CN113416181B - Quinazoline derivative and application thereof - Google Patents

Quinazoline derivative and application thereof Download PDF

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CN113416181B
CN113416181B CN202110880096.5A CN202110880096A CN113416181B CN 113416181 B CN113416181 B CN 113416181B CN 202110880096 A CN202110880096 A CN 202110880096A CN 113416181 B CN113416181 B CN 113416181B
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CN113416181A (en
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杨胜勇
李琳丽
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Sichuan University
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    • 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
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Abstract

The invention discloses a quinazoline derivative and a preparation method and application thereof, belonging to the technical field of medicines. The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The series of compound molecules have inhibitory activity on ATR, can be used for preparing ATR inhibitor medicines, shows stronger cell antiproliferative activity in various cell strains taking LoVo cells as examples, and simultaneously has good antitumor activity in animal experiments; therefore, the series of compounds provide a new effective selection for the preparation of ATR small-molecule inhibitor drugs and drugs for treating and/or preventing cancers, and have good application prospects.
Figure DDA0003191859370000011

Description

Quinazoline derivative and application thereof
Technical Field
The invention belongs to the technical field of organic synthetic drugs, and particularly relates to quinazoline derivatives, and a preparation method and application thereof.
Background
Ataxia telangiectasia and Rad3 related (ATR) are atypical serine/threonine protein kinases that play key roles in DNA replication stress. ATR, ataxia telangiectasia mutated kinase (ATM) and DNA dependent protein kinase (DNA-PK) belong to phosphatidylinositol 3 kinase-like kinase (PIKK) family, and are important components of DNA Damage Response (DDR); DDR has evolved to recognize, signal, and promote repair of damaged DNA. Unlike ATR's response to stress of DNA replication, ATM and DNA-PK are primarily responsive to DNA double strand breaks. Typically, DDRs coordinate the recognition, signaling, and repair of damaged DNA through the network, thereby ensuring genomic stability. Numerous studies have shown that tumor cells with ATM mutations or loss of function, or other DDR defects that promote replicative stress, are generally more dependent on ATR survival. Based on the principle of synthetic lethality, this offers the possibility of using ATR inhibitors to kill cancer cells while retaining normal, non-cancer cells. Therefore, development of ATR kinase inhibitors for use in the treatment of related cancers has important application value.
Disclosure of Invention
The invention develops a novel quinazoline derivative and a preparation method thereof, and the quinazoline derivative shows good antitumor activity on enzymes, cells and animals and can be used for preparing an ATR inhibitor.
The present invention provides, in a first aspect, a compound of formula i:
Figure BDA0003191859350000011
the nitrogen heterocyclic ring A is selected from: a substituted or unsubstituted 4-to 10-membered azacycloalkyl group containing 0 to 2 heteroatoms, which is N, O or S, in addition to N represented by formula I; in the nitrogen heterocyclic ring A, the substituent of the substituted 4-10-membered nitrogen heterocyclic ring alkyl is selected from: C1-C8 alkyl, C1-C8 alkoxycarbonyl, amino and sulfo;
R1selected from: H. substituted or unsubstituted 6-to 10-membered aryl, substituted or unsubstituted 5EA 10-membered heteroaryl, substituted or unsubstituted pyridone, sulfonate; r1Wherein the 5-to 10-membered heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N, O or S; r1Wherein the substituted 6-10 membered aryl, substituted 5-10 membered heteroaryl and substituted pyridone have the following substituents: C1-C8 alkyl, 5-10 membered cycloalkyl, cyano, amino, C1-C8 alkoxycarbonyl; r1Wherein the 5-10 membered cycloalkyl group contains 0-2 heteroatoms, and the heteroatoms are N, O or S;
R2selected from: H. substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted pyridone, sulfonate; r2Wherein the 5-to 10-membered heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N, O or S; r2Wherein the substituent of the substituted 6-10-membered aryl, the substituted 5-10-membered heteroaryl and the substituted pyridone is selected from the following groups: C1-C8 alkyl, 5-10 membered cycloalkyl, cyano, amino, C1-C8 alkoxycarbonyl; r2Wherein the 5-10 membered cycloalkyl group contains 0-2 heteroatoms, and the heteroatoms are N, O or S;
R1and R2Not H at the same time;
R3selected from: a substituted or unsubstituted 6-to 10-membered aryl group, a substituted or unsubstituted 5-to 10-membered heteroaryl group,
Figure BDA0003191859350000021
R3Wherein the 5-to 10-membered heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N, O or S; r3Wherein the substituent of the substituted 6-10 membered aryl or the substituted 5-10 membered heteroaryl is selected from the group consisting of: C1-C8 alkyl, amino, C1-C8 alkoxy, hydroxyl, C1-C8 alkoxycarbonyl, halogen and 5-10 membered cycloalkyl; r is3Wherein the 5-to 10-membered cycloalkyl group contains 0 to 2 hetero atoms, and the hetero atom is N, O or S.
