmol)和对甲苯磺酸(20mg,0.12mmol)在原甲酸三乙酯(10mL)中加热至150℃反应6小时，TLC检测原料反应完全。反应液冷却至室温，析出固体，过滤，滤饼洗涤干燥得到类白色固体标题化合物9a(540mg,收率52％)。
LC-MS:m/z＝311.0[M+H] +
第二步(S)-7-溴-4-氯-6-((四氢呋喃-3-基)氧基)喹唑啉9b
化合物9a(300mg,0.96mmol)分散在1,4-二氧六环(10mL)中，室温下加入吡啶(228mg,2.88mmol)和三氯氧磷(442mg,2.88mmol)，加热至90℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，浓缩，剩余物用饱和碳酸氢钠水溶液中和，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物9b(73mg,收率23％)。
第三步7-溴-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-胺9c
化合物9b(73mg,0.22mmol)和中间体IN-1(52mg,0.22mmol)溶于二甲基亚砜(1mL)中，室温下加入N,N-二异丙基乙胺(57mg,0.44mmol)，加热至100℃反应2小时，TLC检测基本反应完全。反应液冷却至 室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物9c(85mg,收率73％)。
LC-MS:m/z＝527.1[M+H] +
第四步4-(((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈9d
化合物9c(85mg,0.16mmol)溶于N,N-二甲基乙酰胺(3mL)中，室温下加入四三苯基膦钯(18mg,0.016mmol)和氰化锌(47mg,0.40mmol)，氮气氛围下加热至140℃反应7小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物9d(54mg,收率71％)。
LC-MS:m/z＝474.2[M+H] +
第五步4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈9
化合物9d(54mg,0.11mmol)溶于乙醇(5mL)和水(1mL)中，室温下加入氯化铵(29mg,0.55mmol)和还原铁粉(25mg,0.44mmol)，加热至90℃反应2小时，TLC检测原料基本反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物9(32mg,收率63％)。
LC-MS:m/z＝444.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.40(s,1H),8.02(s,1H),7.90(s,1H),6.96(s,2H),6.81(s,1H),5.60(q,J＝6.8Hz,1H),5.37-5.31(m,1H),4.19-4.01(m,3H),3.99-3.94(m,1H),2.48-2.32(m,1H),2.32-2.20(m,1H),1.67(d,J＝6.8Hz,3H).
实施例10
N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((R)-1-甲基哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10-1
N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((S)-1-甲基哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10-2
Figure PCTCN2022072055-appb-000044
第一步5-氨基-2-氯吡啶-4-甲酰胺10a
化合物3c(1.0g,4.96mmol)溶于乙醇(20mL)和水(4mL)中，室温下加入氯化铵(1.3g,24.08mmol)和还原铁粉(1.1g,19.84mmol)，加热至90℃反应3小时，TLC检测原料反应完全。反应液冷却至室温，垫硅藻土过滤，滤液加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄棕色固体标题化合物10a(680mg,粗品)，直接用于下一步。
第二步5-氨基-4-氨基甲酰基-5',6'-二氢-[2,3'-联吡啶]-1'(2'H)-羧酸叔丁酯10c
化合物10a(680mg,粗品)溶于1,4-二氧六环(8mL)水(2mL)中，室温下依次加入5-(4,4,5,5-四甲基-1,3,2- 二氧硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯10b(1.5g,4.93mmol)，碳酸钠(803mg,7.58mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(50mg,0.061mmol)，氮气保护下，加热至80℃反应2小时，TLC检测原料基本反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到黄色固体标题化合物10c(710mg,两步收率45％)。
LC-MS:m/z＝319.2[M+H] +
第三步3-(5-氨基-4-氨基甲酰基吡啶-2-基)哌啶-1-羧酸叔丁酯10d
化合物10c(710mg,2.23mmol)溶于乙醇(20mL)和乙酸乙酯(10mL)中，加入钯碳(100mg,10％)，氢气氛围下，加热至50℃反应5小时，LC-MS检测原料反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，得到黄色固体标题化合物10d(680mg,粗品)，直接用于下一步。
LC-MS:m/z＝321.3[M+H] +
第四步3-(4-羟基-2-甲基吡啶并[3,4-d]嘧啶-6-基)哌啶-1-羧酸叔丁酯10e
化合物10d(680mg,粗品)溶于原乙酸三乙酯(6mL)中，加入对甲苯磺酸(10mg)，加热至150℃反应6小时，TLC检测原料反应完全。反应液冷却至室温，加入少量稀酸(1N)搅拌0.5小时，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到棕色固体标题化合物10e(188mg,两步收率24％)。
第五步3-(4-氯-2-甲基吡啶并[3,4-d]嘧啶-6-基)哌啶-1-羧酸叔丁酯10f
化合物10e(160mg,0.44mmol)溶于1,4-二氧六环(5mL)中，室温下加入三氯氧磷(409mg,2.6mmol)和N,N-二异丙基乙胺(344mg,2.6mmol)，加热至90℃反应1.5小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物经硅胶柱层析纯化得到黄色固体标题化合物10f(95mg,收率57％)。
第六步(R)-3-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)哌啶-1-羧酸叔丁酯10g-1&(S)-3-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)哌啶-1-羧酸叔丁酯10g-2
化合物10f(75mg,0.20mmol)和中间体IN-3(46mg,0.24mmol)溶于二甲基亚砜(1.5mL)中，室温下加入N,N-二异丙基乙胺(80mg,0.60mmol)，加热至95℃反应3小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物经Prep-TLC纯化得到白色固体标题化合物10g(100mg,收率94％)。化合物10g经手性拆分(大赛璐AD-H,30*250mm,5μm,30mL/min,ethanol:Hexane＝5:95)得到白色固体化合物10g-1(1号峰,RT 7.79min)(30mg,收率28％)和白色固体化合物10g-2(2号峰,RT 16.10min)(48mg,收率45％)。化合物构型及性质需进一步检测，暂定10g-1、10g-2为以上构型。
LC-MS:m/z＝516.3[M+H] +
第七步N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((R)-哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10h-1&N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((S)-哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10h-2
化合物10g-1(30mg,0.058mmol)，溶于二氯甲烷(1mL)中，加入三氟乙酸(1mL)，室温搅拌1小时，TLC检测反应完全。反应液浓缩，加水，饱和碳酸钠水溶液中和，乙酸乙酯萃取2次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到黄色固体标题化合物10h-1(25mg,粗品)，直接用于下一步。
化合物10g-2(48mg,0.093mmol)，溶于二氯甲烷(1mL)中，加入三氟乙酸(1mL)，室温搅拌1小时，TLC检测反应完全。反应液浓缩，加水，饱和碳酸钠水溶液中和，乙酸乙酯萃取2次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到黄色固体标题化合物10h-2(30mg,粗品)，直接用于下一步。
化合物构型及性质需进一步检测，暂定10h-1、10h-2为以上构型。
第八步N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((R)-1-甲基哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10-1&N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((S)-1-甲基哌啶-3-基)吡啶并[3,4-d]嘧啶-4-胺10-2
化合物10h-1(25mg,粗品)溶于乙醇(2mL)中，加入甲醛水溶液(4滴,37％)和钯碳(10mg,10％)，氢气氛围下，加热至35℃反应3小时，TLC检测显示反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓 缩，剩余物经Prep-TLC纯化得到白色固体标题化合物10-1(8mg,两步收率32％)。
化合物10h-2(30mg,粗品)溶于乙醇(2mL)中，加入甲醛水溶液(4滴,37％)和钯碳(10mg,10％)，氢气氛围下，加热至35℃反应3小时，TLC检测显示反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，剩余物经Prep-TLC纯化得到白色固体标题化合物10-2(21mg,两步收率53％)。
化合物构型及性质需进一步检测，暂定10-1、10-2为以上构型。
10-1：
LC-MS:m/z＝430.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.96(s,1H),8.26(s,1H),7.66(t,J＝7.2Hz,1H),7.49(t,J＝6.8Hz,1H),7.24(t,J＝7.6Hz,1H),7.00(t,J＝54.8Hz,1H),5.86(q,J＝7.2Hz,1H),3.84-3.35(m,4H),3.24-3.03(m,1H),2.96(s,3H),2.48(s,3H),2.30-1.84(m,4H),1.72(d,J＝7.2Hz,3H).
