CN112824380A - Alpha-fluoro chalcone derivative and application thereof - Google Patents

Alpha-fluoro chalcone derivative and application thereof Download PDF

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CN112824380A
CN112824380A CN202011323949.7A CN202011323949A CN112824380A CN 112824380 A CN112824380 A CN 112824380A CN 202011323949 A CN202011323949 A CN 202011323949A CN 112824380 A CN112824380 A CN 112824380A
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楼金芳
冯恩光
沈锡明
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Hangzhou Bio Sincerity Pharma Tech Corp ltd
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Abstract

The invention provides an alpha-fluoro chalcone derivative and application thereof, wherein the derivative comprises pharmaceutically acceptable salts thereof. The invention also provides application of the derivative and the pharmaceutically acceptable salt thereof in preparing medicaments for treating PPAR receptor related diseases. The derivative provided by the invention has the characteristics of good in-vivo absorption, high bioavailability and strong drug effect, so that the derivative has great clinical application value.

Description

Alpha-fluoro chalcone derivative and application thereof
Technical Field
The invention belongs to the technical field of medicinal preparations, and relates to an alpha-fluoro chalcone derivative and application thereof. In particular to a pharmaceutically acceptable salt and a prodrug thereof, which are peroxisome proliferator-activated receptor (PPAR) agonists, have the application of treating diseases related to the mediation of abnormal PPAR expression and have great clinical application prospect.
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries or regions, meaning that excess fat accumulates in the liver as triglycerides (steatosis > 5% of the liver cell tissue). In addition to excess fat, patients with NAFLD are associated with hepatocellular injury and inflammation (steatohepatitis), the latter non-alcoholic steatohepatitis (NASH). There is no correlation between simple steatosis and short-term increases in morbidity or mortality in NAFLD, but once progression to NASH the risk of cirrhosis, liver failure and hepatocellular carcinoma (HCC) is significantly increased. Cirrhosis due to NASH is an increasing cause of liver transplantation. Morbidity and mortality due to liver disease are greatly increased in NASH patients and are closely related to increased morbidity and mortality of cardiovascular disease. The diagnosis of asymptomatic middle-aged male patients showed: NAFLD is mostly male, elderly, hypertensive and diabetic in 46% of patients with nonalcoholic fatty liver disease (NAFLD, 12.2% nash. NAFLD. 60-76% of diabetic patients have NAFLD, 22% of pediatric patients with nash. NAFLD also increase year by year, and 38-53% of obese children have NAFLD.
At present, only Obeticholic Acid (Obeticholic Acid) is approved by FDA to treat the disease, and polyene phosphatidyl choline, silymarin, ursodeoxycholic Acid, glycyrrhizic Acid and other liver-protecting medicines are commonly used in China clinically.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, which are ligand-activated transcription factors that regulate gene expression, mainly of 3 subtypes: α, γ and δ (or β), the α subtype is mainly expressed in brown adipose tissue, liver, heart and musculoskeletal muscles, playing a major role in the metabolism of bile acids, lipids and sugars; the beta subtype expression specificity is not obvious, and the beta subtype expression specificity possibly has an anti-inflammatory effect; the gamma subtype has a certain effect on insulin resistance. PPARs are associated with a variety of disease states including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, alzheimer's disease, skin diseases, respiratory diseases, ocular disorders, IBD (irritable bowel disease), ulcerative colitis, and crohn's disease. In view of the multiple conditional mechanisms by which PPARs are beneficial to liver function, PPAR agonists are among the most effective potential drugs for the treatment of fatty liver.
Elafibranor (GFT-505), a peroxisome proliferator-activated alpha and delta receptor (PPAR α/δ) agonist developed by Genfit, france, is currently in the third clinical phase of the study for the treatment of nonalcoholic steatohepatitis (NASH), as well as in the second clinical phase of the trial for the treatment of primary cholangitis (PBC). There is no progress in the clinical study of elafinibrand for the treatment of type 2 diabetes (T2DM), dyslipidemia and liver fibrosis. Elafinibranor acts on both subtypes of PPAR (α, δ) and preferentially on the PPAR α family. The drug targets multiple risk factors acting on both microvasculature and macrovascular, such as high and low density lipoprotein cholesterol, triglycerides and inflammation, and has been shown to have positive effects on insulin resistance, diabetes and atherosclerosis in preclinical studies.
The following compounds are reported in the literature as compounds for treating NASH.
Figure BDA0002793720010000011
Some researchers at home and abroad have also carried out early researches on PPAR agonist small molecular compounds, for example, CN108658908A discloses a compound with a bicyclo-ring structure, for example, CN 1930122A discloses a 1, 3-diphenylprop-2-en-1-one derivative compound, which shows better biological activity on all or part of three subtypes of PPAR, for example, WO 2014307138 discloses a deuterated chalcone derivative.
Disclosure of Invention
The invention aims to provide alpha-fluoro chalcone derivatives with a novel structure, and the compounds have PPAR activating activity.
In order to solve the technical problems, the invention adopts the following technical scheme:
an alpha-fluoro chalcone derivative is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000021
wherein: r1、R2Each independently selected from H, halogen, CF3、-CN、C1-6Alkoxy, CF3O、CHF2O、C1-6Alkylthio, CF3S、CHF2S、C1-6Alkyl radical, C1-6Alkyl sulfoxide radical-, CF3SO、C1-6Alkyl sulfone group or CF3SO2Or selected from optionally substituted with 1, 2 or 3R: c1-6Alkyl radical, C1-6alkyl-S (═ O) -, C1-6alkyl-S (═ O)2-、C1-6Alkyl- (═ O)2-、C1-6Alkoxy or C1-6An alkylthio group;
R3、R4are respectively and independently selected from H, halogen and C1-4Alkyl radical, C1-4Alkoxy, including but not limited to Cl, Br, I, CH3、Et、CH3O；
R5、R6Each independently selected from H, C1-6Alkyl radical, C1-6Heteroalkyl, phenyl, 5-to 6-membered heteroaryl, R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl; wherein R is5、R6Including but not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl, or pyridyl; r5、R6The ring formation is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure BDA0002793720010000022
Figure BDA0002793720010000023
R7Is selected from H or C1-6An alkyl group;
n is selected from 0, 1, 2, 3,4, 5 or 6;
r is selected from H, F, Cl, Br, I, OH, CN, NH2、COOH、C(＝O)NH2、Me、Et、CF3、CHF2、CH2F、NHCH3Or N (CH)3)2。
In preferred compounds of formula I, R1,R2Selected from H, halogen, CF3、-CN、C1-6Alkoxy, CF3O、CHF2O、C1-6Alkylthio, CF3S、CHF2S、C1-6Alkyl radical, C1-6Alkyl sulfoxide radical-, CF3SO、C1-6Alkyl sulfone group or CF3SO2(ii) a Wherein R is1、R2Preferably selected from Cl, Me, Et, CH3O、EtO、n-Pr-O、i-PrO、CH3S、EtS、n-PrS、i-PrO、CH3SO、CH3SO2、CF3O、CHF2O、CF3S、CHF2S、CF3SO or CF3SO2。
In preferred compounds of formula I, R3、R4Each independently selected from H, halogen, C1-4Alkyl or C1-4Alkoxy, or each is independently selected from C optionally substituted with 1, 2 or 3R1-4Alkyl radical, C1-4An alkoxy group.