Wherein, in the compound shown in the formula I, the nitrogen heterocyclic ring A is selected from: substituted or unsubstituted 5-to 6-membered cycloalkyl, substituted or unsubstituted 7-to 8-membered bridged cycloalkyl, which contains 0 to 1 hetero atom (S) other than N represented by formula I, wherein the hetero atom is N, O or S; in the nitrogen heterocyclic ring A, the substituent of the substituted 5-6 membered cycloalkyl and the substituted 7-8 membered bridged cycloalkyl is selected from: C1-C6 alkyl, C1-C6 alkoxycarbonyl, amino and C1-C6 alkylsulfo.
Preferably, in the compounds of formula i above, azacyclo a is selected from: substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted piperidine
Figure BDA0003191859350000022
Substituted or unsubstituted
Figure BDA0003191859350000023
Substituted or unsubstituted
Figure BDA0003191859350000024
In nitrogen heterocyclic ring A, the substituted morpholine, substituted piperazine, substituted tetrahydropyrrole, substituted piperidine and substituted piperidine
Figure BDA0003191859350000025
Substituted by
Figure BDA0003191859350000026
Substituted by
Figure BDA0003191859350000027
The substituent(s) is selected from: C1-C4 alkyl, C1-C4 alkoxycarbonyl, -NH2And C1-C4 alkylsulfo.
More preferably, in the compounds of formula i above, azacyclo a is selected from:
Figure BDA0003191859350000028
Figure BDA0003191859350000029
R4selected from the group consisting of: H. C1-C4 alkyl, C1-C4 alkoxycarbonyl, -NH2；R5Is C1-C4 alkyl.
Most preferably, in the compounds of formula I, the azacyclo A is selected from：
Figure BDA0003191859350000031
Figure BDA0003191859350000032
Wherein, in the compound shown in the formula I, R1Selected from: H. substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted pyridone, and C1-C6 sulfonate; r1Wherein the 5-to 6-membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are N, O or S; r1Wherein the substituent of the substituted 6-membered aryl, the substituted 5-6-membered heteroaryl and the substituted pyridone is selected from the following groups: C1-C6 alkyl, 5-6 membered cycloalkyl, cyano, amino, C1-C6 alkoxycarbonyl; r1Wherein the 5-6 membered cycloalkyl group contains 0-1 hetero atom (S), and the hetero atom is N, O or S.
Preferably, in the compounds of formula I above, R1Selected from: H. substituted or unsubstituted phenyl, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrrole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridone, C1-C4 sulfonate group; r1Wherein the substituents of said substituted phenyl, substituted pyrazole, substituted furan, substituted thiophene, substituted thiazole, substituted oxazole, substituted isoxazole, substituted imidazole, substituted pyrrole, substituted pyridine, substituted pyrimidine, substituted pyridone are selected from the group consisting of: C1-C4 alkyl, 5-6 membered epoxy alkyl, cyano, amino, C1-C4 alkoxycarbonyl.
More preferably, in the compound represented by the formula I, R is1Selected from: H.
Figure BDA0003191859350000033
Figure BDA0003191859350000034
R6selected from: C1-C4 alkyl, cyano,
Figure BDA0003191859350000035
R7Selected from: C1-C4 alkyl, 5-6 membered epoxy alkyl, C1-C4 alkoxycarbonyl; r8Selected from: C1-C4 alkyl.
Most preferably, in the compounds of formula I above, R1Selected from: H.
Figure BDA0003191859350000036
Figure BDA0003191859350000037
Figure BDA0003191859350000041
wherein, in the compound shown in the formula I, R2Selected from: H. substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted pyridone, and C1-C6 sulfonate; r2Wherein the 5-to 6-membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are N, O or S; r2Wherein the substituent of the substituted 6-membered aryl, the substituted 5-6-membered heteroaryl and the substituted pyridone is selected from the following groups: C1-C6 alkyl, 5-6 membered cycloalkyl, cyano, amino, C1-C6 alkoxycarbonyl; r2Wherein the 5-6 membered cycloalkyl group contains 0-1 hetero atom (S), and the hetero atom is N, O or S.