10-2：
LC-MS:m/z＝430.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.92(s,1H),8.13(s,1H),7.62(t,J＝7.2Hz,1H),7.49(t,J＝6.8Hz,1H),7.24(t,J＝7.6Hz,1H),7.00(t,J＝54.8Hz,1H),5.86(q,J＝7.2Hz,1H),3.28-3.18(m,2H),3.12-3.04(m,1H),2.65-2.55(m,1H),2.50(s,3H),2.46(s,3H),2.40-2.28(m,1H),2.16-2.06(m,1H),1.98-1.74(m,3H),1.72(d,J＝7.2Hz,3H).
实施例11
(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(4-甲基哌嗪-1-基)喹唑啉-7-甲腈11
Figure PCTCN2022072055-appb-000045
第一步4-溴-5-氟-2-硝基苯甲酸甲酯11a
化合物4c(2.6g,9.85mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碘甲烷(2.8g,19.73mmol)和碳酸钾(4.0g,28.94mmol)，室温反应过夜，TLC检测反应完全。反应液加水(50mL)，乙酸乙酯(100mL)萃取，有机相饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得淡黄色固体标题化合物11a(3.0g,粗品)，直接用于下一步。
第二步4-溴-5-(4-甲基哌嗪-1-基)-2-硝基苯甲酸甲酯11b
化合物11a(3.0g,粗品)溶于乙腈(20mL)中，室温下加入N-甲基吗啉(1.6g,15.98mmol)和碳酸钾(2.0g,14.47mmol)，加热至80℃反应过夜，TLC检测反应完全。反应液加水(50mL)，乙酸乙酯(100mL)萃取，有机相饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩得淡黄色油状标题化合物11b(2.5g,粗品)，直接用于下一步。
第三步2-氨基-4-溴-5-(4-甲基哌嗪-1-基)苯甲酸甲酯11c
化合物11b(2.5g,粗品)溶于乙醇(20mL)中，室温下加入铁粉(1.5g,26.86mmol)，氯化铵(1.5g,28.04mmol)和水(2mL)，加热至80℃反应2小时，TLC检测反应完全。反应液垫硅藻土趁热过滤，滤液加水稀释，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄棕色固体标题化合物11c(1.5g,三步收率47％)。
LC-MS:m/z＝328.1[M+H] +
第四步7-溴-6-(4-甲基哌嗪-1-基)喹唑啉-4-醇11d
化合物11c(1.5g,4.57mmol)溶于乙二醇单甲醚(10mL)中，室温下加入醋酸甲脒(3.0g,28.82mmol)，加热至120℃反应过夜，TLC检测反应完全。反应液冷却至室温，加水，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得淡黄色固体标题化合物11d(1.3g,收率87％)。
LC-MS:m/z＝323.1[M+H] +
第五步7-溴-4-氯-6-(4-甲基哌嗪-1-基)喹唑啉11e
化合物11d(200mg,0.62mmol)溶于1,4-二氧六环(10mL)中，室温下加入N,N-二异丙基乙胺(2mL)和三氯氧磷(1mL)，加热至90℃反应过夜，TLC检测反应完全。反应液冷却至室温，浓缩，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得黄棕色固体标题化合物11e(84mg,粗品)，直接用于下一步。
第六步(R)-7-溴-6-(4-甲基哌嗪-1-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺11f
化合物11e(84mg,粗品)溶于二甲亚砜(2mL)中，室温下依次加入N,N-二异丙基乙胺(70mg,0.54mmol)和中间体IN-1(73mg,0.31mmol)，升温至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得黄棕色固体标题化合物11f(130mg,粗品)，直接用于下一步。
第七步(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-溴-6-(4-甲基哌嗪-1-基)喹唑啉-4-胺11g
化合物11f(130mg,粗品)溶于乙醇(5mL)中，室温下加入铁粉(81mg,1.45mmol)，氯化铵(77mg,1.44mmol)和水(1mL)，加热至90℃反应2小时，TLC检测原料反应完全。反应液垫硅藻土趁热过滤，滤液加水稀释，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得标题化合物淡黄色固体11g(30mg,三步收率10％)。
LC-MS:m/z＝509.1[M+H] +
第八步(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(4-甲基哌嗪-1-基)喹唑啉-7-甲腈11
化合物11g(30mg,0.059mmol)溶于N,N-二甲基乙酰胺(5mL)中，室温下加入氰化锌(30mg,0.26mmol)和三(二亚苄基丙酮)二钯(10mg,0.011mmol),氮气保护下，加热至120℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-HPLC得淡黄色固体标题化合物11(25mg,收率93％)。
LC-MS:m/z＝456.2[M+H] +
1HNMR(400MHz,CD 3OD)δ8.39(s,1H),8.01(s,1H),7.98(s,1H),6.99-6.94(m,2H),6.80(s,1H),5.58(q,J＝7.2Hz,1H),3.38-3.34(m,4H),2.84-2.75(m,4H),2.45(s,3H),1.67(d,J＝7.2Hz,3H).
实施例12
4-(((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈12
Figure PCTCN2022072055-appb-000046
第一步(3-((R)-1-((7-溴-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯12a
化合物4h(110mg,粗品)和中间体IN-5(60mg,0.20mmol)溶于二甲基亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(52mg,0.40mmol)，加热至100℃反应2小时，TLC检测基本反应完全。反应液冷却至室温， 加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物12a(63mg,两步收率34％)。
LC-MS:m/z＝611.2[M+H] +
第二步(3-((R)-1-((7-氰基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯12b
化合物12a(63mg,0.10mmol)溶于N,N-二甲基乙酰胺(3mL)中，室温下加入四三苯基膦钯(18mg,0.016mmol)和氰化锌(29mg,0.25mmol)，氮气保护下加热至140℃反应7小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物12b(73mg,粗品)，直接用于下一步。
第三步4-(((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-甲腈12
化合物12b(73mg,粗品)溶于二氯甲烷(3mL)中，加入三氟乙酸(3mL)，室温反应4小时，TLC检测反应完全。反应液滴加饱和碳酸氢钠水溶液调节至碱性，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到淡黄色固体标题化合物12(31mg,两步收率66％)。
LC-MS:m/z＝458.2[M+H] +
1H NMR(400MHz,CD 3OD)δ7.93(s,1H),7.91(s,1H),7.03-6.72(m,3H),5.76(q,J＝6.8Hz,1H),5.37-5.31(m,1H),4.19-4.01(m,3H),3.99-3.94(m,1H),2.45(s,3H),2.43-2.35(m,1H),2.32-2.22(m,1H),1.67(d,J＝6.8Hz,3H).
