CN117417324A - Heterocyclic carboxamide compound, pharmaceutical composition and application thereof - Google Patents

Heterocyclic carboxamide compound, pharmaceutical composition and application thereof Download PDF

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CN117417324A
CN117417324A CN202311356616.8A CN202311356616A CN117417324A CN 117417324 A CN117417324 A CN 117417324A CN 202311356616 A CN202311356616 A CN 202311356616A CN 117417324 A CN117417324 A CN 117417324A
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compound
esi
synthesis
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章翔宇
王淋
叶科
李林林
毛杰
张阔军
蒋晟
王天雨
童俊
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention discloses a heterocyclic carboxamide compound, a pharmaceutical composition and application thereof. The heterocyclic formamide disclosed by the invention can be used for efficiently and selectively degrading the hematopoietic progenitor cell kinase 1, and has no degradation activity on other proteins in the same family. Compared with the small molecule inhibitor of the hematopoietic progenitor cell kinase 1, the small molecule inhibitor can more efficiently stimulate the anti-tumor immune response of T cells, release effector cell factors and has stronger anti-tumor activity.

Description

Heterocyclic carboxamide compound, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a heterocyclic carboxamide hematopoietic progenitor cell kinase 1 degradation agent and application thereof.
Background
Immunotherapy thoroughly changes the treatment mode of cancer and brings new hopes for patients. In particular, immune checkpoint inhibitors against the PD-1 and CTLA-4 pathways show significant clinical effects, but they are only effective against specific patient populations, specific types of tumors, with low tumor response rates (-30%), and most patients do not show long lasting symptomatic relief, develop resistance after a period of administration. Therefore, a new tumor immunotherapy target is needed to be discovered, the clinical effect of immune check points is improved, and the method has important significance for application and popularization of tumor immunotherapy.
Hematopoietic progenitor kinase 1 (HPK 1, MAP4K 1) is one of the members of the MAP4K family, a Ste20 silk/threonine protein kinase. There are 5 members of the MAP4K family, including MAP4K2, MAP4K3, MAP4K4, MAP4K5 and MAP4K6, in addition to HPK 1. HPK1 is expressed primarily in hematopoietic cells such as T cells, B cells, neutrophils, dendritic Cells (DCs), natural Killer (NK) cells, and macrophages. Numerous studies have shown that HPK1 is a negative regulator of T cell receptors and B cell receptors. After TCR activation, HPK1 in the cytoplasm is recruited to the plasma membrane, where its amino acid residues Y381, S171 and T165 are phosphorylated, resulting in a fully kinase-activated HPK1 kinase. The activated HPK1 phosphorylates the amino acid residue S376 of the linker protein SLP76, provides a binding site for the negative regulatory factor 14-3-3, promotes the degradation of SLP76 by a proteasome, and finally breaks down the stability of the TCR signal complex, thereby blocking the kinase signal pathway downstream for promoting T cell activation and proliferation. In addition to TCR signaling, HPK1 negatively regulates T cell signaling through prostaglandin E2 (PGE 2) receptors. In addition, HPK1 can also be used under the stimulation of growth factor, stress, inflammatory factor, differentiation factor, etcTo transmit immunosuppressive signals in B cells, NK cells and dendritic cells. In addition, a recent study has shown that kinase activity of HPK1 inhibits immune function in a variety of cells, including CD4 + T cells, CD8 + T cells, NK cells and dendritic cells, and demonstrate that inhibition of the kinase activity of HPK1 is sufficient to induce an anti-tumor immune response. In addition, inhibiting the activity of HPK1 kinase can further promote T cell effector function and obviously increase the therapeutic effect of PD-L1 monoclonal antibody. The HPK1 gene deletion, the HPK1 inhibitor or the HPK1 protac degradation agent can enhance the CAR-T cell-based immunotherapy and show better anti-tumor activity in various preclinical hematology and solid tumor mouse models. Notably, neither the HPK1 gene knockout nor the inactivated kinase knockout mice showed a lethal inflammatory response, but these were significant in the absence of some other immune negative regulators, such as CTLA-4 and Cbl-b, indicating a higher safety profile for HPK1 inhibitors. In view of the above, HPK1 is a new target of tumor immunotherapy that is potentially effective, and research and development of HPK1 inhibitors are of great importance for improving the key problems currently faced by tumor immunotherapy.
Over a decade ago, developers discovered that HPK1 could be a potential tumor immunotherapy target, HPK1 inhibitors were favored by various pharmaceutical companies and scientific institutions, various structures of HPK1 inhibitors were reported, and it was not completely counted that 4 HPK1 inhibitors were currently in early clinical research stages, including CFI-402411 of Treadwell Therapeutics, BGB-15025 of baji, and NDI-101150 of PRJ1-3024 and Nimbus Therapeutics of zhuhai. At present, their structure has not been disclosed. Although a variety of HPK1 inhibitors have been reported, no related drugs are currently marketed. The challenges faced in the development of HPK1 inhibitors are mainly the difference in HPK1 family member functions, but the structural homology is very high, and the difficulty in designing highly selective inhibitors is great.
Compared with traditional medicines, PROTAC has the remarkable advantages that: the application range is wider, the activity is higher, and the target can be targeted to a target point which is not patent medicine; the selectivity, activity and safety are improved; overcomes drug resistance of tumor drugs, etc. The PROTAC can realize the selectivity which is difficult to realize by small molecules on certain targets, so that the development of the HPK1 PROTAC molecules is expected to solve the problems of low selectivity, incapacity of dose dependence of drug effect and the like of HPK1 inhibitors, and the HPK1 PROTAC molecules are rarely reported at present. Therefore, the research and development of the HPK1 PROTAC molecule are urgent, and the HPK1 PROTAC molecule has important scientific significance and development value.
Disclosure of Invention
Aiming at the problem of low selectivity of the HPK1 small molecule inhibitor, the invention utilizes the advantage that the selectivity of small molecules can not be realized easily by using PROTAC, develops the PROTAC molecule of the targeted HPK1, and provides a heterocyclic formamide HPK1 PROTAC degradation agent. The PROTAC can degrade HPK1 protein with high efficiency and high selectivity, and has no degradation activity on other proteins in the same family. Compared with the HPK1 small molecule inhibitor, the anti-tumor immune response of the T cells can be stimulated more effectively, the effector cell factor is released, and the anti-tumor activity is stronger.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
The invention provides a heterocyclic carboxamide compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and the structure of the heterocyclic carboxamide compound is shown as follows:
in formula I:
R 1 is hydrogen, halogen or C 1-4 Alkoxy, halo (C) 1-4 Alkoxy) or deuteration (C 1-4 An alkoxy group);
R 2 is halogen, cyano, hydroxy (C) 1-4 Alkyl), halo (C) 1-4 An alkyl group);
m is 0, 1, 2 or 3;
q is N or C;
y is N or C;
e is
W is-CH 2 -、-C(CH 3 ) 2 Or->
R 3 Is C 1-6 An alkyl group;
R 4 is that
R 5 Is hydrogen or C 1-4 An alkyl group;
l isThe terminal is attached to the E terminal, and the "- -" terminal is attached toAre connected;
L 1 is a single bond, -O-, -NR 6 -、Terminal is attached to the E terminal and terminal is attached to L2;
L 2 is a single bond,Terminal is attached to L1, terminal is attached to L3;
L 3 is a single bond,
R 6 Is hydrogen or C 1-3 An alkyl group;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
d is 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5 or 6;
f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
In some embodiments of the present invention, in some embodiments,
l is The terminal is attached to the E terminal, and the "- -" terminal is attached to +. >Are connected;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
c is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
d is 1, 2 or 3;
e is 1, 2, 3, 4 or 5;
f is 1, 2, 3, 4, 5, 6, 7, 8 or 10.
In some embodiments of the present invention, in some embodiments,
l is The terminal is attached to the E terminal, and the "- -" terminal is attached to +.>Are connected;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
b is 1, 2, 3, 4, 5, 6 or 7;
c is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
d is 1, 2 or 3;
e is 1, 2, 3 or 4;
f is 1, 2, 3, 4, 5, 6, 7 or 8.
In some embodiments of the present invention, in some embodiments,
e is
In some embodiments, R 2 Is fluoro, cyano, hydroxymethyl, methyl or trifluoromethyl.
In some embodiments, a heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, has a structural formula as shown in any of the following:
wherein E, L, R 1 ，R 2 And a is as previously described.
In some embodiments, the heterocyclic carboxamide compound of formula I is selected from compounds of any one of the following structures:
the invention provides an application of heterocyclic formamide compounds shown in a formula I or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof in preparing a hematopoietic progenitor cell kinase 1 degradation agent.
The invention provides an application of heterocyclic formamide compounds shown in a formula I or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof in preparing medicines for treating and/or preventing cancers.
In some embodiments, the cancer is one or more of bone cancer, lung cancer, stomach cancer, colon cancer, membranous adenocarcinoma, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cancer of the shoulders, cervical cancer, cancer of the kidneys, head and neck cancer, thyroid cancer, esophageal cancer, lymphatic cancer, leukemia, or skin cancer.
The invention provides a pharmaceutical composition, which contains heterocyclic formamide compounds shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.
In some embodiments, the heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, is used in an amount effective for treatment in the pharmaceutical composition.
The invention provides an application of a pharmaceutical composition in preparing a hematopoietic progenitor cell kinase 1 degradation agent.
The invention provides application of a pharmaceutical composition in preparing a medicament for treating and/or preventing cancer.
In some embodiments, the cancer is one or more of bone cancer, lung cancer, stomach cancer, colon cancer, membranous adenocarcinoma, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cancer of the shoulders, cervical cancer, cancer of the kidneys, head and neck cancer, thyroid cancer, esophageal cancer, lymphatic cancer, leukemia, or skin cancer.
The pharmaceutically acceptable carrier can be an auxiliary material widely used in the field of medicine production. Adjuvants are primarily used to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or sustained release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powder formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosols, such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functionalities, the base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and salts of organic acids including, for example, amino acids (such as arginine and the like), glucuronic acid, and the like.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.
The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.
Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion product from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used inAnd->It means that the corresponding group is linked to other fragments, groups in the compound of formula I through this site.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, the definition of alkoxy group being as defined above. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy.