Preferably, in the compounds of formula I above, R2Selected from: H. substituted or unsubstituted phenyl, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrrole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridone, C1-C4 sulfonate group; r2In (1),the substituent of the substituted phenyl, the substituted pyrazole, the substituted furan, the substituted thiophene, the substituted thiazole, the substituted oxazole, the substituted isoxazole, the substituted imidazole, the substituted pyrrole, the substituted pyridine, the substituted pyrimidine and the substituted pyridone is selected from the following groups: C1-C4 alkyl, 5-6 membered epoxy alkyl, cyano, amino, C1-C4 alkoxycarbonyl.
More preferably, in the compound represented by the formula I, R is2Selected from: H.
Figure BDA0003191859350000042
Figure BDA0003191859350000043
R6selected from: C1-C4 alkyl, cyano,
Figure BDA0003191859350000044
R7Selected from: C1-C4 alkyl, 5-6 membered epoxy alkyl, C1-C4 alkoxycarbonyl; r8Selected from: C1-C4 alkyl.
Most preferably, in the compounds of formula I above, R2Selected from: H.
Figure BDA0003191859350000045
Figure BDA0003191859350000046
wherein, in the compound shown in the formula I, when R is1Selected from the group consisting of substituted or unsubstituted 6-to 10-membered aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted pyridone, R2Is H; when R is1Selected from the group consisting of substituted or unsubstituted 6-to 10-membered aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted pyridone, R2Is H; when R is1In the case of a sulfonate group, R2Is a sulfonate group.
Preferably, in the compounds of formula I above, R1Selected from: substituted or unsubstituted 6-to 10-membered aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, substituted or unsubstitutedUnsubstituted pyridone, sulfonate; r2Selected from the group consisting of: H. sulfonate group, and only when R1In the case of a sulfonate group, R2Is a sulfonate group.
Wherein, in the compound shown in the formula I, R3Selected from: substituted or unsubstituted naphthalene, substituted or unsubstituted benzene, substituted or unsubstituted indole, substituted or unsubstituted azaindole, substituted or unsubstituted pyrazole, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indole, or a pharmaceutically acceptable salt thereof,
Figure BDA0003191859350000051
The substituent of the substituted naphthalene, the substituted benzene, the substituted indole, the substituted azaindole, the substituted pyrazole, the substituted benzopyrazole and the substituted benzimidazole is selected from the following groups: C1-C8 alkyl, amino, C1-C6 alkoxy, hydroxyl, C1-C6 alkoxycarbonyl, halogen and 5-6 membered cycloalkyl; r3Wherein the 5-to 6-membered cycloalkyl group contains 0 to 1 hetero atom, and the hetero atom is N, O or S.
Preferably, in the compounds of formula I above, R3Selected from:
Figure BDA0003191859350000052
Figure BDA0003191859350000053
Figure BDA0003191859350000054
wherein X is C or N; r9 is C1-C7 alkyl, C1-C4 alkoxycarbonyl, 5-6 membered cycloalkyl, wherein the 5-6 membered cycloalkyl contains 0-1 heteroatom, and the heteroatom is N, O or S; r10、R11Independently selected from: C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl and halogen; r12Selected from: C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, or form a 5-6-membered aliphatic ring with an aromatic ring, wherein the 5-6-membered aliphatic ring contains 1-2 heteroatoms, and the heteroatoms are N or O.
Most preferably, in the compounds of formula I above, R3Selected from the group consisting of:
Figure BDA0003191859350000055
Figure BDA0003191859350000056
Figure BDA0003191859350000061
preferably, the compound represented by the formula I specifically includes the following structure:
Figure BDA0003191859350000062
Figure BDA0003191859350000071
Figure BDA0003191859350000081
the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing anti-tumor.
Further, the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing ATR inhibitor medicines.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding auxiliary ingredients.