实施例13
N 4-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-四氢呋喃-3-基)喹唑啉-4,6-二胺13
Figure PCTCN2022072055-appb-000047
第一步(R)-(3-(1-((6-溴-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸叔丁酯13a
化合物8e(600mg,2.09mmol)和中间体IN-5(635mg,2.09mmol)溶于二甲基亚砜(15mL)中，室温下加入N,N-二异丙基乙胺(810mg,6.27mmol)，升温至80℃搅拌过夜，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到淡黄色固体标题化合物13a(1.01g,收率87％)。
LC-MS:m/z＝555.1[M+H] +
第二步(3-(二氟甲基)-4-氟-5-((R)-1-((7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氨基)喹唑啉)-4-基)氨基)乙基)苯基)氨基甲酸叔丁酯13b
化合物13a(100mg,0.18mmol)和(S)-3-氨基四氢呋喃1k(32mg,0.36mmol)溶于甲苯(15mL)中，加入三(二亚苄基丙酮)二钯(33.0mg,0.036mmol)，1,1'-联萘-2,2'-双二苯膦(45mg,0.072mmol)和碳酸铯(117mg,0.36mmol)，氮气保护下，升温至100℃搅拌10小时，TLC检测原料基本反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物13b(70mg,收率69％)。
LC-MS:m/z＝562.3[M+H] +
第三步N 4-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-N 6-((S)-四氢呋喃-3-基)喹唑啉-4,6-二胺13
化合物13b(50.0mg,0.09mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(2mL)，室温反应2小时，TLC检测基本反应完全。反应液浓缩，残余物用饱和碳酸氢钠水溶液中和，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到淡黄色固体标题化合物13(20mg,收率49％)。
LC-MS:m/z＝462.2[M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.20(s,1H),7.03-6.85(m,3H),6.80-6.75(m,1H),5.78(q,J＝6.8Hz,1H),4.41-4.32(m,1H),4.09-3.85(m,6H),3.75-3.72(m,1H),2.48-2.32(m,4H),2.01-1.93(m,1H),1.64(d,J＝7.2Hz,3H).
实施例14
N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-6-((R)-3,4-二甲基哌嗪-1-基)-2-甲基吡啶[3,4-d]嘧啶-4-胺14
Figure PCTCN2022072055-appb-000048
第一步(R)-1,2-二甲基哌嗪14b
(R)-3,4-二甲基哌嗪-1-羧酸叔丁酯14a(1.5g,7.00mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)，室温反应3小时，TLC检测反应完全。反应液浓缩得到黄色油状标题化合物14b(1.5g,粗品)，直接用于下一步。
第二步(R)-3,4-二甲基哌嗪-1-羧酸苄酯14c
化合物14b(1.5g,粗品)分散在四氢呋喃(20mL)和水(10mL)中，加入碳酸钠(6.9g,65.78mmol)，搅拌10分钟，滴加氯甲酸苄酯(930mg,13.15mmol)的四氢呋喃(5mL)溶液，室温反应2小时，TLC检测反应完全。反应液过滤，滤液加乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到透明油状标题化合物14c(1.2g,两步收率70％)。
LC-MS:m/z＝249.2[M+H] +
第三步(R)-1,2-二甲基哌嗪14d
化合物14c(1.2g,4.80mmol)溶于四氢呋喃(15mL)中，加入钯碳(120mg,10％)，氢气氛围下，加热至50℃反应12小时，TLC检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤饼乙酸乙酯洗涤，滤液浓缩得到黄色油状标题化合物14d(620mg,粗品)，直接用于下一步。
第四步(R)-2-(3,4-二甲基哌嗪-1-基)-5-硝基异烟酸甲酯14e
化合物14d(132mg,粗品)和2-氯-5-硝基异烟酸甲酯化合物7a(250mg,1.15mmol)溶于二甲亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(447mg,34.7mmol)，加热至90℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩得到棕色固体标题化合物14e(270mg,粗品)，直接用于下一步。
LC-MS:m/z＝295.2[M+H] +
第五步(R)-5-氨基-2-(3,4-二甲基哌嗪-1-基)异烟酸甲酯14f
化合物14e(270mg,粗品)分散在乙醇/水(5mL/1.5mL)中，室温下加入还原铁粉(258mg,4.6mmol)和氯化铵(258mg,4.6mmol)，加热至100℃反应3小时，TLC检测反应完全。反应液趁热垫硅藻土过滤，滤 饼乙醇洗涤，滤液浓缩，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物14f(230mg,三步收率75％)。
第六步(R)-6-(3,4-二甲基哌嗪-1-基)-2-甲基吡啶并[3,4-d]嘧啶-4-醇14g
化合物14f(130mg,0.49mmopl)溶于乙腈(10mL)中，冷却至0℃，通入盐酸气2小时，加热至80℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，浓缩，低温下加入氨甲醇溶液(15mL,4M)中和，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物14g(120mg,收率95％)。
LC-MS:m/z＝274.2[M+H] +
第七步(R)-4-氯-6-(3,4-二甲基哌嗪-1-基)-2-甲基吡啶并[3,4-d]嘧啶14h
化合物14g(120mg,0.43mmol)溶于1,4-二氧六环(2mL)中，室温下加入N,N-二异丙基乙胺(113mg,0.87mmol)，冷却至0℃，滴加三氯氧磷(134mg,0.87mmol)，滴毕，加热至90℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩得到黄色固体标题化合物14h(126mg,粗品)，直接用于下一步。
第八步N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-6-((R)-3,4-二甲基哌嗪-1-基)-2-甲基吡啶[3,4-d]嘧啶-4-胺14
化合物14h(126mg,粗品)和中间体IN-2(97mg,0.47mmol)溶于二甲亚砜(2mL)中，室温下加入N,N-二异丙基乙胺(167mg,1.29mmol)，加热至95℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物14(28mg,两步收率14％)。
LC-MS:m/z＝460.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.70(s,1H),7.57(s,1H),7.00-6.93(m,1H),6.88(t,J＝55.2Hz,1H),6.75-6.73(m,1H),5.76(q,J＝7.2Hz,1H),4.53-4.37(m,2H),3.46(d,J＝12.4Hz,1H),3.38-3.32(m,1H),3.19-3.00(m,3H),2.81(s,3H),2.45(s,3H),1.67(d,J＝6.8Hz,3H),1.43(d,J＝6.0Hz,3H).