The term "deuteroalkoxy" refers to an alkoxy group substituted with one or more deuterium, the definition of alkoxy group being as described above. Examples of deuterated alkoxy groups include, but are not limited to, -OCD 3 。
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the advantages that:
(1) The heterocyclic formamide compound, namely HPK1 PROTAC molecule, provided by the invention can efficiently and selectively degrade HPK1 protein, and has no degradation activity on proteins such as GLK in the same family.
(2) The HPK1 PROTAC molecules provided by the invention can more effectively stimulate the anti-tumor immune response of T cells
(3) The HPK1 PROTAC molecule provided by the invention has good therapeutic effect on cancers.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1 Synthesis of intermediates 2a-c
2, 4-dichloropyrimidine-5-carboxamide (1.92 g,10 mmol) was dissolved in absolute ethanol (50 mL), 2-aminobenzyl alcohol (1.23 g,10 mmol) was added, DIPEA (5.24 mL,30 mmol) was added, the reaction was refluxed for 3h, quenched with water (150 mL) after completion of the reaction, the product precipitated, the filter cake was suction filtered, washed three times with purified water, and dried to give intermediate 2a (1.80 g, 65%) as a white solid. MS (ESI, M/z): 279 (M) + +1) the intermediate 2b-c can be obtained by replacing the corresponding starting materials.
Example 2 Synthesis of intermediate 10
a) 3-methoxy-phenethylamine (50 g,331 mmol) was dissolved in 1M aqueous HCl, added37% aqueous formaldehyde (107 g,1.32 mol) was added and reacted at 60℃for 1h, after the reaction was completed, cooled to 0℃and 50% aqueous NaOH (43.6 g,1.10 mol) was slowly added, stirred overnight, suction filtered, water washed to give intermediate 4 (48 g, 86%) as a white solid. MS (ESI, M/z): 339 (M) + +1).
b) Compound 4 (48 g,142 mmol) was dissolved in isopropanol (400 mL), concentrated hydrochloric acid (26 g) was added, reacted overnight at room temperature, after completion of the reaction, methyl tert-butyl ether (200 mL) was added and stirred for 2h, the filter cake was suction filtered, washed once with a mixed solution of isopropanol and methyl tert-butyl ether (1:1), dried to give a white solid, which was then washed with saturated NaHCO 3 Aqueous solution (400 mL) was dissolved and stirred overnight and extracted with dichloromethane (200 mL. Times.3) to afford intermediate 5 (37 g, 80%) as a pale yellow oil. MS (ESI, M/z): 164 (M) + +1).
c) Compound 5 (16.3 g,100 mmol) was dissolved in AcOH (100 mL), a mixed solution of AcOH (100 mL) and fuming nitric acid (200 mL) was added dropwise at 0deg.C, reacted for 4h at 0deg.C, quenched slowly with water (300 mL) at 0deg.C after completion of the reaction, pH was adjusted to alkaline, extracted with dichloromethane (200 mL. Times.4), and concentrated under reduced pressure to give crude intermediate 6. MS (ESI, M/z): 209 (M) + +1).
d) The crude compound 6 (2.08 g) was dissolved in acetonitrile (50 mL), a mixed solution of ethyl bromoacetate (1.75 g,10.5 mmol) and DIPEA (8.7 mL,50 mmol) was added at room temperature, reacted at room temperature for 4 hours, quenched with water (30 mL) after completion of the reaction, extracted with diethyl ether (30 mL. Times.3), concentrated under reduced pressure, and purified by column chromatography to give colorless transparent oily liquid intermediate 7 (1.18 g). MS (ESI, M/z): 295 (M) + +1).
e) Compound 7 (2.94 g,10 mmol) was dissolved in a mixed solvent of ethanol (18 mL) and water (6.3 mL), a mixed solution of ferrous sulfate heptahydrate (500 mg,1.8 mmol) and reduced iron powder (494 mg,8.82 mmol) was added at room temperature, reacted at room temperature for 4 hours, after the reaction was completed, concentrated under reduced pressure, and purified by column chromatography to give intermediate 8a (2.11 g, 80%) as a white solid. MS (ESI, M/z): 265 (M) + +1).
f) Compound 8 (2.64 g,10 mmol) and intermediate 2a (2.65 g,9.5mmol in NMP (50 mL) were added at room temperature 4M HCl/Dioxane (6.3 mL,25 mmol), warmed to 110℃and reacted for 4h, after completion of the reaction, with saturated NaHCO 3 Solution (150 mL) quench reactionThe product should be precipitated, the filter cake was suction filtered, washed three times with purified water and dried to give intermediate 9 (3.14 g, 62%) as a brown solid. MS (ESI, M/z): 507 (M) + +1).
g) Compound 9 (506 mg,1 mmol) was dissolved in methanol (10 mL), 2M aqueous NaOH (1.5 mL,3 mmol) was added, and after completion of the reaction, the reaction was reacted at room temperature for 2h, concentrated under reduced pressure, slurried with purified water, suction filtered, washed, and dried to give intermediate 10 (426 mg, 88%) as a brown solid. MS (ESI, M/z): 479 (M) + +1).
Example 3 Synthesis of intermediates 14a-c
a) The crude compound 6 (2.0 g) was dissolved in dichloromethane (25 mL), TFAA (3 mL) was added at 0deg.C, the reaction was carried out at 0deg.C for 3h, 1M aqueous KOH (20 mL) was added after completion of the reaction, stirring was carried out for 1h, the reaction was quenched, extracted with dichloromethane (30 mL. Times.3), concentrated under reduced pressure, and purified by column chromatography to give colorless transparent oily liquid intermediate 11 (1.05 g). MS (ESI, M/z): 305 (M) + +1).
b) Compound 11 (3.04 g,10 mmol) was dissolved in a mixed solvent of ethanol (18 mL) and water (6.3 mL), a mixed solution of ferrous sulfate heptahydrate (500 mg,1.8 mmol) and reduced iron powder (494 mg,8.82 mmol) was added at room temperature, reacted at room temperature for 4 hours, after the reaction was completed, concentrated under reduced pressure, and purified by column chromatography to give intermediate 12 (2.24 g, 82%) as a white solid. MS (ESI, M/z): 275 (M) + +1).
c) Compound 12 (2.72 g,10 mmol) and intermediate 2 (2.65 g,9.5mmol in NMP (50 mL) were added at room temperature 4M HCl/Dioxane (6.3 mL,25 mmol), warmed to 110℃and reacted for 4h, after completion of the reaction, with saturated NaHCO 3 The reaction was quenched with solution (150 mL), the product precipitated, the filter cake was suction filtered, washed three times with purified water, and dried to afford intermediate 13a (3.2 g, 62%) as a brown solid. MS (ESI, M/z): 517 (M) + +1) the intermediate 13b-c can be obtained by simply replacing the corresponding starting materials.
d) Compound 13a (516 mg,1 mmol) was dissolved in methanol (10 mL) and K was added 2 CO 3 (444.6 mg,3.0 mmol), at room temperature for 2h,the filtrate was suction filtered and concentrated under reduced pressure to afford intermediate 14a (426 mg, 88%) as a brown solid. MS (ESI, M/z): 421 (M) + +1) the intermediate 14b-c can be prepared by simply replacing the corresponding starting materials.
Example 4 Synthesis of intermediate 16
a) Compound 5 (1.62 g,9.94 mmol) was dissolved in trifluoroacetic acid (20 mL), NBS (1.96 g,11 mmol) was added, and the mixture was reacted at room temperature for 1h, after the reaction was completed, quenched with water, saturated NaHCO 3 The pH was adjusted to basic, extracted with dichloromethane (20 mL. Times.5), the combined organic phases were concentrated under reduced pressure to give crude intermediate 15 (1.5 g, 63%). MS (ESI, M/z): 242 (M) + +1).
b) Compound 15 (1.0 g,4.15 mmol) was dissolved in dichloromethane (25 mL), TFAA (3 mL) was added at 0deg.C, the reaction was allowed to proceed at 0deg.C for 3h, after completion of the reaction, 1M aqueous KOH (20 mL) was added and stirred for 1h to quench the reaction, extracted with dichloromethane (30 mL. Times.3), concentrated under reduced pressure and purified by column chromatography to afford intermediate 16 (545 mg, 39%) as a colorless, transparent oil. MS (ESI, M/z): 338 (M) + +1).
EXAMPLE 5 Synthesis of intermediate 22
a) Compound 17 (2.33 g,10 mmol) was dissolved in tetrahydrofuran (30 mL) and H was added 2 O 2 (330 mg,11 mmol), after completion of the reaction, was reacted overnight at room temperature, saturated Na was added 2 S 2 O 3 The reaction was quenched with water, extracted with ethyl acetate (30 mL. Times.3), the organic phases combined, washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration to remove salt, and vacuum concentration to obtain intermediate 18 (1.75 g, 75%). MS (ESI, M/z): 250 (M) + +1).
b) Compound 18 (2.50 g,10 mmol) was dissolved in ammonia (20 mL), reacted overnight at room temperature, and after completion of the reaction, concentrated under reduced pressure to afford intermediate 19 (1.01 g, 50%). MS (ESI, M/z): 203 (M) + +1).
c) Compound 19 (2.33 g,10 mmol) was dissolved in toluene (30 mL) under nitrogen and intermediate 16 (3.7 g,11 mmol), cs 2 CO 3 (9.7g,30mmol)，Pd 2 (dba) 3 (1.8 g,2 mmol), t-BuBrettPhos (2.4 g,5 mmol) at 130℃for 3h, after completion of the reaction, quench with water, extract with ethyl acetate (50 mL. Times.3), combine the organic phases, wash with saturated NaCl solution, dry Na 2 SO 4 Drying, suction filtration and salt removal, and concentration under reduced pressure gave intermediate 20 (2.79 g, 65%). MS (ESI, M/z): 431 (M) + +1).
d) According to the synthesis procedure of intermediate 2a, intermediate 21 can be obtained by simply replacing the corresponding starting materials. MS (ESI, M/z): 518 (M) + +1).
e) Intermediate 22 is obtained as per step d of the synthesis of intermediates 14 a-c. MS (ESI, M/z): 422 (M) + +1).