The invention also provides a preparation method of the compound, which comprises the following two synthetic routes:
the first synthetic route is as follows:
Figure BDA0003191859350000082
reaction conditions are as follows: (a) k, K2CO3，DCM，0℃，1.5h；(b)、R1Corresponding boronic acids or boronic esters, Pd [ P (C)6H5)3]4，K2CO31, 4-dioxane/H2O(V/V＝50/1)，95℃，12h；(c)、Pd(dppf)Cl2，K2CO31, 4-dioxane/H2O(V/V＝50/1)，105℃，6h。
The second synthetic route is as follows:
Figure BDA0003191859350000083
reaction conditions are as follows: (d) t-BuOK, THF, 0 deg.C, 1.5 h; (e) pd [ P (C)6H5)3]4，K2CO31, 4-dioxane/H2O(V/V＝50/1)，95℃，12h；(f)、Pd(dppf)Cl2，K2CO31, 4-dioxane/H2O (V/V ═ 50/1), 105 ℃, 6 h; (g) HCl (concentration 4M, solvent 1, 4-dioxane), 1, 4-dioxane/H2O，80℃，1h；(h)、TsCl，DMAP，TEA，DMF，80℃；(i)、R3Corresponding amine, 80 ℃.
Definition of terms:
the compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
The term "alkyl" is a radical of a straight or branched chain saturated hydrocarbon group. Examples of C1-C8 alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-pentyl (C5), and n-hexyl (C6). Unless otherwise indicated, each instance of alkyl is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents. "substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule. In some embodiments, the C1-C8 alkyl is C1-C8 alkyl substituted with halogen (fluoro, chloro, bromo, iodo). In the case where the C1-C8 alkyl group is substituted with a substituent, the number of carbon atoms of the substituent is not counted in.
The term "amino" refers to the group-NH2-NHR or-NRR. Examples of amino groups include, but are not limited to, -NH2N-methylamino, N-ethylaminomethyl, N-dimethylamino, N-formamide and N-acetamide. Unless otherwise indicated, each instance of an amino group is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents. In some embodiments, R and/or R is C1-C8 alkyl, C1-C8 alkanamide.
The cycloalkyl group in the present invention does not mean an alkyl group having only one ring but means a cycloalkyl group having a plurality of rings, for example: spiro cycloalkyl or bridged cycloalkyl.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The term "pharmaceutically acceptable salts" refers to acid and/or base salts of the compounds of the present invention with inorganic and/or organic acids and bases, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by appropriately (e.g., equivalent) mixing the above compound with a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
In certain embodiments of the invention, isotopically-labeled compounds are included, by which is meant the same compounds as listed herein but for the fact that one or more atoms are replaced by another atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S. The compounds of the present invention containing the aforementioned isotopes and/or other atomic isotopes, as well as pharmaceutically acceptable salts of such compounds, are intended to be included within the scope of the present invention. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if desired.
The pharmaceutically acceptable auxiliary materials of the invention refer to substances which are contained in a dosage form besides active ingredients, the addition of the substances does not change the dominance of the pharmaceutical composition in the process of treating diseases, but only plays an auxiliary effect, and the auxiliary effects are only utilization of the known activity of the ingredients and are auxiliary treatment modes which are conventional in the field of medicine. If the auxiliary materials are used together with the pharmaceutical composition of the present invention, the protection scope of the present invention still belongs to.
The invention has the beneficial effects that:
the invention develops a novel quinazoline derivative, the series of compounds can be used for preparing ATR inhibitor drugs, show stronger cell antiproliferative activity in various cell strains taking LoVo cells as examples, and simultaneously have good antitumor activity in animal experiments; therefore, the series of compounds provide a new effective selection for the preparation of ATR small-molecule inhibitor drugs and drugs for treating and/or preventing cancers, and have good application prospects.
Drawings
FIG. 1 is a graph of the growth of subcutaneous tumors in a LoVo xenograft model of human colorectal adenocarcinoma after oral administration of the indicated doses of compounds 4-28 or solvent.
FIG. 2 is a graph of p-ATR, ATR, p-Chk1S in subcutaneous tumor tissue following the indicated dose of compounds 4-28 or solvent treatment of the LoVo xenograft model345And expression Western blot analysis chart of Chk1 protein.
Detailed Description
Target molecule synthesis example 1:
preparation of intermediate (R) -4- (6-bromo-2-chloroquinazolin-4-yl) -3-methylmorpholine (2):
Figure BDA0003191859350000111
6-bromo-2, 4-dichloroquinazoline (1, 10.00g, 46.50mmol, 1.0eq) and (R) -3-methylmorpholine (5.64g, 55.81mmol, 1.2eq) were weighed out and dissolved in 230mL DCM, and K was slowly added2CO3(9.64g, 69.76mmol, 1.5eq), at room temperature for two hours, and the completion of the reaction was monitored by TLC. And (3) post-treatment: the system was added directly to the crude silica gel, spin dried, and separated by prep-CC (petroleum ether/ethyl acetate 4: 1) to give the product as a white solid 14.66g, 92% yield.