实施例15
N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)-2-甲基吡啶[3,4-d]嘧啶-4-胺15
Figure PCTCN2022072055-appb-000049
第一步(S)-4-(4-(((R)-1-(5-氨基-3-二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯15a
化合物5d(91mg,0.24mmol)溶于二甲基亚砜(2mL)中，室温下加入中间体IN-2(50mg,0.24mmol)和N,N-二异丙基乙胺(62mg,0.48mmol),升温至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物15a(50mg,收率38％)。
第二步(S)-4-(4-(((R)-1-(5-乙酰氨基-3-二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯15b
化合物15a(50mg,0.092mmol)溶于二氯甲烷(5mL)中，室温下加入吡啶(22mg,0.28mmol)和醋酸酐(14mg,0.14mmol)，升温至30℃反应4小时，TLC检测反应完全。反应液冷却至室温，浓缩，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物15b(85mg,粗品)，直接用于下一步。
LC-MS:m/z＝588.3[M+H] +
第三步N-(3-(二氟甲基)-4-氟-5-((R)-1-(2-甲基-6-((S)-2-甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)苯基)乙酰胺15c
化合物15b(85mg,粗品)溶于二氯甲烷(2mL)中，室温下加入三氟乙酸(1mL)，升温至30℃反应2小时，TLC检测反应完全。反应液冷却至室温，浓缩，剩余物用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到黄色固体标题化合物15c(55mg,粗品)，直接用于下一步。
LC-MS:m/z＝488.3[M+H] +
第四步N-(3-(二氟甲基)-5-((R)-1-((6-((S)-2,4-二甲基哌嗪-1-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)-4-氟苯基)乙酰胺15d
化合物15c(55mg,粗品)溶于乙醇(5mL)中，加入甲醛水溶液(30mg,0.37mmol,37％)和钯炭(10mg,10％)，室温反应2小时，TLC检测反应完全。反应液垫硅藻土过滤，滤液浓缩得黄色固体到标题化合物15d(66mg,粗品)，直接用于下一步。
第五步N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)-2-甲基吡啶[3,4-d]嘧啶-4-胺15
化合物15d(66mg,粗品)分散在乙醇(2mL)和氢氧化钠水溶液(2.0mL,8.00mmol,4M)中，加热至90℃反应4小时，TLC检测原料基本反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物15(12mg,四步收率29％)。
LC-MS:m/z＝460.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.60(s,1H),7.33(s,1H),7.00-6.55(m,3H),5.65(q,J＝6.8Hz,1H),4.77-4.67(m,2H),4.14(d,J＝14.2Hz,1H),3.18-3.02(m,2H),2.75-2.64(m,1H),2.58-2.47(m,4H),2.34(s,3H),1.56(d,J＝7.2Hz,3H),1.20(d,J＝6.8Hz,3H).
实施例16
N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡啶并[3,4-d]嘧啶-4-胺16
Figure PCTCN2022072055-appb-000050
第一步(1S,4S)-5-(4-氨基甲酰基-5-硝基吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16b
化合物3c(500mg,2.50mmol)和(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16a(500mg,2.50mmol)溶于二甲基亚砜中，室温下加入N,N-二异丙基乙胺(967mg,7.50mmol)，加热至95℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到棕色固体标题化合物16b(1.0g,收率94％)。
第二步(1S,4S)-5-(5-氨基-4-氨基甲酰基吡啶-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16c
化合物16b(1.0g,2.7mmol)溶于乙醇(20mL)和水(5mL)中，室温下加入还原铁粉(770mg,13.7mmol)和氯化铵(770mg,13.7mmol)，加热至100℃反应2小时，TLC检测反应完全。反应液趁热垫硅藻土过滤，滤饼洗涤，滤液浓缩，加水，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到棕色固体标题化合物16c(950mg,粗品)，直接用于下一步。
第三步(1S,4S)-5-(2-甲基-4-氧代-3,4-二氢吡啶并[3,4-d]嘧啶-6-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16d
化合物16c(950mg,粗品)溶于原乙酸三乙酯(9mL)中，室温下加入对甲苯磺酸(30mg,0.17mmol)，加热至150℃反应2小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到棕色固体标题化合物16d(570mg,两步收率58％)
LC-MS:m/z＝358.2[M+H] +
第四步(1S,4S)-5-(4-氯-2-甲基吡啶并[3,4-d]嘧啶-6-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16e
化合物16d(200mg,0.56mmol)溶于1,4-二氧六环(3mL)中，室温下加入三氯氧磷(257mg,1.6mmol)和N,N-二异丙基乙胺(217mg,1.6mmol)，加热至90℃反应1.5小时，TLC检测原料反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物16e(122mg,收率58％)。
第五步(1S,4S)-5-(4-(((R)-1-(3-(二氟甲基)-2-氟-5-((异丙氧基羰基)氨基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯16f
化合物16e(122mg,0.32mmol)溶于二甲基亚砜(2mL)中，室温下加入中间体IN-6(93mg,0.32mmol)和N,N-二异丙基乙胺(42mg,0.96mmol)，加热至95℃反应1.5小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物16f(150mg,粗品)，直接用于下一步。
第六步(3-((R)-1-((6-((1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-甲基吡啶并[3,4-d]嘧啶)-4-基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯16g
化合物16f(150mg,粗品)溶于二氯甲烷(5mL)中，加入三氟乙酸(2.5mL)，室温反应2小时，TLC检测反应完全。反应液浓缩，加冰水淬灭，加饱和碳酸氢钠水溶液调至碱性，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物16g(137mg,粗品)，直接用于下一步。
第七步(3-(二氟甲基)-4-氟-5-((R)-1-((2-甲基-6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)苯基)氨基甲酸异丙酯16h
化合物16g(137mg,粗品)溶于乙醇(3mL)中，加入甲醛溶液(167mg,0.20mmol,37％)和钯碳(10mg,10％)，氢气氛围下加热至30℃反应2小时，TLC检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤饼洗涤，滤液浓缩得到黄色固体标题化合物16h(137mg,粗品)，直接用于下一步。
LC-MS:m/z＝544.3[M+H] +
第八步N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)吡啶并[3,4-d]嘧啶-4-胺16
化合物16h(137mg,粗品)溶于乙醇(2mL)中，室温下加入氢氧化钠水溶液(2mL,6mmol,3M)，加热至95℃反应3小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物16(45mg,四步收率30％)。
LC-MS:m/z＝458.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.55(s,1H),7.07(s,1H),6.95-6.66(m,3H),5.67(q,J＝7.2Hz,1H),4.77(s,1H),3.77(s,1H),3.60(d,J＝10.4Hz,1H),3.51(dd,J＝10.4,2.0Hz,1H),2.98-2.88(m,2H),2.50(s,3H),2.34(s,3H),2.08(d,J＝10.4Hz,1H),1.97(d,J＝10.0Hz,1H),1.59(d,J＝7.2Hz,3H).