In preferred compounds of formula I, R5、R6Each independently selected from H, C1-6Alkyl radical, C1-6Heteroalkyl, phenyl or 5-to 6-membered heteroaryl, R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, R5、R6Including but not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl, or pyridyl; or R5、R6The ring formation is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure BDA0002793720010000024
Figure BDA0002793720010000031
In a preferred compound of the formula I,
Figure BDA0002793720010000032
selected from:
Figure BDA0002793720010000033
Figure BDA0002793720010000034
in a preferred compound of the formula I,
Figure BDA0002793720010000035
selected from:
Figure BDA0002793720010000036
Figure BDA0002793720010000037
an alpha-fluoro chalcone derivative is a compound shown as a formula II or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000038
wherein when R is1Selected from H or-XR, wherein X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2(ii) a Then R is2Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl or halo C1-6An alkoxy group; or
When R is2Selected from H or-XR, wherein X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2(ii) a Then R is1Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl or halo C1-6An alkoxy group;
R3、R4are respectively and independently selected from H, halogen and C1-4Alkyl or C1-6An alkoxy group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
n is selected from 0, 1, 2, 3 or 4;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
Preferably, the compound is represented by formula IIa or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000039
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
Preferably, the compound is represented by formula IIb or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000041
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
Preferably, the compound is represented by formula IIc or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000042
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
Preferably, the compound is represented by formula Id:
Figure BDA0002793720010000043
wherein R is1Selected from H or-XR, X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, orR5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
An α -fluorochalcone derivative which is a compound of numbers P001 to P098 or a pharmaceutically acceptable salt thereof:
Figure BDA0002793720010000051
Figure BDA0002793720010000061
the invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
The invention also provides the application of the pharmaceutical composition in preparing medicines for treating PPAR receptor related diseases.
Preferably, the PPAR receptor associated diseases are: non-alcoholic steatohepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity, kidney disease, or degenerative brain disease.
More preferably, the kidney disease is selected from chronic kidney disease, renal failure, and the degenerative brain disease is selected from alzheimer's disease.
Compared with the prior art, the invention has the following beneficial effects:
the invention is modified on the basis of GFT-505 structure, develops a series of fluoro chalcone derivatives and carries out related biological tests. The experimental result shows that: in an in vitro model, the alpha-fluoro substituted chalcone derivatives have stronger inhibition effect on hepatic fibrosis than positive medicine GFT-505; the bioavailability of the alpha-fluoro substituted chalcone derivatives is also well shown in an in vivo model.
Definition and description of related terms
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts including, but not limited to, sodium, potassium, calcium, magnesium salts, ammonium or organic ammonia.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier vehicle representative of a vehicle capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, excipients, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on The vector, reference may be made to Remington, The Science and Practice of Pharmacy,21st Ed., Lippincott, Williams & Wilkins (2005), The contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The terms "optional," "optionally," or "preferably" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), meaning that two hydrogen atoms are substituted, the keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and each occurrence of R has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When the number of a linking group is 0, e.g., - (CRR)0-, represents that the linking group is a single bond.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C1-C6 alkyl, including but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl.
The term "cycloalkyl" refers to a monocyclic or bicyclic alkyl group consisting of carbon and hydrogen atoms, such as C3-C8 cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, such as C1-C6 alkoxy, including but not limited to methoxy, ethoxy, n-propoxy (containing n-propoxy and isopropoxy), butoxy (containing n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), pentoxy (containing n-pentoxy, isopentoxy, neopentoxy), n-hexoxy, 2-methylhexoxy, and the like.
The term "amino" refers to the group-NH2。
The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic alkyl group consisting of carbon and hydrogen atoms, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a saturated cyclic group having heteroatoms, the group containing 1 or more heteroatoms independently selected from N, O, S, the remainder being carbon-containing groups of a stable 3-to 10-membered saturated heterocyclic ring system. Unless otherwise specifically indicated in the specification, a heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system; when polycyclic, they may be fused, bridged or spiro. In one aspect, typical 4-6 membered monocyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
Figure BDA0002793720010000081
Figure BDA0002793720010000082
And the like. In one aspect, typical 7-10 membered bicyclic heterocycloalkyl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
Figure BDA0002793720010000083
Figure BDA0002793720010000084
And the like.
The term "aryl" refers to an all-carbon aromatic group having a fully conjugated pi-electron system, which may be a single ring or a fused ring, generally having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to an aromatic group containing a heteroatom, which may be a single ring or a fused ring, preferably containing 1 to 4 5-12 membered heteroaryl groups independently selected from N, O, S, including but not limited toBut are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, indolyl, and the like. In one aspect, typical 5-6 membered monocyclic heteroaryl groups containing 1 or more heteroatoms independently selected from N, O, S include, but are not limited to
Figure BDA0002793720010000085
Figure BDA0002793720010000086
And the like.
The term "halo C1-C6Alkyl group "," halogeno C1-C6Alkoxy "means a group in which one or more (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, in particular fluorine or chlorine atoms.
The pharmaceutical composition can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powder, granules, paste, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
The route of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granules, if necessary with the addition of small amounts of excipients, to form tablets or tablet cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).
Detailed Description
The following are specific examples of the present invention and further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes, modifications and equivalents that do not depart from the spirit of the invention are intended to be included within the scope thereof.
Example 1: compound P001
Figure BDA0002793720010000091
The first step is as follows: compound P001-b
Compound P001-a (4.00g,24.06mmol,1.00eq.), N-bromosuccinimide (NBS) (4.37g,24.54mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (4.58g,24.06mmol,1.00eq.) were dissolved in anhydrous acetonitrile 12.00mL at room temperature, and heated to 50 ℃ at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P001-b. The yield thereof is 60%.
MS m/s(ESI):268.9[M+23]。
The second step is that: compounds P001-c
Compound P001-b (3.40g,13.87mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (5.70mL,20.81mmol,1.50eq.) and potassium fluoride (1.21g,20.81mmol,1.50eq.) were dissolved in anhydrous acetonitrile (12.00mL) at room temperature and heated to 80 ℃ under nitrogen for 24 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P001-c. The yield thereof was found to be 34%.
MS m/s(ESI):207.2[M+23].
The third step: compounds P001-d
Compound P001-c (2.19g,11.89mmol,1.00eq.) and 3, 4-dimethyl-4-hydroxybenzaldehyde (1.79g,11.89mmol,1.00eq.) were dissolved in anhydrous methanol (55.00mL,25.11eqv.) at room temperature, piperidine (3.30mL,3.00eqv.) was added, and the mixture was heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P001-d. The yield is 43 percent;
MS(ESI):315.1(M-1)。1H-NMR(400MHz；(CDCl3)δH＝7.83(d,J＝8.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝8.2Hz,2H,ArH),6.77(d,J＝37.2Hz,1H,CF＝CH),2.54(s,3H,SCH3),2.28(s,6H,ArCH3)。
the fourth step: compounds P001-e
At room temperature, compound P001-d (0.50g,1.58mmol,1.00eq.) and tert-butyl α -bromoisobutyrate (3.00mL,15.80mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.20g,10.00eq.), and heated to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P001-e. The yield thereof was found to be 65%.