1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝1.7Hz,1H),7.96(dd,J＝8.9,1.8Hz,1H),7.65(d,J＝8.9Hz,1H),4.67(d,J＝6.6Hz,1H),4.03(d,J＝13.3Hz,1H),3.90(d,J＝11.5Hz,1H),3.84–3.75(m,1H),3.70(s,2H),3.55(t,J＝12.8Hz,1H),1.43(d,J＝6.8Hz,3H)。
13C NMR(101MHz,DMSO-d6)δ163.31,156.10,152.30,137.10,129.72,128.17,118.05,116.08,70.48,66.62,51.80,44.70,15.36。
Preparation of intermediate (R) -4- (6-R1-2-chloroquinazolin-4-yl) -3-methylmorpholine (3-X):
Figure BDA0003191859350000121
intermediate (R) -4- (6-bromo-2-chloroquinazolin-4-yl) -3-methylmorpholine (2, 1.0eq) and the corresponding boronic acid or boronic ester (1.2eq) were weighed and dissolved in dioxane/water (v/v 50: 1) and K was added2CO3(2.0eq) and tetrakis (triphenylphosphine) palladium (0.15eq) under nitrogen at 95 ℃ for 12h, and the reaction was monitored by TLC. And (3) post-treatment: the crude silica gel is directly added into the system, the mixture is dried and stirred, and the product 3a-z is obtained by prep-CC separation (petroleum ether/ethyl acetate: 3: 1-1: 4), wherein the yield is 50-73%.
Preparation of the product (R) -4- (2- (1H-indol-4-yl) -6-R1-quinazolin-4-yl) -3-methylmorpholine (4-X):
Figure BDA0003191859350000122
intermediate (R) -4- (6-R1-2-chloroquinazolin-4-yl) -3-methylmorpholine (3-X, 1.0eq) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indole (2.0eq) were weighed out and dissolved in 5mL dioxane/water (v/v ═ 50: 1) and K was added2CO3(0.10mmol, 2.0eq) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.1eq) was reacted at 95 ℃ for 6h under nitrogen protection and the reaction was monitored by TLC. And (3) post-treatment: directly adding crude silica gel into the system, spin-drying and mixing the sample, and separating by prep-CC to obtain a product 4-X.
Target molecule synthesis example 2:
preparation of intermediate (R) -4- (6-bromo-2-chloroquinazolin-4-yl) -3-methylmorpholine (5):
Figure BDA0003191859350000123
to a solution of 6-bromo-2, 4-dichloroquinazoline (1, 35.98mmol) in THF (36mL) at 0 deg.C was added t-BuOK (35.98mmol, 1.0 eq). It was stirred at 0 ℃ for 3 hours and the reaction was monitored by TLC for completion. And (3) post-treatment: the reaction solution was poured into H2O/NH4Aqueous Cl (25mL/25mL) and extracted with ethyl acetate. The organic layer was dried (Na)2SO4) And filtered. The filtrate was concentrated and purified by prep-CC separation (petroleum ether/ethyl acetate 4: 1) to afford off-white intermediate 5 in 90% yield.
1H NMR(400MHz,Chloroform-d)δ8.18(dd,J＝2.3,0.5Hz,1H),7.85(dd,J＝8.9,2.3Hz,1H),7.69-7.65(m,1H),1.74(s,9H).13C NMR(101MHz,DMSO-d6)δ166.49,155.39,150.69,138.41,129.36,126.64,120.53,117.43,86.30,28.05。
Intermediates 5 to 6 were prepared using the preparation method 2-X to 3-X, and intermediates 6 to 7 were prepared using the preparation method 3-X to 4-X.
Preparation of intermediate 2- (1H-indol-4-yl) -6- (1-methyl-1H-pyrazol-5-yl) -4(3H) -quinazolinone (8):
Figure BDA0003191859350000131
to intermediate 4- (tert-butoxy) -2- (1H-indol-4-yl) -6- (1-methyl-1H-pyrazol-5-yl) quinazoline (7, 5.03mmol) in CH3To the OH (50mL) solution was added concentrated hydrochloric acid (10mL) and the mixture was left at 50 ℃ for 3 h. And (3) post-treatment: the reaction solution was filtered and the solid was washed with DCM. The yellow solid 8 was dried and used for the next step without further purification.