实施例17
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺17
Figure PCTCN2022072055-appb-000051
第一步(S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯17a
化合物6b(63mg,0.17mmol)和中间体IN-1(41mg,0.17mmol)溶于二甲基亚砜(1mL)中，室温下加入N,N-二异丙基乙胺(67mg,0.52mmol)，加热至100℃反应2小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得到黄色固体标题化合物17a(130mg,粗品)，直接用于下一步。
第二步(S)-4-(4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯17b
化合物17a(130mg,粗品)分散在乙醇/水(10mL/2mL)中，室温下加入还原铁粉(64mg,1.15mmol)和氯化铵(64mg,1.15mmol)，加热至100℃反应3小时，TLC检测反应完全。反应液垫硅藻土趁热过滤，滤饼洗涤，滤液浓缩，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物17b(87mg,两步收率94％)。
LC-MS:m/z＝532.3[M+H] +
第三步(S)-4-(4-(((R)-1-(3-乙酰氨基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[3,4-d]嘧啶-6-基)-3-甲基哌嗪-1-羧酸叔丁酯17c
化合物17b(87mg,0.16mmol)溶于二氯甲烷(3mL)中，室温下加入N,N-二异丙基乙胺(42mg,0.32mmol)和醋酸酐(20mg,0.19mmol)，加热至30℃反应4小时，TLC检测反应完全。反应液冷却至室温，浓缩，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物17c(100mg,粗品)，直接用于下一步反应。
第四步N-(3-((R)-1-((6-((S)-2-甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)-5-(三氟甲基)苯基)乙酰胺17d
化合物17c(100mg,粗品)溶于二氯甲烷(3mL)中，室温下加入三氟乙酸(0.5mL)，加热至30℃反应3小时，TLC检测反应完全。反应液浓缩，加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物17d(77mg,两步收率99％)。
第五步N-(3-((R)-1-((6-((S)-2,4-二甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)-5-(三氟甲基)苯基)乙酰胺17e
化合物17d(77mg,0.16mmol)溶于乙醇(3mL)中，室温下加入甲醛水溶液(55mg,0.67mmol,37％)和钯碳(10mg,10％)，加热至35℃反应3小时，TLC检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩得到黄色油状标题化合物17e(78mg,粗品),直接用于下一步。
LC-MS:m/z＝488.3[M+H] +
第六步N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-((S)-2,4-二甲基哌嗪-1-基)吡啶并[3,4-d]嘧啶-4-胺17
化合物17e(78.0mg,粗品)溶于乙醇(2mL)中，室温下加入氢氧化钠水溶液(2.0mL,8.0mmol,4M)，加热至75℃反应过夜，TLC检测反应完全。反应液浓缩，加乙酸乙酯萃取，饱和食盐水洗涤3次，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物17(10mg,两步收率13％)。
LC-MS:m/z＝446.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.74(s,1H),8.24(s,1H),7.30(s,1H),6.95(s,2H),6.81(s,1H),5.54(q,J＝6.8Hz,1H),4.80-7.83(m,1H),4.12(d,J＝12.8Hz,1H),3.29-3.20(m,1H),3.03(d,J＝11.2Hz,1H),2.93(d,J＝11.2Hz,1H),2.44(d,J＝8.0Hz,1H),2.39(s,3H),2.30-2.20(m,1H),1.65(d,J＝6.8Hz,3H),1.26(d,J＝6.8Hz,3H).
实施例18
N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶并[3,4-d]嘧啶-4-胺18
Figure PCTCN2022072055-appb-000052
第一步3-(4-氨基甲酰基-5-硝基吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18b
化合物3c(1.0g,4.96mmol)溶于二甲基亚砜(3mL)中，室温下加入3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18a(990mg,4.99mmol)和N,N-二异丙基乙胺(1.9g,14.70mmol)，加热至90℃反应3小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物18b(1.7g,收率94％)。
LC-MS:m/z＝364.2[M+H] +
第二步3-(5-氨基-4-氨基甲酰基吡啶-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18c
化合物18b(1.7g，4.68mmol)分散在乙醇(20mL)和水(5mL)中，室温下加入还原铁粉(1.5g,26.86mmol)和氯化铵(1.4g,26.17mmol)，加热至90℃反应3小时，TLC检测反应完全。反应液趁热过滤，滤饼乙醇洗涤，滤液浓缩，加水，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得黄色固体标题化合物18c(1.4g,收率90％)。
LC-MS:m/z＝334.2[M+H] +
第三步3-(2-甲基-4-氧代-3,4-二氢吡啶并[3,4-d]嘧啶-6-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18d
化合物18c(1.4g,4.20mmol)分散在原乙酸三乙酯(16mL)中，室温下加入对甲苯磺酸(60mg,0.35mmol)，加热至150℃反应3小时，TLC检测反应完全。反应液冷却至室温，加入稀盐酸(10mL,1N)搅拌10分钟，乙酸乙酯萃取，丢弃有机相，水相用饱和碳酸钠水溶液中和，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析得到黄色固体标题化合物18d(805mg,收率54％)。
第四步3-(4-氯-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18e
化合物18d(100mg,0.29mmol)溶于1,4-二氧六环(3mL)中，加入N,N-二异丙基乙胺(108mg,0.84mmol)，降温至0℃，滴加三氯氧磷(128mg,0.83mmol)，加完加热至90℃反应3小时，TLC检测原料反应完全。反应液冷却至室温，加入冰水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得到黄色固体标题化合物18e(54mg,收率50％)。
第五步3-(4-(((R)-1-(3-(二氟甲基)-2-氟-5-((异丙氧基羰基)氨基)苯基)乙基)氨基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯18f
化合物18e(54mg,0.14mmol)溶于二甲基亚砜(2mL)中，室温下加入中间体IN-6(42mg,0.14mmol)和N,N-二异丙基乙胺(67mg,0.52mmol)，加热至95℃反应1.5小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得绿色固体标题化合物18f(100mg,粗品)，直接用于下一步。
LC-MS:m/z＝630.3[M+H] +
第六步(3-((1R)-1-((6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)-5-(二氟甲基)-4-氟苯基)氨基甲酸异丙酯18g
化合物18f(100mg,粗品)溶于二氯甲烷(5mL)中，加入三氟乙酸(2mL)，室温反应2小时，TLC检测反应完全。反应液浓缩，加水，加饱和碳酸氢钠水溶液调节pH至中性，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得黄色固体标题化合物18g(90mg,粗品)，直接用于下一步。
LC-MS:m/z＝530.3[M+H] +
第七步(3-(二氟甲基)-4-氟-5-((1R)-1-((2-甲基-6-(6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶并[3,4-d]嘧啶-4-基)氨基)乙基)苯基)氨基甲酸异丙酯18h
化合物18g(90mg,粗品)溶于乙醇(3mL)中，加入甲醛溶液(55mg,0.68mmol,37％)和钯碳(10mg,10％)，氢气氛围下加热至30℃反应2小时，TLC检测反应完全。反应液冷却至室温，垫硅藻土过滤，滤液浓缩，粗品经Prep-TLC纯化得到白色固体标题化合物18h(30mg,四步收率19％)。
LC-MS:m/z＝544.3[M+H] +
第八步N-((R)-1-(5-氨基-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(6-甲基-3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶并[3,4-d]嘧啶-4-胺18
化合物18h(30mg,0.055mmol)溶于乙醇(2ml)中，室温下加入氢氧化钠水溶液(2mL,6.00mmol,3N)，加热至95℃反应3小时，TLC检测反应完全。反应液冷却至室温，加水，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得黄色固体标题化合物18(10mg,收率40％)。
LC-MS:m/z＝458.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.73(s,1H),7.33(s,1H),7.03-6.92(m,1H),6.88(t,J＝55.2Hz,1H),6.80-6.72(m,1H),5.77(q,J＝6.8Hz,1H),4.51-3.85(m,6H),3.25-3.10(m,1H),2.97-2.78(m,1H),2.56-2.46(m,2H),2.44(s,3H),2.11-1.93(s,1H),1.68(d,J＝7.2Hz,3H).