MS(ESI):459.2[M+1]。1H-NMR(400MHz；(CDCl3)δH＝7.84(d,J＝8.2Hz,2H,ArH),7.35(s,2H,ArH),7.29(d,J＝8.2Hz,2H,ArH),6.76(d,J＝37.0Hz,1H,CF＝CH),2.54(s,3H,SCH3),2.26(s,6H,ArCH3),1.52(s,9H,OC(CH3)3CO),1.46(s,6H,C(CH3)2)。
The fifth step: compound P001
Compound P001-e (0.23g,0.51mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound P001. The yield thereof was found to be 78%.
MS(ESI):401.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 2: compound P002
Figure BDA0002793720010000101
At room temperature, compound P001-d (100mg,0.32mmol,1.00eq.) and isopropyl 2-bromoisobutyrate (510 μ L,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (437mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P002. The yield thereof was found to be 81%.
MS(ESI):445(M+1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J＝8.2Hz,2H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(m,1H,OCH),2.56(s,3H,SCH3),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3)。
Example 3: compound P003
Figure BDA0002793720010000102
The first step is as follows: compound P003-a
Compound P001-d (1.58mmol,1.00eq.) and tert-butyl 2-bromopropionate (15.80mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (2.20g,10.00eq.) and reaction at room temperature to 70 ℃ for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P003-a. The yield thereof was found to be 87.9%.
MS(ESI):445.2[M+1]。
The second step is that: compound P003
Compound P003-a (0.51mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound P003. The yield thereof was found to be 98.6%.
MS(ESI):387.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(q,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3)。
Compound P003-1
Figure BDA0002793720010000111
Referring to the synthesis method of the compound P003, the chiral target compound P003-1 is obtained by replacing tert-butyl 2-bromopropionate with tert-butyl S-2-bromopropionate.
MS(ESI):389.7[M+1]
Compound P003-2
Figure BDA0002793720010000112
Referring to the synthesis method of the compound P003, the chiral target compound P003-2 is obtained by replacing tert-butyl 2-bromopropionate with tert-butyl R-2-bromopropionate.
MS(ESI):389.7[M+1]。
Example 4: compound P004
Figure BDA0002793720010000113
The first step is as follows: compound P004-a
At room temperature, the compounds P001-d (100mg,0.32mmol,1.00eq.) and ethyl-1-bromobutane carboxylate (510. mu.L, 3.16mmol,10.00eq.) were dissolved in anhydrous ethyl 6.00mL, potassium carbonate (437mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P004-a. The yield thereof was found to be 21%.
MS(ESI):443.2[M+1]。
The second step is that: compound P004
Compound P004-a (0.05mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P004. The yield thereof was found to be 95.0%.
MS(ESI):413.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.55(s,3H,SCH3),2.52-2.62(m,4H,CH2),2.32(s,6H,ArCH3),1.56(m,2H,CH2)。
Example 5: compound P005
Figure BDA0002793720010000121
At room temperature, compound P001-d (100mg,0.32mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (214 μ L,0.95mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, and potassium iodide (5mg,0.10eq.) and potassium carbonate (437mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P005. The yield thereof was found to be 81.2%.
MS(ESI):501.7[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 6: compound P006
Figure BDA0002793720010000122
The first step is as follows: compound P006-a
At room temperature, the compound P001-d (100mg,0.32mmol,1.00eq.) and tert-butyl 2-bromobutyrate (706mg,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (437mg,3.16mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P006-a. The yield thereof was found to be 80.2%.
MS(ESI):459.5[M+1]。
The second step is that: compound P006
Compound P006-a (0.23mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound P006. The yield thereof was found to be 97.2%.
MS(ESI):401.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(t,3H,CH3)。
Compound P006-1
Figure BDA0002793720010000131
Referring to the synthesis method of the compound P006, the chiral target compound P006-1 is obtained by replacing tert-butyl 2-bromobutyrate with tert-butyl R-2-bromobutyrate.
MS(ESI):401.3[M-1]
Compound P006-2
Figure BDA0002793720010000132
Referring to the synthesis method of the compound P006, the chiral target compound P006-1 is obtained by replacing tert-butyl 2-bromobutyrate with tert-butyl S-2-bromobutyrate.
MS(ESI):401.3[M-1]。
Example 7: compound P007
Figure BDA0002793720010000133
The first step is as follows: compound P007-a
At room temperature, compound P001-d (100mg,0.32mmol,1.00eq.) and ethyl 2-bromoisovalerate (661mg,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (437mg,3.16mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P007-a. The yield thereof was found to be 89.2%.
MS(ESI):445.5[M+1]。
The second step is that: compound P007
Compound P007-a (0.25mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P007. The yield thereof was found to be 95.3%.
MS(ESI):415.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝7.5Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 8: compound P008
Figure BDA0002793720010000141
The first step is as follows: compound P008-a
At room temperature, compound P001-d (100mg,0.32mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (157mg,0.95mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium iodide (5mg,0.10eq.) was added, potassium carbonate (437mg,3.16mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P008-a. The yield thereof was found to be 88%.
MS(ESI):445.3[M+1]。
The second step is that: compound P008
Compound P008-a (0.26mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature for 3 hours. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P008. The yield thereof was found to be 89.0%.
MS(ESI):415.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 9: compound P009
Figure BDA0002793720010000142
The first step is as follows: compound P009-a
At room temperature, the compound P001-d (100mg,0.32mmol,1.00eq.) and ethyl 3-chloropropionate (130mg,0.95mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (437mg,10.00eq.) were added, followed by heating to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P009-a. The yield thereof was found to be 89.1%.
MS(ESI):417.7[M+1]。
The second step is that: compound P009
Compound P009-a (0.26mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P009. The yield thereof was found to be 81.2%.
MS(ESI):387.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.45(q,2H,COCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3)。
Example 10: compound P010
Figure BDA0002793720010000151
The first step is as follows: compound P010-a
At room temperature, the compound P001-d (100mg,0.32mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (655mg,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00m (437mg,3.16mmol,10.00eq.) and heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P010-a. The yield thereof was found to be 14%.
MS(ESI):441.4[M+1]。
The second step is that: compound P010
Compound P010-a (0.02mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P010. The yield thereof was found to be 93.5%.
MS(ESI):427.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 11: compound P011
Figure BDA0002793720010000161
The first step is as follows: compound P011-a
At room temperature, the compound P001-d (100mg,0.32mmol,1.00eq.) and methyl 1-bromocyclopropanecarboxylate (566mg,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (437mg,3.16mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P011-a. The yield thereof was found to be 15%.
MS(ESI):415.3[M+1]。
The second step is that: compound P011
Compound P011-a (0.03mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P011. The yield thereof was found to be 90.5%.
MS(ESI):399.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.54(m,4H,CH2)。
Example 12: compound P012
Figure BDA0002793720010000162
The first step is as follows: compound P012-a
At room temperature, compound P001-d (100mg,0.32mmol,1.00eq.) and tert-butyl bromoacetate (617mg,3.16mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.20g,10.00eq.), and heated to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P012-a. The yield thereof was found to be 93.9%.
MS(ESI):431.2[M+1]。
The second step is that: compound P012
Compound P012-a (0.28mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P012. The yield thereof was found to be 95.6%.