Example 6 Synthesis of intermediates 25a-e, 26a-d, 28
a) Nitrogen protection, intermediate 23 (321 mg,1 mmol), pd (dppf) 2 Cl 2 (70 mg,0.1 mmol), 2-acetylenic hexanol (84 mg,1.5 mmol) and CuI (38 mg,0.2 mmol) were dissolved in DMF (10 mL), triethylamine (0.33 mL) was added, the reaction was stirred overnight at 80℃and quenched with water after completion of the reaction, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration for salt removal, and column chromatography purification by vacuum concentration gave intermediate 24a (209 mg, 70%). MS (ESI, M/z): 313 (M) + +1) intermediates 24b-h, 27 can be obtained by simply replacing the corresponding reaction substrate.
b) Intermediate 24a (312 mg,1 mmol) was dissolved in tetrahydrofuran (2 mL), triethylamine (207. Mu.L, 1.5 mmol) was added at 0deg.C, msCl (172 mg,1.5 mmol) was reacted at 0deg.C for 3h and directly dried to give intermediate 25a (343 mg, 88%). MS (ESI, M/z): 391 (M) + +1) the intermediates 25b-f, 28 can be obtained by the same process, with only the replacement of the corresponding starting materials.
c) Will be originalMaterial 24a (312 mg,1 mmol) was dissolved in acetone and 2M Jones reagent (1 mL) was added dropwise at 0deg.C. The reaction was stirred at room temperature for 30min, monitored by TLC for completion, extracted with ethyl acetate, anhydrous Na 2 SO 4 Dried and concentrated under reduced pressure to give intermediate 26a (198mg, 56%). MS (ESI, M/z): 355 (M) + +1) intermediates 26b-d were prepared in the same manner, except that the corresponding starting materials were replaced.
EXAMPLE 7 Synthesis of intermediates 31a-b
a) In the same manner as in the step a of synthesizing the intermediate 25a, the intermediates 30a to b can be obtained by the same preparation method, only by replacing the corresponding raw materials. 30 aMS (ESI, M/z): 327 (M) + +1).
b) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediates 31a to b can be obtained by the same preparation method, only by replacing the corresponding raw materials. 31 aMS (ESI, M/z): 405 (M) + +1).
Example 8 Synthesis of intermediate 34
a) In the same manner as in the step a of synthesizing the intermediate 25a, the intermediate 33 can be obtained by the same production method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 327 (M) + +1).
b) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediate 34 can be obtained by the same production method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 405 (M) + +1).
Example 9 Synthesis of intermediate 37
a) In the same manner as in the synthesis step a of the intermediate 25a, the intermediate 36 can be obtained by the same preparation method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 341 (M) + +1).
b) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediate 37 can be obtained by the same preparation method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 419 (M) + +1).
Example 10 Synthesis of intermediates 39a-f, 41a-c, 43a-g
a) Raw material 38 (2.0 g,7.25 mmol) was dissolved in DMF (10 mL), 2-bromoethylamine (1.08 g,8.69 mmol) and DIPEA (2.84 mL,9.43 mmol) were added to the reaction system, reacted at 90℃for 5h, cooled to room temperature after completion of the reaction, diluted with water, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with saturated NaCl solution, and anhydrous Na 2 SO 4 Drying, suction filtration to remove salt, concentration under reduced pressure, and purification by column chromatography afforded intermediate 39a (1.54 g, 56%). MS (ESI, M/z): 380 (M) + +1) the intermediates 39b-g,40a-c,42a-g can be obtained by the same preparation method, only by replacing the corresponding raw materials.
b) Intermediate 40a (387.4 mg,1 mmol) was dissolved in dioxymethane (2 mL), trifluoroacetic acid (148. Mu.L) was added, and reacted at 25℃for 8h, followed by direct spin-drying to give intermediate 41a (2910 mg, 88%). MS (ESI, M/z): 332 (M) + +1) the intermediates 41b-c were prepared in the same manner, with only the replacement of the corresponding starting materials.
c) Intermediate 42a (416 mg,1 mmol) was dissolved in dichloromethane (0.2 mmol/mL) and methanol (1 mmol/mL), 4M HCl dioxane solution (0.5 mL) was added at 0deg.C, the reaction was allowed to react at room temperature for 4h, after completion of the TLC monitoring, the reaction solution was spun dry, slurried with isopropyl ether, and suction filtered to give intermediate 43a. MS (ESI, M/z): 317 (M) + +1) the intermediates 43b-g were prepared in the same manner, with only the replacement of the corresponding starting materials.
EXAMPLE 11 Synthesis of intermediates 45a-c
Bromoacetic acid (139 mg,1 mmol) was added to the reaction flask,thionyl chloride (1 mL) was added thereto, and the reaction was stirred at 80℃for 5 hours. The reaction is cooled to room temperature completely, dried tetrahydrofuran is added for dissolution after spin drying, then raw material 44 (273 mg,1 mmol) is added for reaction at 50 ℃, after TLC monitoring the reaction is complete, the crude product of intermediate 45a can be obtained after cooling and suction filtration. MS (ESI, M/z): 394 (M) + +1). The intermediates 45b-c were obtained by the same procedure.
EXAMPLE 12 Synthesis of intermediates 46a-b
Raw material 41a (3.31 g,10 mmol) was dissolved in DMF (50 mL), 2-bromoethylamine (1.49 g,12 mmol), DIPEA (5.2 mL,30 mmol) and HATU (5.7 g,15 mmol) were added to the reaction system, reacted at room temperature for 6h, after the reaction was completed, diluted with water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration to remove salt, and concentration under reduced pressure gave intermediate 46a (2.83 g, 65%) which was purified by column chromatography. MS (ESI, M/z): 437 (M) + +1) the intermediate 46b can be obtained by the same method of preparation, with only the replacement of the corresponding starting materials.
EXAMPLE 13 Synthesis of intermediates 48a-c
a) In the same manner as in the synthesis of intermediate 46a, intermediates 47a-c were obtained by the same method of preparation, with only the replacement of the corresponding starting materials. 47 aMS (ESI, M/z): 403 (M) + +1).
b) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediates 48a to c can be obtained by the same preparation method, only by replacing the corresponding raw materials. 48a MS (ESI, M/z): 481 (M) + +1).
Example 14 Synthesis of intermediates 50a-c, 53, 55a-b
a) Raw material 49 (1.57 g,5.71 mmol) was dissolved in DMF (57 mL) and K was added 2 CO 3 (1.19 g,8.58 mmol) and 1, 3-dibromopropane (1.15 g,5.71 mmol), stirring at room temperature for 2h, quenching with water after completion of the reaction, extracting with dichloromethane (30 mL. Times.3), combining the organic phases, washing with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration for salt removal, and column chromatography purification by vacuum concentration gave intermediate 50a (2.09 g, 93%). MS (ESI, M/z): 395 (M) + +1) intermediates 50b-c, 51, 54a-b can be obtained by the same preparation method.
b) Raw material 51 (576 mg,1 mmol) was dissolved in dichloromethane (5 mL), TFA (2 mmol) was added dropwise at 0℃and the reaction was stirred at room temperature for 3h, followed by concentration under reduced pressure to give intermediate 52 (470 mg, 90%). MS (ESI, M/z): 333 (M) + +1).
c) Raw material 52 (332 mg,1 mmol), 2-bromoethylamine (124 mg,1 mmol), HATU (570 mg,1.5 mmol) were dissolved in DMF (5 mL), DIPEA (524. Mu.L, 3 mmol) was added, after completion, quenched with water, extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, washed with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration of salt, concentration under reduced pressure gave intermediate 53 (393 mg, 90%) which was purified by column chromatography. MS (ESI, M/z): 438 (M) + +1).
d) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediates 55a to b can be obtained by the same preparation method, only by replacing the corresponding raw materials. 55 aMS (ESI, M/z): 485 (M) + +1).
Example 15 Synthesis of intermediate 57a-b
Raw material 56 (498 mg,1 mmol), 4-bromobutyric acid (200 mg,1.2 mmol), HATU (560 mg,1.5 mmol) and DIPEA (3838 mg,3 mmol) were dissolved in THF, stirred at room temperature for 2h, extracted with ethyl acetate after completion of the reaction, anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure and purified by column chromatography to give intermediate 57a (492 mg, 85%). MS (ESI, M/z): 579 (M) + +1) intermediate 57b can be obtained by the same preparation method.
EXAMPLE 16 Synthesis of intermediate 59a-b
In the same manner as in the synthesis of intermediate 57a, intermediates 59a-b were obtained by the same preparation method, except that the corresponding raw materials were replaced. 59aMS (ESI, M/z): 579 (M) + +1).
Example 17 Synthesis of intermediate 62
a) In the same manner as in the synthesis of intermediate 57a, intermediate 61 can be obtained by the same method as in the above, except that the corresponding raw materials are replaced. MS (ESI, M/z): 612 (M) + +1).
b) In the same manner as in the synthesis step b of the intermediate 25a, the intermediate 62 can be obtained by the same preparation method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 690 (M) + +1).
Example 18 Synthesis of intermediate 65
a) In the same manner as in the synthesis of intermediate 57a, intermediate 64 can be obtained by the same method as in the preparation, except that the corresponding raw materials are replaced. MS (ESI, M/z): 646 (M) + +1).
b) In the same manner as in the step b for synthesizing the intermediate 25a, the intermediate 65 can be obtained by the same production method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 724 (M) + +1).
Example 19 Synthesis of intermediate 68
a) In the same manner as in the synthesis of intermediate 57a, only the corresponding starting materials need to be replaced,intermediate 67 was obtained by the same procedure. MS (ESI, M/z): 515 (M) + +1).
b) In the same manner as in the synthesis step b of the intermediate 25a, the intermediate 68 can be obtained by the same preparation method, except that the corresponding raw materials are replaced. MS (ESI, M/z): 593 (M) + +1).
EXAMPLE 20 Synthesis of Compound S1
Raw material 14a (420 mg,1 mmol) was dissolved in DMF (5 mL), 25a (585 mg,1.5 mmol), DIPEA (0.53 mL,3 mmol) and NaI (15 mg,0.1 mmol) were added to the solution, reacted at 60℃for 5h, after the completion of the reaction, concentrated under reduced pressure and purified by column chromatography to give compound S1 (250 mg, 35%). 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝7.2,2.3Hz,1H),7.53-7.43(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.11(m,4H),7.09(s,1H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.52(qdd,J＝12.5,5.5,0.9Hz,2H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),3.10(s,2H),2.92-2.85(m,3H),2.78(s,1H),2.67-2.56(m,4H),2.17(s,1H),2.12(s,1H).MS(ESI,m/z):715(M + +1).