测试例1化合物对K-562细胞增殖抑制的IC 50测定
本发明中使用的人慢性髓原性白血病细胞K-562(CCL-243)购自American Type Culture Collection(ATCC)。细胞在10％胎牛血清(FBS)及1％双抗的RPMI 1640培养基，在37℃，5％CO 2的环境中生长。
化合物对体外培养的K-562细胞增殖抑制作用通过以下方法进行测定：
1)细胞接种：取对数生长期状态良好的K-562细胞以20000个/孔、90μL接种到96孔板中，在37℃、5％CO 2条件下培养24小时。
2)加药：将需要测试的化合物以完全培养基进行梯度稀释，取10μL稀释的化合物加入到90μL的细胞中，使化合物终浓度为10000、3000、1000、300、100、30、10、3、1nM，同时设相应的溶媒对照。置于37℃、5％CO 2细胞培养箱中培养96小时。
3)检测：每孔加10μL 5mg/mL MTT工作液(ABCONE,M9609)，37℃作用4小时后，加入三联液(10％SDS,0.5％异丙醇，0.1mol/L HCL)，至细胞裂解物完全溶解，使用TECAN SPARK酶标仪读取OD570和OD690数值。
4)计算：以下列公式计算细胞生长抑制率：
抑制率＝(对照孔 OD570nm-OD690nm－给药孔 OD570nm-OD690nm)/对照孔 OD570nm-OD690nm×100％
用Graphpad prism 5.0软件根据化合物浓度与对应的抑制率计算IC 50值。试验结果见表1。
表1本发明中化合物对K-562细胞的增殖抑制的IC 50(nM)
化合物编号 K-562 化合物编号 K-562
BI-3406 35.2 10-1 303.8
1 36.4 10-2 147.8
2 111.0 11 40.7
3 138.9 12 210.25
4 203.4 13 22.5
5 89.5 14 35.6
6 129.1 15 19.0
7 92.4 16 143.7
8 153.4 17 32.7
9 105.7 18 10.0
结论：本发明实施例化合物对K-562细胞具有增殖抑制作用，且多个化合物的活性与BI-3402相当。
测试例2化合物对K-562细胞中KRAS下游信号分子ERK1/2磷酸化水平的影响
本发明的化合物对K-562细胞中ERK1/2磷酸化水平的影响通过以下方法检测：
1)细胞接种：取对数生长期状态良好的K-562细胞以1*10 6个/孔接种到六孔板中，在37℃、5％CO2条件下培养过夜。
2)加药：将需要测试的化合物以完全培养基进行梯度稀释后，加入细胞中，使化合物的终浓度为1000、100、10、1nM。置于37℃、5％CO 2细胞培养箱中培养24小时。
3)蛋白样品制备：收集细胞悬液，500g离心5分钟，弃上清，PBS洗涤3次，以1×SDS凝胶上样缓冲液(50mM Tris-HCl(pH 6.8)，100mM DTT，2％SDS，10％甘油，0.1％溴酚蓝)100μL裂解细胞。细胞裂解物在100℃中加热10分钟变性。
4)Western blot：将蛋白样品进行SDS-PAGE电泳，电泳结束后，用湿转系统将蛋白转移至PVDF膜，将PVDF膜置于封闭液(5％脱脂奶粉稀释于TBS/T)中室温封闭1小时，然后I，II抗反应；洗膜后，用Immobilon Western HRP Substrate luminal reagent试剂发色，Western Blot成像仪(Tanon,4600)拍照。以下是所用抗体信息：p-ERK1/2(CST:4370)；ERK1/2(CST:9102)；β-tubulin(CST:2146)。
化合物对K-562细胞中ERK1/2磷酸化水平影响的结果见图1。
结论：本发明实施例化合物对K-562细胞ERK1/2的磷酸化具有明显抑制作用，抑制活性呈浓度梯度依赖。
测试例3化合物对SOS1的抑制活性
实验步骤：
化合物的处理
配制400倍终浓度的化合物，如检测终浓度为5uM，配制成400倍浓度，即2mM。用自动微孔移液 器将化合物梯度稀释成设置的浓度点个数。
转移化合物到384孔板反应板
用超声波纳升液体处理系统将上述稀释好的化合物从Echo 384孔板中转移50nL到384孔反应板中，阴性对照和阳性对照均转移50nL的100％DMSO。
配制并转移4倍Tag1-SOS1溶液
用试剂盒中提供的Diluent配制4倍Tag1-SOS1溶液，转移5ul至384孔反应板中，对于阴性对照孔，转移5ul Diluent替代酶溶液，1000rpm离心1分钟。
配制4倍Tag2-KRAS G12C溶液
用试剂盒中提供的Diluent配制4倍Tag2-KRAS G12C溶液，转移5ul至384孔反应板中，1000rpm离心1分钟。
转移2倍检测溶液溶液
用试剂盒中提供的Detection Buffer配制2倍Anti-Tag1-Tb3+和Anti-Tag2-XL665溶液，转移10ul至384孔反应板中，1000rpm离心1分钟，室温下孵育60分钟。
读数
用酶标仪Envision读取数据荧光信号数值(Ex665/Em615)。
抑制率计算与IC50拟合
从读板仪器上复制数值，其中最大值是指阳性对照的读值，最小值是指阴性对照的读值。抑制率(％)＝(最大值-样本值)/(最大值-最小值)×100％。
将数据导入MS Excel并用XLFit excel add-in version5.4.0.8拟合IC50值；
表2化合物对SOS1的抑制活性
化合物编号 IC50(nM) 化合物编号 IC50(nM) 化合物编号 IC50(nM)
1 5.7 2 6.7 3 10.1
5 6.6 6 7.5 8 5.4
9 8.5 10-2 13.0 11 11
12 6.5 13 4.0 14 5.6
15 4.7 16 5.4 17 5.1
18 4.2        
拟合公式：Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)
测试例4化合物对小鼠和人的肝微粒体稳定性实验
实验步骤:
(1).从-80℃冰箱中取出肝微粒体(20mg蛋白/mL)，置于37℃水浴恒温振荡器上预温孵3min，融化待用。
(2).按照上面“实验温孵体系的构成”比例，制备温孵体系混合溶液(不含β-NADPH)。
(3).制备100μM的测试化合物工作溶液，备用。
(4).对照组(不含β-NADPH)：分别取25μL PB溶液到75μL(2)所述温孵体系混合液中，涡旋30s，混匀，反应总体积100μL，复样。放入到37℃水浴恒温振荡器中进行孵育，并开始计时，取样时间点为0min和60min。
(5).样品组：分别取25μL β-NADPH溶液(4mM)加入75μL(2)所述反应体系中，涡旋30s，混匀，反应总体积100μL，复样。放入到37℃水浴恒温振荡器中进行孵育，并开始计时，取样时间点为0min,5min,15min,30min,60min。
(6).于各个时间点将样品管中取出，加入300μL冷的终止剂(含内标)，终止反应。
(7).涡旋并离心。
(8).取上清液150μL加入150μL水，涡旋混匀，LC-MS/MS进样分析。
数据分析
用下列一级动力学公式计算半衰期(t1/2)和清除率(CL)
Ct＝C0*e-kt
Ct＝(1/2)*C0
t1/2＝ln2/k＝0.693/k
CL＝Vd*k
Vd＝1/肝微粒体中蛋白含量
CLint(liver)＝CLint(mic)×肝重体重比×每克肝脏中的肝微粒体蛋白浓度
公式中的参数见表3：
表3参数列表
Figure PCTCN2022072055-appb-000053
实验结果见表4：
表4化合物在不同种属中的微粒体稳定性
Figure PCTCN2022072055-appb-000054
在人肝微粒体稳定性实验中，化合物13的稳定性显著好于BI-3406；在小鼠肝微粒体稳定性实验中，化合物16、17的稳定性显著好于BI-3406。综上，实施例中多个化合物的在不同种属的肝微粒体稳定性都显著好于BI-3406。
测试例5化合物的大鼠药代动力学性质