MS(ESI):373.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3),2.32(s,6H,ArCH3)。
Example 13: compound P013
Figure BDA0002793720010000171
The first step is as follows: compound P013-b
Compound P013-a (5.00g,22.71mmol,1.00eq.), N-bromosuccinimide (NBS) (4.12g,23.16mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (4.32g,22.71mmol,1.00eq.) were dissolved in anhydrous acetonitrile (12.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P013-b. The yield is 70 percent; MS M/s (ESI) 322.9[ M +23 ].
The second step is that: compound P013-c
Compound P013-b (3.50g,11.70mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (5.00mL,17.55mmol,1.50eq.) and potassium fluoride (1.05g,17.55mmol,1.50eq.) were dissolved in anhydrous acetonitrile (12.00mL,3.53eqv.) at room temperature for 24h at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P013-c. The yield is 30 percent; MS M/s (ESI) 261.2[ M +23 ].
The third step: compound P013-d
Compound P013-c (2.00g,8.40mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (1.79g,8.40mmol,1.00eq.) were reacted at room temperature with 2.30mL piperidine, 3.00eqv in dry methanol (55.00mL,27.50eqv.), and heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P013-d. The yield thereof was found to be 48%.
MS(ESI):369.1(M-1)。
The fourth step: compound P013-e
At room temperature, compound P013-d (500mg,1.35mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (2.60mL,13.50mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (1.87g,10.00eqv.), and heated to 70 ℃ under nitrogen atmosphere for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P013-e. The yield thereof was found to be 67%.
MS(ESI):513.2[M+1]。
The fifth step: compound P013
Compound P013-e (300mg,0.59mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound P013. The yield thereof was found to be 77%.
MS(ESI):455.7[M-1]。1H-NMR(400MHz；(CDCl3)δH 7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 14: compound P014
Figure BDA0002793720010000181
The first step is as follows: compound P014-b
Compound P014-a (4.00g,19.78mmol,1.00eq.), N-bromosuccinimide (NBS) (3.59g,20.18mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (3.84g,19.78mmol,1.00eq.) were dissolved in anhydrous acetonitrile (12.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P014-b. The yield is 58 percent; MS M/s (ESI) 304.9[ M +23 ].
The second step is that: compound P014-c
Compound P014-b (3.00g,10.67mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (4.40mL,16.01mmol,1.50eq.) and potassium fluoride (930mg,16.01mmol,1.50eq.) were dissolved in anhydrous acetonitrile (12.00mL) at room temperature for 24 hours at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P014-c. The yield is 34%; MS M/s (ESI) 243.2[ M +23 ].
The third step: compound P014-d
Compound P014-c (700mg,3.18mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (478mg,3.18mmol,1.00eq.) were reacted at room temperature with piperidine (873 μ L,3.00eqv.) in dry methanol (10.00mL) under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P014-d yield: 43%.
MS(ESI):351[M-1]。
The fourth step: compound P014
Compound P014-d (100mg,0.27mmol,1.00eq.) and isopropyl 2-bromoisobutyrate (504 μ L,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (373mg,2.70mmol,10.00eq.) and reaction under nitrogen at 70 ℃ for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P014. The yield thereof was found to be 81%.
MS(ESI):481[M+1]。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J＝8.2Hz,2H,ArH),7.20(t,J＝38.3Hz,1H,CHF2),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(m,1H,OCH),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3)。
Example 15: compound P015
Figure BDA0002793720010000191
The first step is as follows: compound P015-a
At room temperature, compound P013-d (100mg,0.27mmol,1.00eq.) and tert-butyl 2-bromopropionate (2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added potassium carbonate (373mg,2.70mmol,10.00eq.), and heated to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P015-a. The yield thereof was found to be 92.6%.
MS(ESI):499.3[M+1]。
The second step is that: compound P015
Compound P015-a (0.22mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with a saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P015. The yield thereof was found to be 90.6%.
MS(ESI):441.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(q,J＝6.6Hz,1H,OCH),2.32(s,6H,ArCH3),1.56(d,J＝6.6Hz,3H,CH3)。
Example 16: compound P016
Figure BDA0002793720010000192
The first step is as follows: compound P016-a
Compound P014-d (95mg,0.27mmol,1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (438 μ L,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile (6.00mL) at room temperature, followed by addition of potassium carbonate (373mg,2.70mmol,10.00eq.) and reaction under nitrogen at 70 ℃ for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P016-a. The yield thereof was found to be 26.0%.
MS(ESI):479.2[M+1]。
The second step is that: compound P016
Compound P016-a (0.05mmol,1.00eq.) is dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P016. The yield thereof was found to be 83.6%.
MS(ESI):449.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),7.25(t,J＝37.2Hz,1H,CHF2),6.77(d,J＝36.8Hz,1H,CF＝CH),2.85-2.75(m,2H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3)。
Example 17: compound P017
Figure BDA0002793720010000201
Compound P013-d (100mg,0.27mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (214. mu.L, 0.81mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile at room temperature, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (373mg,2.70mmol,10.00eq.) were added and heated to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P017. The yield thereof was found to be 88.3%.
MS(ESI):555.7[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 18: compound P018
Figure BDA0002793720010000202
The first step is as follows: compound P018-a
Compound P014-d (95mg,0.27mmol,1.00eq.) and tert-butyl 2-bromobutyrate (527mg,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (373mg,2.70mmol,10.00eq.) and reaction under nitrogen at 70 ℃ for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P018-a. The yield thereof was found to be 80.1%.
MS(ESI):495.5[M+1]。
The second step is that: compound P018
Compound P018-a (0.19mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P018. The yield thereof was found to be 92.2%.
MS(ESI):437.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),7.21(t,J＝37.2Hz,1H,CHF2),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(t,3H,CH3)。
Example 19: compound P019
Figure BDA0002793720010000211
The first step is as follows: compound P019-a
At room temperature, compound P013-d (100mg,0.27mmol,1.00eq.) and ethyl 2-bromoisovalerate (565mg,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (373mg,2.70mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P019-a. The yield thereof was found to be 56.2%.
MS(ESI):499.5[M+1]。
The second step is that: compound P019
Compound P019-a (0.13mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature, and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P019. The yield thereof was found to be 95.0%.
MS(ESI):469.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 20: compound P020
Figure BDA0002793720010000212
The first step is as follows: compound P020-a
Compound P014-d (100mg,0.27mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (134mg,0.81mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium iodide (5mg,0.10eq.) and potassium carbonate (373mg,2.70mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P020-a. The yield thereof was found to be 84%.
MS(ESI):481.3[M+1]。
The second step is that: compound P020
Compound P020-a (0.20mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P020. The yield thereof was found to be 80.0%.
MS(ESI):451.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d，J＝7.2Hz，2H，ArH)，7.21(t，J＝37.5Hz，1H，CHF2)，6.77(d，J＝36.8Hz，1H，CF＝CH)，4.45(s，2H，OCH2)，2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 21: compound P021
Figure BDA0002793720010000221
The first step is as follows: compound P021-a
At room temperature, compound P013-d (100mg,0.27mmol,1.00eq.) and ethyl 3-chloropropionate (111mg,0.81mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (373mg,2.70mmol,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P021-a. The yield thereof was found to be 93.1%.