EXAMPLE 21 Synthesis of Compound S2
Synthetic method referring to example 20, compound S2 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝7.1,2.2Hz,1H),7.52-7.43(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.16(m,3H),7.18-7.07(m,2H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.52(qdd,J＝12.5,5.5,0.9Hz,2H),4.38(s,1H),4.32(s,1H),4.01(s,1H),3.93(s,3H),3.84(d,J＝1.1Hz,2H),2.90-2.85(m,3H),2.78(d,J＝4.9Hz,3H),2.57(d,J＝9.5Hz,2H),2.52-2.41(m,2H),2.17(s,1H),2.12(s,1H),1.76(s,2H).MS(ESI,m/z):729(M + +1).
EXAMPLE 22 Synthesis of Compound S3
Synthetic method referring to example 20, compound S3 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝6.1,3.4Hz,1H),7.49-7.37(m,3H),7.27-7.07(m,5H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.52(qdd,J＝12.5,5.5,1.0Hz,2H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H),2.65-2.54(m,4H),2.49(s,2H),2.17(s,1H),2.12(s,1H),1.57-1.40(m,5H),1.37(d,J＝12.5Hz,1H).MS(ESI,m/z):757(M + +1).
EXAMPLE 23 Synthesis of Compound S4
Synthetic method referring to example 20, compound S4 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝7.1,2.2Hz,1H),7.52-7.43(m,2H),7.39-7.33(m,2H),7.30-7.23(m,2H),7.21(d,J＝2.8Hz,3H),6.86(t,J＝1.0Hz,1H),5.41(t,J＝5.5Hz,1H),4.59-4.46(m,3H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),2.89-2.80(m,4H),2.64-2.56(m,4H),2.53-2.42(m,2H),2.19(s,1H),2.12(s,1H),1.54-1.46(m,4H),1.37-1.24(m,6H).MS(ESI,m/z):785(M + +1).
EXAMPLE 24 Synthesis of Compound S5
Synthetic method referring to example 20, compound S5 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝7.1,2.2Hz,1H),7.52-7.43(m,2H),7.39-7.33(m,2H),7.30-7.23(m,2H),7.21(d,J＝2.8Hz,3H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),4.59-4.45(m,3H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),2.89-2.80(m,4H),2.64-2.56(m,4H),2.46(d,J＝1.1Hz,2H),2.19(s,1H),2.12(s,1H),1.57-1.46(m,4H),1.35-1.21(m,10H).MS(ESI,m/z):813(M + +1).
EXAMPLE 25 Synthesis of Compound S6
Starting material 14a (420 mg,1 mmol), starting material 26a (268 mg,1 mmol) were dissolved in DMF (5 mL), BOP (264 mg,1.5 mmol) and DIPEA (0.53 mL,3 mmol) were added to the solution, reacted overnight at room temperature, after completion of the reaction concentrated under reduced pressure and purified by column chromatography to give compound S6 (293 mg, 38%). 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝7.2,2.3Hz,1H),7.51-7.40(m,2H),7.27-7.21(m,1H),7.21-7.18(m,2H),7.18-7.12(m,2H),7.10(d,J＝10.8Hz,1H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.61-4.46(m,4H),4.34(s,1H),4.21(s,1H),4.01(s,1H),3.93(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J＝5.0,1.0Hz,2H),2.63-2.54(m,4H),2.27(s,2H),2.17(s,1H),2.12(s,1H),1.95(d,J＝12.3Hz,1H),1.89(d,J＝12.5Hz,1H).MS(ESI,m/z):757(M + +1).
EXAMPLE 26 Synthesis of Compound S7
Synthetic method referring to example 25, compound S7 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.26(d,J＝10.2Hz,1H),10.99(s,1H),8.67(d,J＝3.2Hz,1H),8.07(s,1H),8.02(s,1H),7.89-7.78(m,2H),7.71(d,J＝9.0Hz,1H),7.63(t,J＝8.5Hz,1H),7.57-7.40(m,2H),7.32(d,J＝6.6Hz,1H),7.31-7.10(m,2H),6.81(d,J＝5.2Hz,1H),5.25-5.09(m,2H),4.54-4.42(m,3H),4.32(d,J＝18.5Hz,3H),3.81(d,J＝7.8Hz,3H),3.63(d,J＝5.8Hz,2H),2.90(s,1H),2.79(s,1H),2.69(s,1H),2.55(m,J＝7.3Hz,2H),2.44(dd,J＝17.3,7.6Hz,2H),2.00(d,J＝7.6Hz,1H),1.73(s,2H),1.65(s,2H),1.04(d,J＝6.1Hz,2H).MS(ESI,m/z):771(M + +1).
EXAMPLE 27 Synthesis of Compound S8
Synthetic method referring to example 25, compound S8 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝6.1,3.4Hz,1H),7.49-7.41(m,2H),7.27-7.07(m,6H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.59-4.49(m,3H),4.49-4.43(m,1H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J＝5.0,1.0Hz,2H),2.64-2.54(m,4H),2.27(s,2H),2.17(s,1H),2.12(s,1H),1.67-1.50(m,4H),1.34(s,2H).MS(ESI,m/z):785(M + +1).
EXAMPLE 28 Synthesis of Compound S9
Synthetic method referring to example 25, compound S8 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝6.1,3.4Hz,1H),7.49-7.41(m,2H),7.27-7.18(m,3H),7.18-7.12(m,2H),7.10(d,J＝10.8Hz,1H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.59-4.43(m,4H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J＝5.0,1.0Hz,2H),2.61-2.48(m,4H),2.30(d,J＝0.7Hz,2H),2.17(s,1H),2.12(s,1H),1.58(s,2H),1.49(d,J＝2.2Hz,2H),1.29-1.23(m,6H).MS(ESI,m/z):813(M + +1).
EXAMPLE 29 Synthesis of Compound S10
Synthetic method referring to example 20, compound S10 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.88(d,J＝7.5Hz,1H),7.62-7.53(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.16(m,3H),7.18-7.07(m,2H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.59-4.43(m,3H),4.33(d,J＝0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.84(d,J＝1.1Hz,2H),2.90-2.85(m,3H),2.78(d,J＝4.9Hz,3H),2.59(d,J＝10.1Hz,2H),2.52-2.41(m,2H),2.18(s,1H),2.12(s,1H),1.80(s,2H).MS(ESI,m/z):729(M + +1).
EXAMPLE 30 Synthesis of Compound S11
Synthetic method referring to example 20, compound S11 can be prepared by replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(d,J＝7.5Hz,1H),7.62-7.53(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.59-4.45(m,3H),4.33(d,J＝0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H),2.62-2.55(m,3H),2.54-2.47(m,3H),2.18(s,1H),2.12(s,1H),1.57-1.47(m,4H),1.42-1.31(m,2H).MS(ESI,m/z):757(M + +1).
EXAMPLE 31 Synthesis of Compound S12
Synthetic method referring to example 20, compound S12 can be prepared by replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.86(d,J＝2.0Hz,1H),7.46(dd,J＝7.5,2.0Hz,1H),7.39(t,J＝1.0Hz,1H),7.27-7.04(m,6H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.60-4.46(m,4H),4.01(s,1H),3.93(s,3H),3.84(d,J＝1.1Hz,2H),2.90-2.82(m,5H),2.78(s,1H),2.59(d,J＝10.1Hz,2H),2.52-2.41(m,2H),2.18(s,1H),2.12(s,1H),1.80-1.68(m,2H).MS(ESI,m/z):729(M + +1).
EXAMPLE 32 Synthesis of Compound S13
Synthetic method referring to example 20, compound S13 can be prepared by replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.56(dd,J＝7.5,2.0Hz,1H),7.39(t,J＝1.0Hz,1H),7.34(t,J＝7.5Hz,1H),7.27-7.16(m,3H),7.16-7.07(m,3H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),4.59-4.45(m,3H),4.33(d,J＝0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),2.92-2.85(m,4H),2.60-2.47(m,6H),2.17(s,1H),2.12(s,1H),1.51(dd,J＝17.2,1.1Hz,4H).MS(ESI,m/z):743(M + +1).
EXAMPLE 33 Synthesis of Compound S14
Synthetic method referring to example 20, compound S14 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝6.5,3.0Hz,1H),7.51-7.42(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.07(m,5H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),5.40(t,J＝4.9Hz,1H),4.52(dd,J＝4.9,0.9Hz,2H),4.38(s,1H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.86(d,J＝0.9Hz,2H),3.04(s,1H),2.86(d,J＝1.1Hz,2H),2.78(s,1H),2.70(s,1H),2.64-2.54(m,8H),2.47(s,2H),2.17(s,1H),2.12(s,1H),1.91(s,2H),1.83(s,2H),1.72(s,2H).MS(ESI,m/z):812(M + +1).
EXAMPLE 34 Synthesis of Compound S15
Raw material 14a (420 mg,1 mmol) was dissolved in DMF (5 mL) and raw material 39a (569 mg,1.5 mmol) and K were added to the solution 2 CO 3 (0.53 mL,3 mmol), reacted at 60℃for 6h, after the reaction was completed, concentrated under reduced pressure and purified by column chromatography to give Compound S15 (319 mg, 36%). 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.4,2.1Hz,1H),7.45-7.33(m,3H),7.29(s,1H),7.27-7.16(m,3H),7.16-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),3.48(s,2H),2.92-2.85(m,4H),2.66(d,J＝19.2Hz,3H),2.55(s,1H),2.49(s,1H),1.99(s,1H).MS(ESI,m/z):720(M + +1).
EXAMPLE 35 Synthesis of Compound S16
Synthetic method referring to example 34, compound S16 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.80(dd,J＝7.4,2.1Hz,1H),7.52(dd,J＝7.4,2.1Hz,1H),7.45(t,J＝7.5Hz,1H),7.35(t,J＝0.9Hz,1H),7.27-7.18(m,3H),7.21-7.07(m,2H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(qdd,J＝12.5,5.5,0.9Hz,2H),3.93(s,3H),3.86(d,J＝0.9Hz,2H),3.49-3.39(m,2H),2.92-2.84(m,3H),2.80(s,1H),2.63(s,1H),2.53-2.47(m,4H),1.99(s,1H),1.88(s,2H).MS(ESI,m/z):734(M + +1).