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.27(d,J＝2.0Hz,1H),8.08(dd,J＝8.5,1.9Hz,1H),7.95(d,J＝8.5Hz,1H),7.74–7.68(m,3H),7.59(t,J＝2.6Hz,1H),7.56(d,J＝1.8Hz,1H),7.29(t,J＝7.8Hz,1H),7.11(s,1H),6.61(d,J＝1.8Hz,1H),3.95(s,2H)。
13C NMR(101MHz,DMSO-d6)δ161.51,156.50,141.84,138.51,136.96,135.52,129.24,128.22,126.33,125.92,125.27,121.42,121.29,121.11,120.95,116.63,107.11,107.08,102.20,38.18。
Preparation of product 4-R3-2- (1H-indol-4-yl) -6- (1-methyl-1H-pyrazol-5-yl) quinazoline (4-X):
Figure BDA0003191859350000132
to a solution of 2- (1H-indol-4-yl) -6- (1-methyl-1H-pyrazol-5-yl) -4(3H) -quinazolinone (8, 0.88mmol), DMAP (0.088mmol, 0.1eq), TEA (1.76mmol, 2.0eq) in DMF (3mL) was added TsCl (0.97mmol, 1.1 eq). The reaction was carried out under nitrogen at 80 ℃ for 1 hour, followed by addition of the corresponding amine (1.76mmol, 2.0eq) for 2 hours and monitoring of the completion by TLC. And (3) post-treatment: the reaction solution was concentrated and purified by pre-column chromatography (petroleum ether/ethyl acetate 1: 1 to 0: 1) with a yield of compound 4-X of 10-35%.
Example molecular and nuclear magnetic data:
Figure BDA0003191859350000133
Figure BDA0003191859350000141
Figure BDA0003191859350000151
Figure BDA0003191859350000161
Figure BDA0003191859350000171
Figure BDA0003191859350000181
Figure BDA0003191859350000191
Figure BDA0003191859350000201
Figure BDA0003191859350000211
Figure BDA0003191859350000221
Figure BDA0003191859350000231
Figure BDA0003191859350000241
Figure BDA0003191859350000251
Figure BDA0003191859350000261
Figure BDA0003191859350000271
Figure BDA0003191859350000281
Figure BDA0003191859350000291
Figure BDA0003191859350000301
Figure BDA0003191859350000311
Figure BDA0003191859350000321
Figure BDA0003191859350000331
Figure BDA0003191859350000341
Figure BDA0003191859350000351
Figure BDA0003191859350000361
note: example synthesis of molecules was selected from route one or route two synthesis.
Evaluation of pharmacological Activity of Compound
In vitro kinase assay for quinazoline derivatives
In vitro Kinase assays were performed using the Kinase Profile service provided by Eurofins. A mixture of test compound 4-X and kinase ATRIP/ATRIP was incubated with 50nM GST-CMyc-p53 and Mg ion in ATP buffer to initiate the reaction by Mg/ATP. After incubation for 30 min at room temperature, the reaction was stopped by addition of EDTA-containing stop buffer, followed by addition of detection buffer containing d 2-tagged anti-GST monoclonal antibody and phosphorylated p 53-tagged anti-phosphorylated monoclonal antibody. The reaction plate was placed in a microplate reader, and the HTRF signal value was calculated according to the formula HTRF ═ (Em665nm/Em620nm) × 10000, using a time-resolved fluorescence (HTRF) mode.
And (3) test results: the inhibition of ATR activity by Compound 4-X was determined and the results are shown in Table 2 (A represents IC)50<100nM, B500 nM>IC50>100nM, C1000 nM>IC50>500nM))。
In vitro cell experiments of quinazoline derivatives
(1) Cell culture consumables:
cell culture medium: DMEM medium (Gibco), RPMI-1640 (Gibco); fetal bovine serum (FBS, Hyclone); penicillin solution and streptomycin solution (Invitrogen Bio Inc.)
Cell: HT-29 (human colorectal adenocarcinoma cells), LoVo (human colorectal adenocarcinoma cells), NCI-H23 (human non-small cell lung carcinoma cells), A549 (human lung carcinoma cells), HL60 (human myelogenous leukemia cells) were all purchased from the American Type Culture Collection (ATCC).
Cell culture consumables: pancreatin (Invitrogen bio); 6-well plate, 24-well plate, 96-well plate, centrifuge tube, gun tip, etc. (Corning Co.), 20, 100mm cell culture dish (WHB Co.).