MS(ESI):471.7[M+1]。
The second step is that: compound P021
Compound P021-a (0.21mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P021. The yield thereof was found to be 52.2%.
MS(ESI):441.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.45(q,2H,COCH2),2.32(s,6H,ArCH3)。
Example 22: compound P022
Figure BDA0002793720010000222
The first step is as follows: compound P022-a
At room temperature, compound P013-d (100mg,0.27mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (560mg,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (373mg,2.70mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P022-a. The yield thereof was found to be 10%.
MS(ESI):497.4[M+1]。
The second step is that: compound P022
Compound P022-a (0.01mmol, 1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P022. The yield thereof was found to be 69.5%.
MS(ESI):481.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 23: compound P023
Figure BDA0002793720010000231
The first step is as follows: compound P023-a
Compound P014-e (95mg,0.27mmol,1.00eq.) and methyl 1-bromocyclopropanecarboxylate (483mg,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (373mg,2.70mmol,10.00eq.) and reaction at 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P023-a. The yield thereof was found to be 25%.
MS(ESI):451.3[M+1]。
The second step is that: compound P023
Compound P023-a (0.04mmol,1.00eq.) is dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P023. The yield thereof was found to be 91.5%.
MS(ESI):435.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),7.20(t,J＝38.3Hz,1H,CHF2),6.77(d,J＝36.8Hz,1H,CF＝CH),2.32(s,6H,ArCH3),1.54(m,4H,CH2)。
Example 24: compound P024
Figure BDA0002793720010000232
The first step is as follows: compound P024-a
Compound P013-d (100mg,0.27mmol,1.00eq.) and tert-butyl bromoacetate (527mg,2.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (373mg,2.70mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P024-a. The yield thereof was found to be 93.8%.
MS(ESI):485.2[M+1]。
The second step is that: compound P024
Compound P024-a (0.23mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. Diluting the reaction solution by adding 4mL of dichloromethane, adding 15mL of saturated sodium bicarbonate solution, washing to be alkalescent, washing to be faintly acid by using saturated ammonium chloride solution, extracting by using dichloromethane (10mL multiplied by 3), combining organic phases, washing once by using water, washing once by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain P024. The yield thereof was found to be 95.6%.
MS(ESI):427.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.89(s,2H,OCH2CO),2.32(s,6H,ArCH3)。
Example 25: compound P025
Figure BDA0002793720010000241
The first step is as follows: compound P025-b
Compound P025-a (5.00g,25.25mmol,1.00eq.), N-bromosuccinimide (NBS) (4.587g,25.57mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (4.80g,25.25mmol,1.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to afford compound P025-b. The yield is 60 percent; MS M/s (ESI) 300.9[ M +23 ].
The second step is that: compounds P025-c
Compound P025-b (3.50g,12.63mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (5.20mL,18.94mmol,1.50eq.) and potassium fluoride (1.10g,18.94mmol,1.50eq.) were dissolved in anhydrous acetonitrile (18.00mL,5.14eqv.) at room temperature for 24 hours at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to afford compound P025-c. The yield is 42%; MS M/s (ESI) 239.2[ M +23 ].
The third step: compounds P025-d
Compound P025-c (1.10g,5.09mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (764mg,5.09mmol,1.00eq.) were reacted at room temperature with piperidine (1.40mL,3.00eqv.) in dry methanol (27.50mL,25.00eqv.) and heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to afford compound P025-d. The yield thereof was found to be 53%.
MS(ESI):347.1(M-1)。
The fourth step: compound P025-g
At room temperature, compound P025-d (0.50g,1.44mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL,14.35mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.20g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to afford compound P025-e. The yield thereof was found to be 67%.
MS(ESI):491.2[M+1]。
The fifth step: compound P025
Compound P025-e (0.25g,0.58mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 25. The yield thereof was found to be 80%.
MS(ESI):433.4[M-1]。1H-NMR(400MHz；(CDCl3)δH＝8.54(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.32(s,3H,SO2CH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 26: compound P026
Figure BDA0002793720010000251
Compound P025-d (100mg,0.29mmol,1.00eq.) and 2-bromoisopropyl isobutyrate (463 μ L,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (397mg,2.87mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P026. The yield thereof is 85%.
MS(ESI):477(M+1)。1H-NMR(400MHz；(CDCl3)δH＝8.56(d,J＝8.2Hz,2H,ArH),7.46(s,2H,ArH),7.41(d,J＝8.2Hz,2H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(m,1H,OCH),3.32(s,3H,SO2CH3),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3)。
Example 27: compound P027
Figure BDA0002793720010000252
The first step is as follows: compound P027-a
Compound P025-d (100mg,0.29mmol,1.00eq.) and tert-butyl 2-bromopropionate (477mg,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (397mg,2.87mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P027-a. The yield thereof was found to be 82.9%.
MS(ESI):477.2[M+1]。
The second step is that: compound P027
Compound P027-a (0.22mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P027. The yield thereof was found to be 92.6%.
MS(ESI):419.7[M-1]。1H NMR(400MHz，CDCl3)δH＝8.54(d，J＝8.3Hz，2H，ArH)，7.40(s，2H，ArH)，7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(q,1H,OCH),3.32(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3)。
Example 28: compound P028
Figure BDA0002793720010000261
The first step is as follows: compound P028-a
Compound P025-d (100mg,0.29mmol,1.00eq.) and ethyl-1-bromocyclobutanecarboxylic acid ester (465 μ L,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (397mg,2.87mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P028-a. The yield thereof was found to be 26%.
MS(ESI):475.2[M+1]。
The second step is that: compound P028
Compound P028-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P028. The yield thereof was found to be 92.0%.
MS(ESI):445.7[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.32(s,3H,SO2CH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3)。
Example 29: compound P029
Figure BDA0002793720010000262
The compound P025-d (100mg,0.29mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (195. mu.L, 0.86mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile at room temperature, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (397mg,2.87mmol,10.00eq.) were added and the mixture was heated to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P029. The yield thereof was found to be 82.6%.
MS(ESI):533.7[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),3.32(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 30: compound P030
Figure BDA0002793720010000271
The first step is as follows: compound P030-a
At room temperature, compound P025-d (100mg,0.29mmol,1.00eq.) and tert-butyl 2-bromobutyrate (560mg,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (397mg,2.87mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P030-a. The yield thereof was found to be 84.2%.
MS(ESI):491.5[M+1]。
The second step is that: compound P030
Compound P030-a (0.22mmol,1.00eq.) is dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P030. The yield thereof was found to be 97.2%.
MS(ESI):433.3[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 31: compound P031
Figure BDA0002793720010000272
The first step is as follows: compound P031-a
At room temperature, compound P025-d (100mg,0.29mmol,1.00eq.) and ethyl 2-bromoisovalerate (601mg,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (397mg,2.87mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P031-a. The yield thereof was found to be 79.2%.
MS(ESI):477.5[M+1]。
The second step is that: compound P031
Compound P031-a (0.20mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P031. The yield thereof was found to be 91.3%.
MS(ESI):447.7[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 32: compound P032
Figure BDA0002793720010000281
The first step is as follows: compound P032-a
Compound P025-d (100mg,0.29mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (142mg,0.86mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium iodide (5mg,0.10eq.) and potassium carbonate (397mg,2.87mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P032-a. The yield thereof was found to be 82%.