EXAMPLE 36 Synthesis of Compound S17
Synthesis method referring to example 34, only the corresponding changes are required The compound S17 can be prepared by the raw materials of the formula (I). 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.4,2.1Hz,1H),7.53-7.41(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.07(m,5H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(qdd,J＝12.5,5.5,1.0Hz,2H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),3.56(s,2H),2.89-2.80(m,4H),2.63(s,1H),2.55(s,2H),2.51(s,1H),2.24(d,J＝0.9Hz,2H),1.64(s,2H),1.55(d,J＝0.9Hz,2H),1.43(d,J＝0.9Hz,2H).MS(ESI,m/z):762(M + +1).
EXAMPLE 37 Synthesis of Compound S18
Synthetic method referring to example 34, compound S18 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.53(dd,J＝7.5,2.0Hz,1H),7.45(t,J＝7.4Hz,1H),7.39(t,J＝1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82(s,1H),2.63(s,1H),2.53-2.41(m,3H),2.24(d,J＝0.9Hz,2H),1.64(s,2H),1.50(s,2H),1.36-1.24(m,8H).MS(ESI,m/z):804(M + +1).
EXAMPLE 38 Synthesis of Compound S19
Synthetic method referring to example 34, compound S19 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.53(dd,J＝7.5,2.0Hz,1H),7.45(t,J＝7.4Hz,1H),7.39(t,J＝1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.56(s,2H),2.90-2.85(m,3H),2.82(s,1H),2.63(s,1H),2.57-2.45(m,3H),2.24(d,J＝1.0Hz,2H),1.64(s,2H),1.54(s,2H),1.35-1.24(m,6H).MS(ESI,m/z):790(M + +1).
EXAMPLE 39 Synthesis of Compound S20
Synthetic method referring to example 34, compound S20 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.56-7.46(m,2H),7.39(t,J＝1.0Hz,1H),7.32-7.26(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H),2.56-2.49(m,2H),2.46(d,J＝12.4Hz,1H),2.24(d,J＝1.0Hz,2H),1.64(s,2H),1.51(s,2H),1.36-1.21(m,12H).MS(ESI,m/z):832(M + +1).
EXAMPLE 40 Synthesis of Compound S21
Synthetic method referring to example 25, compound S21 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.50(t,J＝7.4Hz,1H),7.39(dd,J＝7.5,2.0Hz,1H),7.27-7.07(m,7H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.59-4.43(m,4H),3.92(s,3H),3.69-3.60(m,4H),2.88(d,J＝0.9Hz,2H),2.63(s,1H),2.51(s,1H),2.32(s,2H),2.24(d,J＝0.9Hz,2H),1.63(d,J＝14.0Hz,4H).MS(ESI,m/z):776(M + +1).
EXAMPLE 41 Synthesis of Compound S22
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Synthetic method referring to example 25, compound S22 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.53(dd,J＝7.5,2.0Hz,1H),7.48-7.41(m,1H),7.27-7.18(m,3H),7.18-7.12(m,2H),7.10(d,J＝10.8Hz,1H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),6.74(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.59-4.49(m,3H),4.49-4.43(m,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),3.50-3.39(m,2H),2.88(dd,J＝5.0,1.0Hz,2H),2.63(s,1H),2.51(s,1H),2.29-2.21(m,4H),1.66(s,2H),1.58(s,2H),1.34(s,2H),1.24(d,J＝0.7Hz,2H).MS(ESI,m/z):804(M + +1).
EXAMPLE 42 Synthesis of Compound S23
Synthetic method referring to example 25, compound S23 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.70(s,1H),7.47-7.36(m,2H),7.27-7.07(m,6H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),6.75(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.84(d,J＝0.9Hz,2H),3.73(d,J＝12.5Hz,1H),3.62(d,J＝12.5Hz,1H),3.38(s,2H),3.17(d,J＝1.8Hz,2H),2.98(s,1H),2.93(s,1H),2.86(dd,J＝3.1,0.9Hz,2H),2.63(s,1H),2.50(d,J＝7.3Hz,2H),1.99(s,1H).MS(ESI,m/z):777(M + +1).
EXAMPLE 43 Synthesis of Compound S24
Synthetic method referring to example 25, compound S24 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.64(s,1H),7.53(dd,J＝7.5,2.0Hz,1H),7.48-7.41(m,1H),7.27-7.07(m,7H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.84(d,J＝0.9Hz,2H),3.56(s,2H),3.15(d,J＝13.2Hz,4H),2.95(s,1H),2.90-2.84(m,3H),2.63(s,1H),2.51(s,1H),2.24(d,J＝0.9Hz,2H),1.64(s,2H),1.54-1.44(m,2H).MS(ESI,m/z):805(M + +1).
EXAMPLE 44 Synthesis of Compound S25
Synthetic method referring to example 25, compound S25 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.96(s,1H),7.77(d,J＝6.2Hz,2H),7.60-7.51(m,2H),7.45(d,J＝7.6Hz,1H),7.32(s,1H),7.24(t,J＝7.5Hz,1H),7.15(t,J＝7.4Hz,1H),7.03(dd,J＝14.2,7.8Hz,2H),6.73(s,1H),6.50(t,J＝5.8Hz,1H),5.17(t,J＝5.2Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.48(d,J＝5.1Hz,2H),3.79(s,3H),3.31-3.22(m,4H),3.16(q,J＝6.6Hz,2H),3.05(s,2H),2.95-2.81(m,1H),2.77(d,J＝5.9Hz,2H),2.66(d,J＝5.9Hz,2H),2.63(s,1H),2.51(s,1H),2.02(d,J＝11.6Hz,1H),1.56(q,J＝7.3Hz,2H),1.53-1.44(m,2H),1.33(d,J＝7.6Hz,2H).MS(ESI,m/z):819(M + +1).
EXAMPLE 45 Synthesis of Compound S26
Synthetic method referring to example 25, compound S26 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.56-7.46(m,3H),7.32-7.23(m,2H),7.23-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.84(d,J＝0.9Hz,2H),3.57-3.46(m,2H),3.19-3.03(m,4H),2.95(s,1H),2.90-2.84(m,3H),2.66(s,1H),2.54(s,1H),2.24(d,J＝0.9Hz,2H),1.66(d,J＝0.7Hz,2H),1.49(s,2H),1.38-1.24(m,4H).MS(ESI,m/z):833(M + +1).
EXAMPLE 46 Synthesis of Compound S27
Synthetic method referring to example 25, compound S27 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.56-7.44(m,3H),7.32-7.07(m,6H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3H),3.84(d,J＝1.0Hz,2H),3.49(d,J＝2.0Hz,2H),3.13(dd,J＝15.3,1.4Hz,4H),2.95(s,1H),2.90-2.84(m,3H),2.66(s,1H),2.54(s,1H),2.24(d,J＝1.0Hz,2H),1.66(s,2H),1.48(s,2H),1.34(d,J＝0.7Hz,4H),1.28(s,2H).MS(ESI,m/z):847(M + +1).
EXAMPLE 47 Synthesis of Compound S28
Synthetic method referring to example 25, compound S28 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.56-7.46(m,3H),7.32-7.07(m,6H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3H),3.84(d,J＝0.9Hz,2H),3.57-3.46(m,2H),3.14(d,J＝1.4Hz,2H),3.12-3.02(m,2H),2.95(s,1H),2.90-2.84(m,3H),2.66(s,1H),2.54(s,1H),2.24(d,J＝0.9Hz,2H),1.64(s,2H),1.47(d,J＝2.9Hz,2H),1.35-1.22(m,8H).MS(ESI,m/z):861(M + +1).
EXAMPLE 48 Synthesis of Compound S29
Reference examples of the synthesis method25, the compound S29 can be prepared by only replacing corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.56-7.46(m,3H),7.32-7.17(m,3H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3H),3.84(d,J＝1.0Hz,2H),3.57-3.46(m,2H),3.13(dd,J＝15.3,1.4Hz,4H),2.95(s,1H),2.90-2.84(m,3H),2.66(s,1H),2.54(s,1H),2.24(d,J＝1.0Hz,2H),1.64(s,2H),1.47(d,J＝2.9Hz,2H),1.39-1.23(m,12H).MS(ESI,m/z):889(M + +1).
EXAMPLE 49 Synthesis of Compound S30
Synthetic method referring to example 25, compound S30 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.05(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.44(dd,J＝7.5,2.0Hz,1H),7.36(t,J＝1.0Hz,1H),7.27-7.16(m,4H),7.17-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.88(t,J＝1.0Hz,1H),5.99(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.59-4.46(m,2H),4.48-4.41(m,3H),4.35(d,J＝12.3Hz,1H),3.93(s,3H),3.76(d,J＝5.1Hz,2H),2.89(dd,J＝10.1,0.9Hz,2H),2.63(s,1H),2.51(s,1H),2.25(d,J＝11.2Hz,2H).MS(ESI,m/z):734(M + +1).
EXAMPLE 50 Synthesis of Compound S31
Synthetic method referring to example 34, compound S31 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.55(s,1H),9.16(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.5,2.0Hz,1H),7.78(dd,J＝7.5,2.0Hz,1H),7.43(t,J＝7.5Hz,1H),7.27-7.16(m,4H),7.17-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(qdd,J＝12.5,5.5,0.9Hz,2H),3.93(s,3H),3.84(d,J＝0.9Hz,2H),3.32(s,2H),2.97(s,1H),2.93(s,1H),2.85(dd,J＝3.7,1.0Hz,2H),2.54(s,1H),2.48(s,1H),2.24(d,J＝0.9Hz,2H).MS(ESI,m/z):734(M + +1).
EXAMPLE 51 Synthesis of Compound S32
Synthetic method referring to example 34, compound S32 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(dd,J＝7.4,2.1Hz,1H),7.57(dd,J＝7.5,2.0Hz,1H),7.48(t,J＝7.5Hz,1H),7.39(t,J＝1.1Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.02(d,J＝1.1Hz,1H),3.92(d,J＝1.7Hz,4H),2.98(s,1H),2.93(s,1H),2.89(d,J＝1.1Hz,2H),2.54(s,1H),2.52-2.43(m,5H),2.24(d,J＝0.9Hz,2H),2.02-1.92(m,2H).MS(ESI,m/z):762(M + +1).