将实施例1的化合物(10mg/kg)给禁食过夜的SD大鼠(雄性，n＝3/时间点)口服。给药2h后再给大鼠喂食。分别在给药前以及给药后1.5h、4h和8h采集血样，在4℃离心(4500rpm)10min，获得血清。分别在给药前和给药后1.5h、4h和8h采集肝脏。然后将肝脏样品快速冷冻并储存在-80℃。将100μL MeOH/ACN(1:1，v/v)添加到10μL血清中将混合物沉淀，之后涡旋1min，再离心(11000rpm)5min获得上清液。将20μL上清液溶解于20μL ACN/H2O(1:1，v/v)并用超高效液相色谱仪对其进行分析。肝脏样品中加入10倍重量的MeOH/ACN(1:1，v/v)，然后用匀浆机在50Hz条件下匀浆120s后获得匀浆。将匀浆离心(11000rpm)5分钟并收集上清液。然后将20μL上清液重新溶解于20μL ACN/H2O(1:1，v/v)中，并用超高效液相色谱仪对其进行分析。结果如表5：
表5化合物的大鼠药物代谢动力学特征
Figure PCTCN2022072055-appb-000055
由表5可知，化合物1在大鼠体内较好的血浆暴露量，较好的半衰期。
测试例6化合物的体内抗肿瘤活性
在雌性BALB/c小鼠(6-8周)的右侧皮下注射人胰腺癌细胞MIAPaCa-2或PANC-1(1.0×107细胞/小鼠)。小鼠灌胃给药，化合物1(Cpd 1)(50mg/kg)、Trametinib(0.125mg/kg,bid)，以及化合物1和Trametinib的联合用药(合用)，一天两次给药(bid)，连续给药。每天监测小鼠并且当肿瘤变得可见时开始卡尺测量。肿瘤的体积通过测量两个垂直直径使用如下公式计算得到：(L*W2)/2，其中的L和W指的是肿瘤直径的长度和宽度。当肿瘤平均体积到达100mm3时，将小鼠分组(D0，n＝5/组)并且施以化合物。在给药期间，肿瘤体积及小鼠体重每3天测量1次。结果如下图2-5所示。
结论：实验结果表明，本发明实施例化合物1在单用和合用的剂量下，对KRAS不同的突变肿瘤模型具有很好的抗肿瘤活性。两个抗肿瘤模型中，实施例化合物1在单用和合用的剂量下，对小鼠的体重无明显的影响，表现出较好的安全性。实施例化合物1单用对PANC-1(KRAS G12D)裸鼠移植瘤具有一定的抑制活性，肿瘤生长抑制率为40.6％(P<0.01)；实施例化合物1对MIAPaCa-2(KRAS G12C)裸鼠移植瘤具有一定的抑制活性，肿瘤生长抑制率为65.4％(P<0.01),与MEK抑制剂Trametinib合用组的肿瘤抑制率为105.6％，合用组所有老鼠的肿瘤发生退缩，与单用组相比活性显著增强(P<0.001)。
申请人声明，本发明通过上述实施例来说明本发明的一种作为SOS1抑制剂的多环嘧啶类衍生物及其制备方法和应用，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。

Claims (12)

  1. 一种多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物的结构如式(I)所示：
    Figure PCTCN2022072055-appb-100001
    其中：R 1选自氢或C 1-C 3烷基；优选为氢或甲基；
    A 1选自N或C-R 11；
    R 11选自H、C 1-C 3烷基或C 1-C 3卤代烷基；
    A 2选自N或C-R 2；
    R 2选自-OR 21或氰基；
    R 21选自H、C 1-C 3烷基、3-7元环烷基、4-7元杂环基，其中C 1-C 3烷基、3-7元环烷基、4-7元杂环基任选地被1-3个R 22所取代；
    R 22选自卤素、C 1-C 4烷基、氰基、羟基；
    L不存在或选自O、NH或NCH 3；
    R 3选自3-7元环烷基、4-7元杂环基、6-10元的稠杂环基、6-10元的桥杂环基、6-10元的螺杂环基，其中3-7元环烷基、4-7元杂环基、6-10元的稠杂环基、6-10元的桥杂环基、6-10元的螺杂环基任选地被1-3个R 31所取代；
    R 31选自C 1-C 3烷基、C 1-C 3卤代烷基、羟基、卤素、氰基、-NR aR b、C 1-C 3烷氧基、＝O、-NHCOR 32或-COR 32；
    R 32选自C 1-C 3烷基、C 1-C 3卤代烷基、3-7元环烷基或4-7元杂环基；
    R 4为-CH 3；
    AR选自6-10元的芳基或5-10元的杂芳基，其中的芳基或杂芳基任选被1-4个R 5所取代；
    R 5选自卤素、C 1-C 4烷基、C 1-C 4卤代烷基、羟基-C 1-C 4烷基、羟基-C 1-C 4卤代烷基、3-6元环烷基、4-7元杂环基、-OR a、-NR aR b；
    R a选自H、C 1-C 4烷基、C 1-C 4卤代烷基、3-6元环烷基或4-7元杂环基；
    R b选自H、C 1-C 4烷基、C 1-C 4卤代烷基、3-6元环烷基或4-7元杂环基；
    上述定义中，如下条件不能同时出现：
    1)A 1为C-R 11；
    2)A 2为C-OR 21；
    3)L为O或不存在；
    所述式(I)中的杂环基、杂芳基中的杂原子为1-3个并选自氧、氮和硫中的一种或多种。
  2. 如权利要求1所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物的结构如式(Ⅱ)所示：
    Figure PCTCN2022072055-appb-100002
    其中，R 1、L、R 3和R 5具有与权利要求1相同的限定范围；n＝1-4；
    优选地，对于式(II)化合物，所述的苯基任选被1-4个R 5所取代，当所述R 5的个数为2-4个时，所述的R 5可相同或不同；
    和/或，当所述R 5为C 1-C 4卤代烷基时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
    和/或，当所述R 5为C 1-C 4卤代烷基时，其中的卤原子为氟或氯；
    和/或，当所述R 5为卤素时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
    和/或，当所述R 5为卤素时，其中的卤原子为氟或氯；
    和/或，当所述R 5为-NR aR b时，所述的R 5为1-3个，当存在2-3个R 5时，所述的R 5可相同或不同；
    和/或，当所述R 5为-NR aR b时，所述的R a和R b可相同或不同。
  3. 如权利要求1所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物的结构如式(III)所示：
    Figure PCTCN2022072055-appb-100003
    其中，R 1、R 21、R 3和R 5具有与权利要求1相同的限定范围；n＝1-4；
    优选地，对于式(III)化合物，R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的4-7元杂环基为5-6元杂环基；
    和/或，R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基含有1-2个杂原子；
    和/或，所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基的杂原子为氮和/或氧；
    和/或，所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述杂环基的杂原子为两个时，两个杂原子相同或不同；
    和/或，所述R 21选自H或任选地被1-3个R 22所取代的C 1-C 3烷基，所述R 22选自卤素、C 1-C 4烷基、氰基、羟基；
    其中，R 31和R 22具有与权利要求1相同的限定范围。
  4. 如权利要求1所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物的结构如式(IV)所示：
    Figure PCTCN2022072055-appb-100004
    其中，R 1、L、R 3和R 5具有与权利要求1相同的限定范围；n＝1-4；
    优选地，对于式(IV)化合物，当L不存在或为O时，R 3为任选地被1-3个R 31所取代的3-7元环烷基或4-7元杂环基；
    和/或，当所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的杂环基中杂原 子为氮和/或氧；