MS(ESI):477.3[M+1]。
The second step is that: compound P032
Compound P032-a (0.21mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P032. The yield thereof was found to be 81.0%.
MS(ESI):447.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝8.54(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.45(s,2H,OCH2),3.34(s,3H,SO2CH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 33: compound P033
Figure BDA0002793720010000282
The first step is as follows: compound P033-a
At room temperature, compound P025-d (100mg,0.29mmol,1.00eq.) and ethyl 3-chloropropionate (118mg,0.86mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (397mg,2.87mmol,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P033-a. The yield thereof was found to be 90.1%.
MS(ESI):449.7[M+1]。
The second step is that: compound P033
Compound P033-a (0.25mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P033. The yield thereof was found to be 81.2%.
MS(ESI):419.3[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3)。
Example 34: compound P034
Figure BDA0002793720010000291
The first step is as follows: compound P034-a
At room temperature, compound P025-d (100mg,0.29mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (600mg,2.87mmol,10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, potassium carbonate (397mg,2.87mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P034-a. The yield thereof was found to be 17%.
MS(ESI):475.4[M+1]
The second step is that: compound P034
Compound P034-a (0.02mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P034. The yield thereof was found to be 90.5%.
MS(ESI):459.2[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 35: compound P035
Figure BDA0002793720010000292
The first step is as follows: compound P035-a
At room temperature, compound P025-d (100mg,0.29mmol,1.00eq.) and methyl 1-bromocyclohexanecarboxylate (636mg,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (397mg,2.87mmol,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P035-a. The yield thereof was found to be 16%.
MS(ESI):489.3[M+1]。
The second step is that: compound P035
Compound P035-a (0.02mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P035. The yield thereof was found to be 95.5%.
MS(ESI):473.2[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3),1.94-1.50(m,10H,CH2)。
Example 36: compound P036
Figure BDA0002793720010000301
The first step is as follows: compound P036-a
Compound P025-d (100mg,0.29mmol,1.00eq.) and tert-butyl bromoacetate (560mg,2.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (397mg,2.87mmol,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P036-a. The yield thereof was found to be 50.9%.
MS(ESI):463.2[M+1]。
The second step is that: compound P036
Compound P036-a (0.12mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL,17.24eqv.) at room temperature and reacted for 1.5 h at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, the solution is washed once by water, the solution is washed once by saturated saline solution, anhydrous sodium sulfate is dried, filtered and concentrated under reduced pressure to obtain P036. The yield thereof was found to be 91.6%.
MS(ESI):405.4[M-1]。1H NMR(400MHz,CDCl3)δH＝8.54(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.89(s,2H,OCH2CO),3.34(s,3H,SO2CH3),2.32(s,6H,ArCH3)。
Example 37: compound P037
Figure BDA0002793720010000302
The first step is as follows: compound P037-b
Compound P037-a (5.00g,33.29mmol,1.00eq.), N-bromosuccinimide (NBS) (6.04g,33.96mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (6.33g,33.29mmol,1.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P037-b. The yield is 66 percent; MS M/s (ESI) 252.4[ M +23 ].
The second step is that: compound P037-c
Compound P037-b (3.50g,15.28mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (6.30mL,22.92mmol,1.50eq.) and potassium fluoride (1.33g,22.92mmol,1.50eq.) were dissolved in anhydrous acetonitrile (18.00mL,5.14eqv.) at room temperature for 24 hours at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P037-c. The yield is 32 percent; MS M/s (ESI) 191.2[ M +23 ].
The third step: compound P037-d
Compound P037-c (1.50g,8.92mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (1.34g,8.92mmol,1.00eq.) were reacted at room temperature with piperidine (1.40mL,3.00eqv.) in dry methanol (30.00mL,20.00eqv.) under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P037-d. The yield thereof was found to be 43%.
MS(ESI):299.1(M-1)。
The fourth step: compound P037-e
At room temperature, compound P037-d (500mg,1.66mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL,16.65mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.30g,10.00eq.), and heated to 70 ℃ under nitrogen atmosphere for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P037-e. The yield thereof is 60%.
MS(ESI):443.2[M+1]。
The fifth step: compound P037
Compound P037-e (250mg,0.56mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound P037. The yield thereof was found to be 90%.
MS(ESI):385.4[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.70(s,3H,OCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 38: compound P038
Figure BDA0002793720010000311
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and 2-bromoisopropyl isobutyrate (537 μ L,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (460mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen for reaction for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P038. The yield thereof was found to be 83%.
MS(ESI):429(M+1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d J＝8.2Hz，2H，ArH)，7.46(s，2H，ArH)，7.41(d,J＝8.2Hz,2H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(m,1H,OCH),3.70(s,3H,OCH3),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3)。
Example 39: compound P039
Figure BDA0002793720010000321
The first step is as follows: compound P039-a
Compound P037-d (100mg,0.33mmol,1.00eq.) and tert-butyl 2-bromopropionate (553mg,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (460mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P039-a. The yield thereof was found to be 80.9%.
MS(ESI):429.2[M+1]。
The second step is that: compound P039
Compound P039-a (0.24mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P039. The yield thereof was found to be 94.6%.
MS(ESI):371.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(q,1H,OCH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3)。
Example 40: compound P040
Figure BDA0002793720010000322
The first step is as follows: compound P040-a
Compound P037-d (100mg,0.33mmol,1.00eq.) and ethyl-1-bromocyclobutane carboxylate (539 μ L,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (460mg,10.00eq.) and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P040-a. The yield thereof was found to be 22%.
MS(ESI):427.2[M+1]。
The second step is that: compound P040
Compound P040-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature, and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P040. The yield thereof was found to be 95.0%.
MS(ESI):397.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.70(s,3H,OCH3),2,85-2.75(m,2H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3)。
Example 41: compound P041
Figure BDA0002793720010000331
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (225 μ L,1.00mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (460mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P041. The yield thereof was found to be 81.6%.
MS(ESI):485.6[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 42: compound P042
Figure BDA0002793720010000332
The first step is as follows: compound P042-a
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and tert-butyl 2-bromobutyrate (650mg,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, followed by addition of potassium carbonate (460mg,10.00eq.), and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P042-a. The yield thereof was found to be 87.2%.
MS(ESI):443.5[M+1]。
The second step is that: compound P042
Compound P042-a (0.26mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P042. The yield thereof was found to be 93.2%.
MS(ESI):385.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 43: compound P043
Figure BDA0002793720010000341
The first step is as follows: compound P043-a
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and ethyl 2-bromoisovalerate (696mg,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (460mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P043-a. The yield thereof was found to be 75.2%.
MS(ESI):429.5[M+1]。
The second step is that: compound P043
Compound P043-a (0.22mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P043. The yield thereof was found to be 90.3%.
MS(ESI):399.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 44: compound P044
Figure BDA0002793720010000342
The first step is as follows: compound P044-a
Compound P037-d (100mg,0.33mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (165mg,1.00mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium iodide (5mg,0.10eq.) and potassium carbonate (460mg,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P044-a. The yield thereof was found to be 87%.
MS(ESI):429.3[M+1]。
The second step is that: compound P044
Compound P044-a (0.26mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P044. The yield thereof was found to be 88.0%.