EXAMPLE 52 Synthesis of Compound S33
Synthetic method referring to example 34, compound S33 can be prepared by replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(dd,J＝7.4,2.1Hz,1H),7.57(dd,J＝7.5,2.0Hz,1H),7.48(t,J＝7.5Hz,1H),7.39(t,J＝1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),2.93(s,1H),2.90-2.85(m,3H),2.60-2.52(m,3H),2.48(s,1H),2.42(d,J＝0.7Hz,2H),2.24(d,J＝0.9Hz,2H),1.65-1.50(m,4H),1.43(d,J＝1.8Hz,2H).MS(ESI,m/z):790(M + +1).
EXAMPLE 53 Synthesis of Compound S34
Synthetic method referring to example 34, compound S34 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J＝7.5,2.0Hz,1H),7.70(s,1H),7.45-7.38(m,2H),7.30(t,J＝7.5Hz,1H),7.27-7.09(m,5H),7.02(s,1H),6.95(s,1H),6.86(d,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.62(d,J＝12.5Hz,1H),4.59-4.46(m,3H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.31-3.17(m,4H),2.93-2.85(m,3H),2.76(s,1H),2.63(s,1H),2.51(s,1H),2.25(d,J＝11.2Hz,2H).MS(ESI,m/z):777(M + +1).
EXAMPLE 54 Synthesis of Compound S35
Synthetic method referring to example 34, compound S35 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J＝7.5,2.0Hz,1H),7.64(s,1H),7.44(dd,J＝7.5,2.0Hz,1H),7.39(t,J＝1.0Hz,1H),7.30(t,J＝7.4Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),6.12(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.59-4.44(m,3H),4.36(d,J＝12.5Hz,1H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.16(s,2H),2.90-2.85(m,3H),2.80(s,1H),2.63(s,1H),2.53-2.43(m,3H),2.25(d,J＝11.2Hz,2H),1.69(s,2H),1.48(d,J＝1.1Hz,2H).MS(ESI,m/z):805(M + +1).
EXAMPLE 55 Synthesis of Compound S36
Synthetic method referring to example 20, compound S36 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.64(s,1H),7.51-7.41(m,2H),7.39(t,J＝1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.89-6.84(m,1H),6.75(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.02(d,J＝1.1Hz,1H),3.92(d,J＝1.0Hz,4H),3.51-3.38(m,4H),2.98(s,1H),2.93(s,1H),2.89(d,J＝1.1Hz,2H),2.63(s,1H),2.53-2.44(m,4H),2.26(d,J＝1.1Hz,2H),1.99(s,1H),1.93(d,J＝12.2Hz,1H),1.79(d,J＝12.5Hz,1H).MS(ESI,m/z):805(M + +1).
EXAMPLE 56 Synthesis of Compound S37
Synthetic method referring to example 20, compound S37 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J＝6.8,2.7Hz,1H),7.70(s,1H),7.54-7.45(m,2H),7.39(t,J＝1.0Hz,1H),7.29(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),6.75(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.54(d,J＝12.5Hz,1H),3.50-3.42(m,2H),3.41(d,J＝12.3Hz,1H),2.93(s,1H),2.90-2.85(m,3H),2.66(s,1H),2.58(s,2H),2.54(s,1H),2.49(s,1H),2.15(s,2H),1.99(s,1H),1.59(dd,J＝28.8,1.3Hz,4H),1.38(s,2H).MS(ESI,m/z):833(M + +1).
EXAMPLE 57 Synthesis of Compound S38
Synthetic method referring to example 20, compound S38 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J＝6.8,2.7Hz,1H),7.66(s,1H),7.54-7.45(m,2H),7.39(t,J＝1.0Hz,1H),7.29(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),6.75(s,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3H),3.78(d,J＝1.1Hz,2H),3.54(d,J＝12.5Hz,1H),3.50-3.38(m,3H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H),2.54(d,J＝5.0Hz,3H),2.49(s,1H),2.11(d,J＝2.9Hz,2H),1.99(s,1H),1.61-1.49(m,4H),1.34(s,2H),1.26(d,J＝4.8Hz,4H).MS(ESI,m/z):861(M + +1).
EXAMPLE 58 Synthesis of Compound S39
Synthetic method referring to example 34, compound S39 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.78(dd,J＝7.5,2.0Hz,1H),7.43-7.33(m,2H),7.27-7.16(m,3H),7.16-7.11(m,1H),7.11-7.06(m,2H),7.02(s,1H),6.86(d,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.21(s,2H),3.92(d,J＝4.4Hz,5H),2.92-2.84(m,3H),2.80(s,1H),2.62(d,J＝11.4Hz,3H),2.50(d,J＝7.3Hz,2H),2.00(d,J＝8.3Hz,3H).MS(ESI,m/z):735(M + +1).
EXAMPLE 59 Synthesis of Compound S40
Synthetic method referring to example 34, compound S40 can be prepared by simply replacing the corresponding starting materials. H NMR (500 mhz, chloroform-d) delta 11.22 (s, 1H), 11.11 (s, 1H), 8.76 (s, 1H), 8.69 (s, 1H), 7.84 (dd, j=7.5, 2.0hz, 1H), 7.46-7.37 (M, 2H), 7.27-7.17 (M, 2H), 7.17-7.07 (M, 4H), 7.02 (s, 1H), 6.86 (t, j=1.0 hz, 1H), 5.40 (t, j=5.5 hz, 1H), 5.10 (s, 1H), 4.52 (qdd, j=12.5, 5.5,1.0hz, 2H), 3.97 (s, 2H), 3.92 (s, 3H), 3.78 (d, j=1.1 hz, 2H), 2.89-2.80 (M, 4H), 7.17-7.07 (M, 4H), 7.02 (s, 1H), 6.86 (t, j=1.0 hz, 1H), 5.40 (t, j=5 hz, 1H), 5.10 (s, 1H), 4.52 (qdd, j=12.5, 5, 1.5, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.9 (d), 1.7 hz, 2H), 1.9 (1H) + +1).
EXAMPLE 60 Synthesis of Compound S41
Synthetic method referring to example 34, compound S41 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.84(dd,J＝7.5,2.0Hz,1H),7.46-7.37(m,2H),7.27-7.04(m,6H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.00(s,2H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H),2.63(s,1H),2.59-2.47(m,4H),1.99(s,1H),1.79(d,J＝1.8Hz,2H),1.52(s,2H),1.41(s,2H),1.31(d,J＝1.7Hz,4H).MS(ESI,m/z):791(M + +1).
EXAMPLE 61 Synthesis of Compound S42
Synthetic method referring to example 34, compound S42 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J＝7.4,2.1Hz,1H),7.70(s,1H),7.40(t,J＝1.0Hz,1H),7.27-7.07(m,7H),7.02(s,1H),6.86(t,J＝1.0Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.59-4.46(m,4H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.29(d,J＝12.5Hz,1H),3.19(dd,J＝14.6,12.5Hz,2H),3.04(d,J＝12.5Hz,1H),2.90-2.85(m,3H),2.76(s,1H),2.63(s,1H),2.51(s,1H),2.25(d,J＝11.2Hz,2H).MS(ESI,m/z):778(M + +1).
EXAMPLE 62 Synthesis of Compound S43
Synthetic method referring to example 20, compound S43 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.14(s,1H),8.75(s,1H),8.00(dd,J＝7.5,2.0Hz,1H),7.39-7.32(m,3H),7.30-7.23(m,2H),7.21(d,J＝2.8Hz,3H),7.07(dd,J＝7.5,2.0Hz,1H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.12(s,1H),4.59-4.46(m,2H),4.24(d,J＝1.6Hz,2H),3.92(d,J＝8.4Hz,5H),3.86-3.80(m,3H),3.80-3.71(m,3H),3.59(d,J＝0.9Hz,2H),2.86(dd,J＝1.8,0.9Hz,2H),2.76(s,1H),2.68(d,J＝16.7Hz,2H),2.54(d,J＝1.3Hz,3H),2.25(d,J＝11.2Hz,2H).MS(ESI,m/z):809(M + +1).
EXAMPLE 63 Synthesis of Compound S44
Synthetic method referring to example 20, compound S44 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.97(dd,J＝7.5,2.0Hz,1H),7.46-7.38(m,2H),7.29(ddt,J＝7.3,2.1,1.0Hz,1H),7.24-7.07(m,5H),7.02(s,1H),6.86(t,J＝0.9Hz,1H),5.40(t,J＝5.5Hz,1H),5.10(s,1H),4.52(qdd,J＝12.5,5.5,1.1Hz,2H),4.28-4.17(m,2H),3.93-3.79(m,10H),3.79-3.73(m,3H),3.72-3.63(m,3H),3.58(d,J＝12.5Hz,1H),2.88(d,J＝1.1Hz,2H),2.76(s,1H),2.68(d,J＝16.7Hz,2H),2.54(d,J＝1.3Hz,3H),2.25(d,J＝11.2Hz,2H).MS(ESI,m/z):853(M + +1).
EXAMPLE 64 Synthesis of Compound S45
Synthetic method referring to example 20, compound S45 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),8.14(s,1H),7.73(s,1H),7.69-7.63(m,2H),7.37(t,J＝1.0Hz,1H),7.35-7.17(m,8H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.06(d,J＝4.9Hz,1H),4.61-4.46(m,3H),4.31-4.25(m,3H),4.01(d,J＝4.9Hz,1H),3.89(s,3H),3.78(d,J＝1.1Hz,2H),3.47(d,J＝9.5Hz,1H),3.32(d,J＝9.5Hz,1H),2.93(s,1H),2.89-2.84(m,3H),2.62-2.52(m,2H),2.34(s,3H),2.14(s,2H),2.04(d,J＝4.2Hz,2H),1.62-1.55(m,4H),1.38(s,2H),0.99(s,9H).MS(ESI,m/z):947(M + +1).