(2) Cell culture:
HT-29 and LoVo cells were cultured in DMEM medium (containing 10% fetal bovine serum, 100U/mL penicillin and 100. mu.g/mL streptomycin); NCI-H23, A549, HL60 cells were cultured in RPMI1640 medium (containing 10% fetal bovine serum, 100U/mL penicillin and 100. mu.g/mL streptomycin). All cells were simultaneously incubated at 37 ℃ in 5% CO2The culture was performed in a humidified cell incubator. In the cell culture process, cells are digested by pancreatin for reasonable passage, the cell density is ensured to be appropriate, and cells in logarithmic growth phase are adopted in all experiments.
(3) MTT assay
A. Solution preparation
5mg/mL MTT solution: the MTT powder is dissolved by normal saline to prepare a solution of 5mg/mL, and the solution is filtered by a 0.22 mu m filter membrane, stored at 4 ℃ in the dark and used up within 1 month.
20% acidic SDS solution: 80g of SDS powder was weighed and ultrapure water was added to 320 mL. After the solution is dissolved by ultrasonic wave, 400 mul of concentrated hydrochloric acid is added, and finally the volume is adjusted to 400mL by ultrapure water.
B. Adherent cell (HT-29, LoVo, A549) treatment
Cells in logarithmic growth phase were seeded in 96-well plates (seeding numbers of LoVo, HT-29 and a549 cells were 3500, 2000 and 3000 per well, respectively) per 100 μ L per well, a blank group and a cell control group were set aside, 200 μ L of physiological saline for injection was added to the side wells, the plates were cultured overnight in a cell incubator, 100 μ L of a medium containing compounds at different concentrations was added to the plates seeded with cells, and 3 duplicate wells were set for each group. And (5) incubating in a cell incubator for 72 h.
C. Suspension cell (NCI-H23 and HL60) treatment
After 100. mu.L of the culture medium containing the compounds with different concentrations was added to the well plate inoculated with the cells, the cells in the logarithmic growth phase were inoculated into a 96-well plate per 100. mu.L per well (the inoculation numbers of NCI-H23 and HL60 cells were 8000 and 10000 per well, respectively), 3 multiple wells were set for each group, a blank group and a cell control group were set, 200. mu.L of physiological saline for injection was added to the side wells, and incubation was carried out in a cell incubator for 72H.
D. Color development
mu.L of 5mg/mL MTT staining solution was added to each well, incubated in a cell incubator for 2-4h, microscopic to confirm complete cell staining, and 50. mu.L of 20% acidic SDS solution was added and incubation was continued overnight in the cell incubator. And finally, detecting the absorption light value at 570nm by using a multifunctional microplate reader.
E. Computing IC50
The viability of the cells at different concentrations of compound was calculated using absorbance of each well and IC was calculated using GraphPad Prism 5.0 software fitting with compound concentration as the abscissa and viability as the ordinate50. The survival rate is 100-.
Lovo cell assay results inhibition of ATR activity by Compound 4-X was determined and the results are shown in Table 2.
TABLE 2 kinase Activity and cellular Activity data
Figure BDA0003191859350000381
Kinase selectivity assay for Compounds 4-28
TABLE 3 inhibition data of compounds 4-28 against 13 targets
Figure BDA0003191859350000391
In a kinase selectivity test, the invention finds that the compounds 4-28 with the concentration of 10 μ M show excellent selectivity on 403 recombinant human protein kinase targets, and as can be seen from table 3, the inhibition rate of 13 kinase targets is more than 50%. Further IC50Tests showed that the kinase activity of compounds 4-28 to 9 of these targets was within 10 μ M, with the best off-target activity being the ATR target and second being the B-Raf target. Overall, compounds 4-28 showed at least 118-fold selectivity for 403 recombinant human protein kinases, with excellent kinase selectivity.
LoVo tumor xenograft model experiment
LoVo cells in a logarithmic growth phase are collected, the cells are washed 3 times by serum-free DMEM medium, finally the cell suspension density is adjusted to 1 × 108 cells/mL by using the serum-free medium, and the LoVo cells are subcutaneously injected into the right side of a 6-week-old female Balb/C mouse (after the 5-week-old female Balb/C mouse is cultured adaptively for 1 week) in the number of 1 × 107 cells per cell, namely 100 μ L of LoVo cell suspension. When the tumor grows to 130-150mm3Thereafter, the mice were randomly divided into 3 groups of 6 mice each, and the body weight and tumor volume of the mice were measured, and this was taken as the first day. Mice were orally gavaged twice daily with 50mg/kg, 100mg/kg of compounds 4-28 dissolved in 10% (v/v) DMSO, 40% (v/v) PEG 300, 5% (v/v) Tween 80, and 45% (v/v) physiological saline, and controls were administered twice daily200 μ L of the same solvent was used for oral gavage. Tumor volumes were determined in mice every 2-3 days and recorded. After 30 days of administration, subcutaneous tumor tissue was taken from the mice, and tumor tumors were weighed and photographed. A part of tumor tissues are taken to be soaked in 4% of the methanol polymer, and the heart, the liver and the spleen of a mouse are taken down to be soaked in the 4% of the methanol polymer for immunohistochemical detection. Mouse subcutaneous tumor volume calculation: v (mm)3) 0.5 × a × b × b, a is the width of the tumor and b is the length of the tumor in mm.