MS(ESI):399.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d，J＝7.2Hz，2H，ArH)，6.77(d，J＝36.8Hz，1H，CF＝CH)，4.45(s，2H，OCH2)，2.28(s，6H，ArCH3)，1.55(s，6H,CH3)。
Example 45: compound P045
Figure BDA0002793720010000351
The first step is as follows: compound P045-a
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and ethyl 3-chloropropionate (137mg,1.00mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (460mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P045-a. The yield thereof was found to be 91.5%.
MS(ESI):401.7[M+1]。
The second step is that: compound P045
Compound P045-a (0.27mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P045. The yield thereof was found to be 83.2%.
MS(ESI):371.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),3.70(s,3H,OCH3),2.32(s,6H,ArCH3)。
Example 46: compound P046
Figure BDA0002793720010000352
The first step is as follows: compound P046-a
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (690mg,3.33mmol,10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, followed by addition of potassium carbonate (460mg,10.00eq.), and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P046-a. The yield thereof was found to be 19%.
MS(ESI):427.4[M+1]。
The second step is that: compound P046
Compound P046-a (0.04mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P046. The yield thereof was found to be 90.0%.
MS(ESI):411.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 47: compound P047
Figure BDA0002793720010000361
The first step is as follows: compound P047-a
At room temperature, compound P037-d (100mg,0.33mmol,1.00eq.) and methyl 1-bromocyclohexanecarboxylate (737mg,3.33mmol,10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, followed by addition of potassium carbonate (460mg,10.00eq.), and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P047-a. The yield thereof was found to be 17%.
MS(ESI):441.3[M+1]。
The second step is that: compound P047
Compound P047-a (0.03mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), and the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P047. The yield thereof was found to be 90.5%.
MS(ESI):425.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),3.70(s,3H,OCH3),2.32(s,6H,ArCH3),1.94-1.50(m,10H,CH2)。
Example 48: compound P048
Figure BDA0002793720010000362
The first step is as follows: compound P048-a
Compound P037-d (100mg,0.33mmol,1.00eq.) and tert-butyl bromoacetate (650mg,3.33mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (460mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P0P 48-a. The yield thereof was found to be 84.9%.
MS(ESI):415.2[M+1]。
The second step is that: compound P048
Compound P048-a (0.25mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P048. The yield thereof was found to be 90.6%.
MS(ESI):357.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.89(s,2H,OCH2CO),3.70(s,3H,OCH3),2.32(s,6H,ArCH3)。
Example 49: compound P049
Figure BDA0002793720010000371
The first step is as follows: compound P049-b
Compound P049-a (5.00g,41.61mmol,1.00eq.), N-bromosuccinimide (NBS) (7.56g,42.45mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (7.92g,41.61mmol,1.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P049-b. The yield is 62 percent; MS M/s (ESI) 222.4[ M +23 ].
The second step is that: compound P049-c
Compound P049-b (3.00g,15.08mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (6.20mL,22.61mmol,1.50eq.) and potassium fluoride (1.31g,22.61mmol,1.50eq.) were dissolved in anhydrous acetonitrile (18.00mL,6.00eqv.) at room temperature for 24 hours at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P049-c. The yield is 30 percent; MS M/s (ESI) 161.2[ M +23 ].
The third step: compound P049-d
Compound P049-c (1.00g,7.24mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (1.09g,7.24mmol,1.00eq.) were reacted at room temperature with piperidine (2.00mL,3.00eqv.) in dry methanol (20.00mL,20.00eqv.) under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P049-d. The yield thereof was found to be 40%.
MS(ESI):269.1(M-1)。
The fourth step: compound P049-e
At room temperature, compound P049-d (500mg,1.85mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (3.50mL,18.50mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.56g,10.00eq.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P049-e. The yield thereof is 60%.
MS(ESI):413.2[M+1]。
The fifth step: compound P049
Compound P049-e (250mg,0.61mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P049. The yield thereof was found to be 92%.
MS(ESI):355.4[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 50: compound P050
Figure BDA0002793720010000381
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and isopropyl 2-bromoisobutyrate (734mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P050. The yield thereof was found to be 80%.
MS(ESI):399.4(M+1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,2H,ArH),7.46(s,2H,ArH),7.40(m,3H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(q,1H,OCH),2.17(s,6H,ArCH3),1.39(s,6H,CH3),1.26(d,6H,CH3)。
Example 51: compound P051
Figure BDA0002793720010000382
The first step is as follows: compound P051-a
Compound P049-d (100mg,0.37mmol,1.00eq.) and tert-butyl 2-bromopropionate (774mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (511mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P051-a. The yield thereof was found to be 81.9%.
MS(ESI):399.2[M+1]。
The second step is that: compound P051
Compound P051-a (0.27mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, the solution is washed once by water, the solution is washed once by saturated saline solution, anhydrous sodium sulfate is dried, and the solution is filtered and concentrated under reduced pressure to obtain P051. The yield thereof was found to be 97.6%.
MS(ESI):341.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(q,1H,OCH),2.32(s,6H,ArCH3),1.56(d,3H,CH3)。
Example 52: compound P052
Figure BDA0002793720010000391
The first step is as follows: compound P052-a
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and ethyl-1-bromocyclobutane carboxylate (767mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P052-a. The yield thereof was found to be 20%.
MS(ESI):397.2[M+1]。
The second step is that: compound P052
Compound P052-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P052. The yield thereof was found to be 94.0%.
MS(ESI):367.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3),2.10-1.93(m,2H,CH2),1.56(d,3H,CH3)。
Example 53: compound P053
Figure BDA0002793720010000392
The compound P049-d (100mg,0.37mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (817mg,1.00mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (511mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P053. The yield thereof was found to be 86.6%.
MS(ESI):455.5[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 54: compound P054
Figure BDA0002793720010000401
The first step is as follows: compound P054-a
At room temperature, the compound P049-d (100mg,0.37mmol,1.00eq.) and tert-butyl 2-bromobutyrate (722mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P054-a. The yield thereof was found to be 84.2%.
MS(ESI):413.5[M+1]。
The second step is that: compound P054
Compound P054-a (0.28mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, water is washed once, saturated salt solution is used for washing once, anhydrous sodium sulfate is dried, and the filtration and the concentration under reduced pressure are carried out to obtain P054. The yield thereof was found to be 86.2%.
MS(ESI):355.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 55: compound P055
Figure BDA0002793720010000402
The first step is as follows: compound P055-a
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and ethyl 2-bromoisovalerate (774mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P055-a. The yield thereof was found to be 70.0%.
MS(ESI):399.5[M+1]。
The second step is that: compound P055
Compound P055-a (0.23mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P055. The yield thereof was found to be 80.8%.
MS(ESI):369.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 56: compound P056
Figure BDA0002793720010000411
The first step is as follows: compound P056-a
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (183mg,1.11mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.10eq.) and potassium carbonate (511mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P056-a. The yield thereof was found to be 89%.
MS(ESI):399.3[M+1]。
The second step is that: compound P056
Compound P056-a (0.31mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P056. The yield thereof was found to be 86%.