EXAMPLE 65 Synthesis of Compound S46
Synthetic method referring to example 20, compound S46 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),8.14(s,1H),7.71-7.63(m,3H),7.39-7.20(m,8H),7.20(d,J＝3.2Hz,1H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.06(d,J＝4.9Hz,1H),4.61-4.46(m,3H),4.28(dd,J＝1.5,0.7Hz,3H),4.04-3.98(m,2H),3.94-3.87(m,4H),3.42(d,J＝9.3Hz,1H),3.31(d,J＝9.5Hz,1H),2.98(s,1H),2.93(s,1H),2.88(d,J＝0.9Hz,2H),2.56(d,J＝12.5Hz,1H),2.49(d,J＝12.5Hz,1H),2.34(s,3H),2.30-2.19(m,2H),2.06-1.95(m,3H),1.88(d,J＝12.5Hz,1H),0.99(s,9H).MS(ESI,m/z):919(M + +1).
EXAMPLE 66 Synthesis of Compound S47
Synthetic method referring to example 20, compound S47 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.81-7.71(m,4H),7.34(d,J＝1.5Hz,2H),7.31-7.23(m,3H),7.23-7.17(m,2H),7.14-7.08(m,2H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.20-5.15(m,1H),5.06(d,J＝4.9Hz,1H),4.59-4.52(m,2H),4.50(ddd,J＝12.5,5.5,0.9Hz,1H),4.28(s,1H),4.05(d,J＝1.0Hz,1H),4.01(d,J＝4.9Hz,1H),3.95(d,J＝0.9Hz,1H),3.89(s,3H),3.47(d,J＝9.5Hz,1H),3.36(d,J＝9.3Hz,1H),2.92-2.83(m,3H),2.74(s,1H),2.72-2.64(m,3H),2.61(d,J＝12.5Hz,1H),2.34(s,3H),2.04(d,J＝4.2Hz,2H),1.50(s,3H),0.99(s,9H).MS(ESI,m/z):919(M + +1).
EXAMPLE 67 Synthesis of Compound S48
Synthetic method referring to example 20, compound S48 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.81-7.73(m,3H),7.69(s,1H),7.39-7.33(m,2H),7.31-7.17(m,5H),7.14-7.08(m,2H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.20-5.15(m,1H),5.06(d,J＝4.9Hz,1H),4.59-4.46(m,3H),4.27(s,1H),4.04-3.98(m,2H),3.94-3.87(m,4H),3.42(d,J＝9.3Hz,1H),3.31(d,J＝9.5Hz,1H),2.98(s,1H),2.93(s,1H),2.88(d,J＝0.9Hz,2H),2.56(d,J＝12.5Hz,1H),2.49(d,J＝12.5Hz,1H),2.34(s,3H),2.30-2.19(m,2H),2.06-1.95(m,3H),1.88(d,J＝12.5Hz,1H),1.50(s,3H),0.99(s,9H).MS(ESI,m/z):933(M + +1).
EXAMPLE 68 Synthesis of Compound S49
Synthetic method referring to example 20, compound S49 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.82-7.76(m,2H),7.64(s,1H),7.52(s,1H),7.39-7.33(m,2H),7.31-7.17(m,7H),6.86(t,J＝0.9Hz,1H),6.75(s,1H),5.41(t,J＝5.5Hz,1H),5.07-5.00(m,2H),4.62(s,1H),4.52(qdd,J＝12.5,5.5,1.0Hz,2H),4.09-4.03(m,2H),3.89(s,3H),3.78(d,J＝1.1Hz,2H),3.47(d,J＝9.5Hz,1H),3.29(d,J＝9.5Hz,1H),3.11(d,J＝2.4Hz,2H),2.97-2.84(m,5H),2.80(s,1H),2.55-2.43(m,2H),2.42-2.32(m,5H),2.26(s,3H),1.87(s,1H),1.69(s,2H),1.48(d,J＝1.4Hz,2H),1.12(s,3H),1.07(s,3H).MS(ESI,m/z):1014(M + +1).
EXAMPLE 69 Synthesis of Compound S50
Synthetic method referring to example 20, compound S50 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.85(s,1H),7.82-7.76(m,3H),7.64(s,1H),7.39-7.33(m,2H),7.31-7.24(m,5H),7.24-7.17(m,2H),6.86(t,J＝0.9Hz,1H),5.41(t,J＝5.5Hz,1H),5.10-5.03(m,2H),4.59-4.52(m,2H),4.50(ddd,J＝12.5,5.5,0.9Hz,1H),4.28(s,1H),4.12(d,J＝4.9Hz,1H),3.89(s,3H),3.78(d,J＝1.1Hz,2H),3.47(d,J＝9.5Hz,1H),3.32(d,J＝9.5Hz,1H),3.11(d,J＝2.4Hz,2H),2.94(d,J＝12.3Hz,1H),2.91-2.84(m,4H),2.80(s,1H),2.57(d,J＝4.9Hz,2H),2.52(d,J＝12.5Hz,1H),2.46(d,J＝12.3Hz,1H),2.34(s,3H),2.09-2.01(m,4H),1.69(s,2H),1.48(d,J＝1.4Hz,2H),0.99(s,9H).MS(ESI,m/z):1048(M + +1).
EXAMPLE 70 Synthesis of Compound S51
Synthetic method referring to example 20, compound S51 can be prepared by replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),7.58(s,1H),7.52(s,1H),7.42-7.31(m,6H),7.31-7.17(m,6H),6.86(t,J＝0.9Hz,1H),6.75(s,1H),5.41(t,J＝5.5Hz,1H),5.10(q,J＝0.8Hz,1H),5.04(d,J＝5.1Hz,1H),4.59-4.46(m,3H),4.09-4.03(m,2H),3.89(s,3H),3.78(d,J＝1.1Hz,2H),3.47(d,J＝9.5Hz,1H),3.29(d,J＝9.5Hz,1H),3.11(d,J＝2.4Hz,2H),2.97-2.84(m,5H),2.80(s,1H),2.52(d,J＝12.5Hz,1H),2.46(d,J＝12.3Hz,1H),2.39(d,J＝16.9Hz,2H),2.26(s,3H),1.87(s,1H),1.69(s,2H),1.48(d,J＝1.4Hz,2H),1.12(s,3H),1.07(s,3H).MS(ESI,m/z):917(M + +1).
EXAMPLE 71 Synthesis of Compound S52
Synthetic method referring to example 20, compound S52 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.08(d,J＝13.0Hz,2H),7.76(dd,J＝7.3,2.0Hz,1H),7.62-7.52(m,3H),7.47(t,J＝7.5Hz,1H),7.42-7.33(m,2H),7.20(t,J＝1.0Hz,1H),3.47(s,1H),3.29(s,1H),3.22(s,1H),2.76(dd,J＝18.3,1.0Hz,2H),2.63(d,J＝1.1Hz,1H),2.56(d,J＝1.1Hz,1H),2.40(s,2H),2.26(d,J＝11.9Hz,2H),2.17(s,1H),2.12(s,1H),2.03(d,J＝14.1Hz,3H),1.97(s,1H).MS(ESI,m/z):774(M + +1).
EXAMPLE 72 Synthesis of Compound S53
Synthetic method referring to example 20, compound S53 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.26(s,1H),9.03(s,1H),7.82(dd,J＝7.1,2.2Hz,1H),7.68(dd,J＝7.5,2.0Hz,1H),7.62(t,J＝7.4Hz,1H),7.52-7.43(m,2H),7.39-7.32(m,2H),7.25(s,1H),7.04(dd,J＝7.4,2.1Hz,1H),6.86(t,J＝0.9Hz,1H),4.45(s,1H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),2.89-2.80(m,4H),2.63-2.56(m,4H),2.55-2.45(m,2H),2.19(s,1H),2.12(s,1H),1.49(d,J＝4.1Hz,4H).MS(ESI,m/z):799(M + +1).
EXAMPLE 73 Synthesis of Compound S54
Synthetic method referring to example 34, compound S54 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J＝7.3,2.2Hz,1H),7.63(dd,J＝7.5,2.0Hz,1H),7.56-7.41(m,3H),7.39(t,J＝1.0Hz,1H),7.12-7.04(m,2H),6.93(s,1H),6.90-6.84(m,2H),5.10(s,1H),3.92(s,3H),3.78(d,J＝1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H),2.56-2.49(m,2H),2.46(d,J＝12.5Hz,1H),2.24(d,J＝0.9Hz,2H),1.64(s,2H),1.55(s,2H),1.36-1.24(m,6H).MS(ESI,m/z):846(M + +1).
EXAMPLE 74 Synthesis of Compound S55
Synthetic method referring to example 20, compound S55 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J＝6.5,3.0Hz,1H),7.55-7.42(m,3H),7.39(t,J＝1.0Hz,1H),7.22(m,1H),7.08-7.00(m,3H),6.86(t,J＝1.0Hz,1H),4.32(s,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),2.92-2.85(m,4H),2.64-2.53(m,4H),2.53-2.47(m,2H),2.24(d,J＝0.9Hz,3H),2.17(s,1H),2.12(s,1H),1.50(d,J＝4.3Hz,4H).MS(ESI,m/z):745(M + +1).
EXAMPLE 75 Synthesis of Compound S56
Synthetic method referring to example 20, compound S56 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.08(d,J＝13.0Hz,2H),7.90(dd,J＝7.4,2.1Hz,1H),7.72(dd,J＝7.5,2.0Hz,1H),7.64(t,J＝7.5Hz,1H),7.45-7.38(m,2H),7.26(ddd,J＝7.5,5.4,4.1Hz,1H),7.20(t,J＝1.0Hz,1H),7.18-7.10(m,2H),6.61(t,J＝5.5Hz,1H),6.15(s,1H),4.53(ddd,J＝12.5,5.4,0.7Hz,1H),3.86(ddd,J＝12.4,5.5,0.7Hz,1H),3.24(s,1H),2.86(d,J＝12.3Hz,1H),2.81-2.72(m,3H),2.63(d,J＝1.1Hz,1H),2.56(d,J＝1.1Hz,1H),2.29-2.17(m,4H),2.04(s,1H),1.97(s,1H),1.92(s,2H),1.78(q,J＝12.4Hz,2H),1.56(d,J＝3.5Hz,2H).MS(ESI,m/z):751(M + +1).