    和/或，当所述R 3为任选地被1-3个R 31所取代的4-7元杂环基时，所述的杂原子为1-2个；
    其中，R 31具有与权利要求1相同的限定范围。
  5. 如权利要求1所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物的结构如式(V)所示：
    Figure PCTCN2022072055-appb-100005
    其中，R 1、A 2、L、R 3和R 5具有与权利要求1相同的限定范围；n＝1-4。
  6. 如权利要求1所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体，其特征在于，所述多环嘧啶类衍生物选自如下结构的任意一种：
    Figure PCTCN2022072055-appb-100006
    Figure PCTCN2022072055-appb-100007
  7. 一种如权利要求1-6中任一项所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体的制备方法，其选自如下四种方法中的一种：
    方法一、
    Figure PCTCN2022072055-appb-100008
    其中，A 1、A 2、AR、R 1、R 3、R 4和L具有与权利要求1相同的限定范围；
    方法二、
    Figure PCTCN2022072055-appb-100009
    其中，A 1、A 2、AR、R 1、R 3、R 4和L具有与权利要求1相同的限定范围；
    方法三、
    Figure PCTCN2022072055-appb-100010
    其中，A 1、A 2、AR、R 1、R 3、R 4和L具有与权利要求1相同的限定范围；L优选NH；A 1优选C；A 2优选CR 2，R 2优选-OR 2；
    方法四、
    Figure PCTCN2022072055-appb-100011
    其中，X 1、X 2和X 3为卤素；X 1优选氟；X 2优选溴；X 3优选氯；A 1、A 2、AR、R 1、R 3、R 4和L具有与权利要求1相同的限定范围；A 1优选C；A 2为CR 2，R 2优选氰基；L优选O；R 1优选甲基。
  8. 一种药物组合物，其特征在于，所述药物组合物包括如权利要求1-6中任一项所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体或其立体异构体；
    优选地，所述药物组合物还包括可药用载体和/或赋形剂。
  9. 如权利要求1-6中任一项所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或如权利要求8所述的药物组合物单用或联合MEK信号通路抑制剂在制备用于治疗癌症的药物或在制备SOS1抑制剂中的用途；优选地，所述癌症包括但不限于星形细胞癌、乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、食道癌、胃癌、头颈部癌、肝细胞癌、喉癌、胰腺癌、肺癌、口腔癌、卵巢癌、前列腺癌、甲状腺癌、肉瘤、肾癌和胆管癌；进一步优选地，所述癌症包括但不限于：胰腺癌、结直肠癌、肺癌、肝细胞癌、肾癌、胃癌和胆管癌。和/或所述MEK信号通路抑制剂如RAF、KRAS、MEK或ERK1/2抑制剂。
  10. 如权利要求9所述的用途，所述多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或药物组合物的剂量范围为10-100mg/kg；和/或MEK抑制剂的剂量范围选自0.1-0.2mg/kg；优选地，所述多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或药物组合物的剂量范围为25-50mg/kg；和/或MEK抑制剂的剂量范围选自0.125mg/kg；和/或所述MEK抑制剂为Trametinib。
  11. 如权利要求9所述的用途，其中癌症是RAS家族相关的癌症；优选KRAS、HRAS或NRAS G12C相关癌，KRAS、HRAS或NRAS G12D相关癌，KRAS、HRAS或NRAS G12S相关癌，KRAS、HRAS或NRAS G12A相关癌，KRAS、HRAS或NRAS G12V相关癌，KRAS、HRAS或NRAS G13D相关癌，KRAS、HRAS或NRAS G13C相关癌，KRAS、HRAS或NRAS Q61X相关癌，KRAS、HRAS或NRAS A146T相关癌，KRAS、HRAS或NRAS A146V相关癌或KRAS、HRAS或NRAS A146P等相关癌。
  12. 一种用于治疗和/或预防癌症的方法，其包括向人类给予治疗有效量的如权利要求1-6中任一项所述的多环嘧啶类衍生物、其药学上可接受的盐、其互变异构体、其立体异构体或如权利要求8所述的药物组合物。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024035921A1 (en) * 2022-08-12 2024-02-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Degraders of son of sevenless homolog 1
WO2024074827A1 (en) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited New treatments for pain
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
CN113801114A (zh) * 2020-06-11 2021-12-17 江苏恒瑞医药股份有限公司 稠合二环杂芳基类衍生物、其制备方法及其在医药上的应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230029385A1 (en) * 2019-10-15 2023-01-26 Bayer Aktiengesellschaft 2-methyl-aza-quinazolines
CN114539245A (zh) * 2020-11-26 2022-05-27 上海翰森生物医药科技有限公司 含嘧啶并环类衍生物调节剂、其制备方法和应用
CN114685488A (zh) * 2020-12-31 2022-07-01 南京圣和药业股份有限公司 作为sos1抑制剂的化合物及其应用
CN116546985A (zh) * 2021-01-28 2023-08-04 浙江海正药业股份有限公司 吡啶并嘧啶类衍生物及其制备方法和用途
CN115724843A (zh) * 2021-08-31 2023-03-03 勤浩医药（苏州）有限公司 Sos1抑制剂、包含其的药物组合物及其用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
CN113801114A (zh) * 2020-06-11 2021-12-17 江苏恒瑞医药股份有限公司 稠合二环杂芳基类衍生物、其制备方法及其在医药上的应用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024035921A1 (en) * 2022-08-12 2024-02-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Degraders of son of sevenless homolog 1
WO2024074827A1 (en) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited New treatments for pain
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof

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