Relative Tumor Volume (RTV): RTV-Vt/V0, Vt being tumor volume at the time point of measurement and V0 being tumor volume size at the time of initial dosing.
Relative tumor proliferation rate: r ═ TRTV/CRTV × 100%, TRTV is the relative tumor volume in the treatment group, and CRTV is the relative tumor volume in the treatment group. The drug is considered effective when R < 60%.
As can be seen from FIG. 1, 4-28 inhibited tumor growth in a dose-dependent manner in all treatment groups, with a tumor inhibition of 72.8% at 100mg/kg BID dose.
To investigate the relationship between ATR inhibition and in vivo anti-tumor efficacy, a western blot analysis was used to determine ATR activity (p-ATR, p-Chk 1S) in the LoVo tumor xenograft model following different doses of 4-28 treatment345). As shown in fig. 2, 4-28 significantly inhibited the phosphorylation of ATR and Chk1 compared to the control group. These results indicate that 4-28 inhibited the growth of LoVo xenograft tumors in vivo by inhibiting ATR activity.
Preliminary pharmacokinetic Properties of Compounds 4-28:
TABLE 4 important pharmacokinetic parameters for Compounds 4-28
Drug substitution parameters Intravenous injection (5mg/kg) Oral administration (10 m)g/kg)
Half life t1/2(h) 1.4 1.1
Maximum absorption time tmax(h) 0.1 1.7
Peak concentration of drug Cmax(ng/mL) 3396.3 895.3
Area under the time curve AUC(0-∞)ng/mL*h 3151.3 2719.6
Plasma clearance Cl (mL/min/kg) 26.5 —
Steady state apparent distribution volume Vss (L/kg) 2.03 —
Bioavailability Bioavailability F — 43.1％
To assess the applicability of compounds 4-28 in vivo experiments, we tested compounds 4-28 for preliminary pharmacokinetic properties. Preliminary pharmacokinetic properties of compounds 4-28 were determined by Shanghai Medeci biomedical corporation. Preliminary pharmacokinetic properties were determined by oral administration of 10mg/kg and intravenous administration of 5mg/kg in male Sprague-Dawley rats, and detailed pharmacokinetic data are presented in Table 4. In oral administration, the elimination half-life (t1/2), peak (Cmax), area under the concentration-time curve (AUC0- ∞) and bioavailability (F) were 1.1h, 895.3ng/mL, 2719.6ng/mL × h, 43.1%. In intravenous injection, the elimination half-life (t1/2), peak (Cmax), area under the concentration-time curve (AUC0- ∞), plasma clearance (Cl) and apparent volume of distribution (Vss) were 1.4h, 3396.3ng/mL, 3151.3ng/mL x h, 26.5mL/min/kg and 2.03L/kg. The compound SKLB-197 has good bioavailability, completely supports the oral administration mode, but has a half-life of not too long, only 1.1 hours.
The compound of the invention, as an ATR small molecule inhibitor, shows strong cell antiproliferative activity in various cell strains taking LoVo cells as an example, and simultaneously has good antitumor activity in animal experiments.

Claims (5)

1. A compound of formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0003570197560000011
the nitrogen heterocyclic ring A is selected from:
Figure FDA0003570197560000012
Figure FDA0003570197560000013
R1selected from:
Figure FDA0003570197560000014
Figure FDA0003570197560000015
R2selected from: H.
Figure FDA0003570197560000016
R3selected from:
Figure FDA0003570197560000017
Figure FDA0003570197560000021
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising the structure:
Figure FDA0003570197560000022
Figure FDA0003570197560000031
Figure FDA0003570197560000041
3. use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of colorectal cancer.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an ATR inhibitor.
5. A pharmaceutical composition characterized by: the compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2 is used as an active ingredient, and auxiliary ingredients are added to prepare the preparation.
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