EXAMPLE 76 Synthesis of Compound S57
Synthetic method referring to example 20, compound S57 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.06(s,1H),7.58-7.49(m,2H),7.40(t,J＝1.0Hz,1H),7.33(ddd,J＝11.8,7.3,2.2Hz,2H),7.23(td,J＝7.5,2.0Hz,1H),7.18-7.08(m,2H),7.04(ddt,J＝7.4,1.9,0.9Hz,1H),6.61(t,J＝5.5Hz,1H),4.53(ddd,J＝12.4,5.5,1.1Hz,1H),3.86(ddd,J＝12.4,5.5,1.1Hz,1H),3.47(s,1H),3.29(s,1H),3.22(s,1H),2.76(dd,J＝18.3,1.0Hz,2H),2.63(d,J＝1.1Hz,1H),2.61-2.54(m,3H),2.26(d,J＝11.9Hz,2H),2.17(s,1H),2.12(s,1H),2.03(d,J＝14.1Hz,3H),1.97(s,1H).MS(ESI,m/z):719(M + +1).
EXAMPLE 77 Synthesis of Compound S58
Synthetic method referring to example 20, compound S58 can be prepared by simply replacing the corresponding starting materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.25(s,1H),7.82(dd,J＝7.3,2.0Hz,1H),7.52(t,J＝7.5Hz,1H),7.49-7.43(m,2H),7.39(t,J＝1.0Hz,1H),7.35(s,1H),7.30-7.14(m,4H),6.90(t,J＝1.0Hz,1H),5.42(t,J＝5.5Hz,1H),4.58-4.43(m,3H),4.32(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J＝1.1Hz,2H),2.92-2.83(m,4H),2.64-2.56(m,4H),2.55-2.45(m,2H),2.19(s,1H),2.12(s,1H),1.49(d,J＝4.1Hz,4H).MS(ESI,m/z):744(M + +1).
EXAMPLE 78 test of the Compounds of the invention for HPK1 kinase Activity
HPK1 kinase domain (1-307 aa) was solubilized in the kinase buffer (20mM HEPES pH7.5,10mM MgCl) 2 1mM EGTA,0.5mM TCEP,0.01%BriJ-35,0.05% BSA) was added to a 96-well plate at a final concentration of 20nM, then a gradient of a test compound of the present invention (10 concentration points were set for each compound), HPK1 kinase was pre-incubated with the compound of the present invention for 30min, then 20. Mu.L of a substrate solution (SLP 76-SH at a final concentration of 0.5 mg/mL) was added to each well 2 Domain and 10 μm ATP) initiates the enzymatic reaction. Incubation was performed for 1h at room temperature, and the inhibition of HPK1 kinase activity by the compounds of the invention was then determined at each concentration according to the instructions of Luminescent Kinase Assay Kit (Beyotime Biotechnology Company). By using GraphPad fitting calculation of the inhibitory Activity of the Compounds of the invention against HPK1 kinase IC 50 Values, compound a, served as positive control. The experimental results are shown in table 1.
TABLE 1 kinase inhibitory Activity of the inventive Compounds against HPK1 protein (IC 50 nM)
/>
Compared with the positive control compound A, the compound of the invention has basically equivalent activity to the positive control, which shows that the compound of the invention basically maintains the HPK1 inhibitory activity and has better combination with HPK1 protein.
EXAMPLE 79 assay of the degradation Activity of some of the compounds of the invention on HPK1 protein
(1) Collecting cells: jurkat cells were cultured for 12h with adherence, and a portion of the compounds of the invention (0.1. Mu.M, 1. Mu.M, 10. Mu.M) was incubated with the cells for 12h.
(2) Extracting protein: the original culture medium is discarded, the cells are washed three times by precooled PBS, a proper amount of lysate is added, the mixture is evenly mixed and placed on ice for being cracked for 30min, the mixture is centrifuged for 5min at 12000rpm at 4 ℃, and the supernatant after centrifugation is transferred into a new centrifuge tube for preparation for quantification.
(3) Protein quantification: protein is quantified by adopting BCA, and BCA working solution is obtained after the solution A and the solution B are evenly mixed according to the proportion of 50:1. 100. Mu.L of BCA working solution, 9. Mu.L of triple distilled water and 1. Mu.L of protein sample were added to a 96-well plate, and incubated at 37℃for 30min after mixing, absorbance was measured with a full-wavelength microplate reader, and protein concentration was calculated from a standard curve. The quantified protein was mixed with a 5×loading buffer at a ratio of 4:1, denatured in boiling water for 8min, placed on ice, cooled and stored at-20℃until use.
(4) Preparing SDS-PAGE gel, concentrating gel at 90V, separating gel at 120V and at 4deg.C, transferring membrane at 100V for 1 hr, immediately placing protein membrane into 5% BSA solution, slowly shaking on shaking table, and sealing at room temperature for 1 hr.
(5) Referring to the instructions of HPK1 anti-body (4472 SCST), GLK (D1L 4G) Rabbit mAb (92427 SCST), rabbit mAb (92711 TCST), β -actin Mouse Monoclonal Antibody (BE 0021 easybio), the primary Antibody was diluted in the appropriate proportions, incubated overnight with slow shaking at 4℃and washed 3 more times with PBST for 10 min/time.
(6) According to the primary antibody selection of the Goat Anti-Rabbit IgG (H & L) -HRP Conjubed (BE 0101 easy) or Goat Anti-Mouse IgG (H & L) -HRP Conjubed (BE 0102 easy), reference to the second antibody instructions, in proper proportion dilution of the second antibody, slow shaking incubation at room temperature for 1H, washing 3 times with PBST, 10 min/time.
(7) ECL luminescence was added, the results were observed by a developing instrument, western results were quantified using Image J software, and degradation rates (HPK 1 and GLK) were calculated by comparison with a control group without compound. The experimental results are shown in table 2.
TABLE 2 degradation Activity of the inventive Compounds on HPK1 HPK1 and GLK proteins
Experimental results show that the compound has good degradation activity on HPK1 protein and is dose-dependent, and the degradation rate of the compound on GLK protein is low at 1.0 mu M, which indicates that the compound can efficiently and selectively reduce HPK1 protein.
Example 80T cell cytokine Release assay
HPK1 kinase inhibits T cell effector cytokine release, and thus it was examined whether the compounds of the present invention could enhance T cell cytokine release capacity by ELISA method. Human PBMC cells were thawed and suspended in RPMI 1640 (Gibco) medium containing 10% bovine placental serum and cells were seeded in 96-well plates (1X 1)0 5 /hole). The compound of the invention was added in a gradient dilution to a 96-well plate at 37℃with 5% CO 2 Incubate in incubator for 1h. PBMCs cells were activated by the addition of 100. Mu.L of anti-CD3/CD28 antibody (final concentration 1. Mu.g/mL) and then incubated at 37℃with 5% CO 2 The supernatant was diluted with 8-fold PBS and 100. Mu.L of the diluted supernatant was used to measure the release of cytokine IL-2 at each concentration of the compounds of the invention using a human IL-2ELISA kit (4 abio). Calculation of EC of the compounds of the invention using GraphPad fitting 50 Values. The experimental results are shown in table 3.
TABLE 3 results of assays for the IL-2 cytokine Activity of the inventive compounds to stimulate PBMC release
Numbering of compounds EC 50 (nM)
S1 65
S3 45
S4 42
S17 23
S18 18
S19 15
S20 28
S38 45
S39 40
S40 56
S46 40
S48 58
A 140nM
The compound of the invention can significantly enhance the release of IL-2 by PBMC cells and is superior to positive control compound A. This demonstrates that the compounds of the invention are capable of enhancing T cell effector cytokine release by degrading the HPK1 protein, thereby restoring or enhancing an anti-tumor immune response.

Claims (10)

1. A heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structural formula:
in formula I:
R 1 is hydrogen, halogen or C 1-4 Alkoxy, halo (C) 1-4 Alkoxy) or deuteration (C 1-4 An alkoxy group);
R 2 is halogen, cyano, hydroxy (C) 1-4 Alkyl) or halo (C) 1-4 An alkyl group);
m is 0, 1, 2 or 3;
q is N or C;
y is N or C;
e is
W is-CH 2 -、-C(CH 3 ) 2 Or->
R 3 Is C 1-6 An alkyl group;
R 4 is that
R 5 Is hydrogen or C 1-4 An alkyl group;
l is The terminal is attached to the E terminal, and the "- -" terminal is attached to +.>Are connected;
L 1 is a single bond, -O-, -NR 6 -、 The terminal is attached to the E terminal, and the "- -" terminal is attached to L 2 Are connected;
L 2 is a single bond, The terminal is attached to L1, and the "- -" terminal is attached to L 3 Are connected;
L 3 is a single bond,
R 6 Is hydrogen or C 1-3 An alkyl group;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
d is 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5 or 6;
f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
2. The heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, characterized in that:
L is The terminal is attached to the E terminal, and the "- -" terminal is attached to +.>Are connected;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
c is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
d is 1, 2 or 3;
e is 1, 2, 3, 4 or 5;
f is 1, 2, 3, 4, 5, 6, 7, 8 or 10.
3. The heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, characterized in that:
l is The terminal is attached to the E terminal, and the "- -" terminal is attached to +.>Are connected;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
b is 1, 2, 3, 4, 5, 6 or 7;
c is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
d is 1, 2 or 3;
e is 1, 2, 3 or 4;
f is 1, 2, 3, 4, 5, 6, 7 or 8.
4. The heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, characterized in that:
e is
5. The heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, characterized in that:
R 2 Is fluoro, cyano, hydroxymethyl, methyl or trifluoromethyl.
6. The heterocyclic carboxamide compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, according to claim 1, characterized in that the structural formula is any of the following:
wherein E, L, R 1 ，R 2 And a is as claimed in any one of claims 1 to 5.
7. The heterocyclic carboxamide compound of formula I according to claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, characterized in that the heterocyclic carboxamide compound of formula I is selected from compounds of any of the following structures:
8. a pharmaceutical composition comprising a therapeutically effective amount of a heterocyclic carboxamide compound as described in any of claims 1 to 7, comprising a heterocyclic carboxamide compound as described in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, in combination with a pharmaceutically acceptable carrier or adjuvant.
9. Use of a heterocyclic carboxamide compound of formula I as described in any of claims 1 to 7, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as described in claim 8, for the preparation of a hematopoietic progenitor kinase 1 degrading agent.
10. Use of a heterocyclic carboxamide compound of formula I as described in any of claims 1 to 7, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as described in claim 8 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
CN202311356616.8A 2023-10-19 2023-10-19 Heterocyclic carboxamide compound, pharmaceutical composition and application thereof Pending CN117417324A (en)

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