MS(ESI):369.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.45(s,2H,OCH2),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 57: compound P057
Figure BDA0002793720010000412
The first step is as follows: compound P057-a
At room temperature, the compound P049-d (100mg,0.37mmol,1.00eq.) and ethyl 3-chloropropionate (152mg,1.11mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (511mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P057-a. The yield thereof was found to be 90.5%.
MS(ESI):471.7[M+1]。
The second step is that: compound P057
Compound P057-a (0.31mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P057. The yield thereof was found to be 83.0%.
MS(ESI):341.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.32(s,6H,ArCH3)。
Example 58: compound P058
Figure BDA0002793720010000421
The first step is as follows: compound P058-a
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (766mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P058-a. The yield thereof was found to be 20%.
MS(ESI):397.4[M+1]。
The second step is that: compound P058
Compound P058-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P058. The yield thereof was found to be 86.0%.
MS(ESI):381.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 59: compound P059
Figure BDA0002793720010000422
The first step is as follows: compound P059-a
At room temperature, compound P049-d (100mg,0.37mmol,1.00eq.) and methyl 1-bromocyclopropanecarboxylate (662mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (511mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P059-a. The yield thereof was found to be 35%.
MS(ESI):369.3[M+1]。
The second step is that: compound P059
Compound P059-a (0.11mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P059. The yield thereof was found to be 90.0%.
MS(ESI):353.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.39(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.32(s,6H,ArCH3),1.54(m,4H,CH2)。
Example 60: compound P060
Figure BDA0002793720010000431
The first step is as follows: compound P060-a
Compound P049-d (100mg,0.37mmol,1.00eq.) and tert-butyl bromoacetate (722mg,3.70mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (511mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P060-a. The yield thereof was found to be 85.9%.
MS(ESI):385.2[M+1]。
The second step is that: compound P060
Compound P060-a (0.30mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P060. The yield thereof was found to be 90.0%.
MS(ESI):327.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.40(s,2H,ArH),7.30(m,3H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.89(s,2H,OCH2CO),2.32(s,6H,ArCH3)。
Example 61: compound P061
Figure BDA0002793720010000432
The first step is as follows: compound P061-b
Compound P061-a (4.00g,21.95mmol,1.00eq.), N-bromosuccinimide (NBS) (4.00g,22.39mmol,1.02eq.) and P-toluenesulfonic acid monohydrate (4.17g,21.95mmol,1.00eq.) were dissolved in anhydrous acetonitrile (12.00mL,3.00eqv.) at room temperature for 24 hours at 50 ℃. The reaction solution was concentrated under reduced pressure, mixed with 40mL of saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P061-b. The yield is 69%; MS M/s (ESI) 260.9[ M-1 ].
The second step is that: compound P061-c
Compound P061-b (3.50g,13.40mmol,1.00eq.), tetrabutylammonium fluoride (TBAF) (5.60mL,20.10mmol,1.50eq.) and potassium fluoride (1.17g,20.10mmol,1.50eq.) were dissolved in anhydrous acetonitrile (14.00mL,4.00eqv.) at room temperature for 24 hours at 80 ℃. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate 95:5) to give compound P061-c. The yield is 30 percent; MS M/s (ESI) 199.2[ M-1 ].
The third step: compound P061-d
Compound P061-c (2.00g,9.99mmol,1.00eq.) and 3, 5-dimethyl-4-hydroxybenzaldehyde (1.50g,9.99mmol,1.00eq.) were reacted at room temperature with piperidine (2.80mL,3.00eqv.) in dry methanol (50.00mL,25.00eqv.) under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P061-d. The yield thereof was found to be 48%.
MS(ESI):331.1(M-1)。
The fourth step: compound P061-e
At room temperature, compound P061-d (0.50g,1.50mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (3.00mL,15.04mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.08g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P061-e. The yield thereof is 60%.
MS(ESI):473.2[M-1]。
The fifth step: compound P061
Compound P061-e (200mg,0.42mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the mixture is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, water is washed once, saturated salt water is washed once, anhydrous sodium sulfate is dried, and the mixture is filtered and concentrated under reduced pressure to obtain P061. The yield thereof was found to be 88%.
MS(ESI):417.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 62: compound P062
Figure BDA0002793720010000441
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and 2-bromoisopropyl isobutyrate (629mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (416mg,3.01mmol,10.00eqv.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P062. The yield thereof was found to be 80%.
MS(ESI):459(M-1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,1H,ArH),7.46(s,2H,ArH),7.41(d,J＝8.2Hz,1H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),6.75(s,1H,ArH),4.99(m,1H,OCH),2.56(s,3H,SCH3)，2.17(s，6H，ArCH3)，1.39(s，6H，OC(CH3)2)，1.26(d，6H，CH3)。
Example 63: compound P063
Figure BDA0002793720010000451
The first step is as follows: compound P063-a
Compound P061-d (100mg,0.30mmol,1.00eq.) and tert-butyl 2-bromopropionate (630mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (416mg,10.00eqv.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to afford compound P063-a. The yield thereof was found to be 80.5%.
MS(ESI):459.2[M-1]。
The second step is that: compound P063
Compound P063-a (0.22mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL,17.24eqv.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then saturated ammonium chloride solution is used for washing to be faintly acid, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, water is washed once, saturated salt water is used for washing once, anhydrous sodium sulfate is used for drying, filtering and reduced pressure concentration are carried out, and P063 is obtained. The yield thereof was found to be 92.6%.
MS(ESI):403.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.65(q,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.56(d,3H,CH3)。
Example 64: compound P064
Figure BDA0002793720010000452
The first step is as follows: compound P064-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and ethyl-1-bromocyclobutane carboxylate (624mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (416mg,10.00eqv.) was added, and the mixture was heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P064-a. The yield thereof was found to be 18%.
MS(ESI):457.2[M-1]。
The second step is that: compound P064
Compound P064-a (0.03mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P064. The yield thereof was found to be 95.0%.
MS(ESI):429.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),2.55(s,3H,SCH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,6H,ArCH3)。
Example 65: compound P065
Figure BDA0002793720010000461
The first step is as follows: compound P065
Compound P061-d (100mg,0.30mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (199mg,0.90mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile at room temperature, followed by addition of potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (416mg,10.00eqv.), and reaction was carried out by heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P065. The yield thereof was found to be 93.2%.
MS(ESI):515.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 66: compound P066
Figure BDA0002793720010000462
The first step is as follows: compound P066-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and tert-butyl 2-bromobutyrate (588mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (416mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P066-a. The yield thereof was found to be 88.2%.
MS(ESI):473.5[M-1]。
The second step is that: compound P066
Compound P066-a (0.24mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, the solution is washed once by water, the solution is washed once by saturated saline solution, anhydrous sodium sulfate is dried, and the filtration and the concentration under reduced pressure are carried out to obtain P066. The yield thereof was found to be 91.2%.
MS(ESI):417.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.65(t,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 67: compound P067
Figure BDA0002793720010000471
The first step is as follows: compound P067-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and ethyl 2-bromoisovalerate (630mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (416mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P067-a. The yield thereof was found to be 83.2%.
MS(ESI):459.5[M-1]。
The second step is that: compound P067
Compound P067-a (0.22mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P067. The yield thereof was found to be 92.3%.
MS(ESI):431.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.63(d,1H,OCH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 68: compound P068
Figure BDA0002793720010000472
The first step is as follows: compound P068-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (149mg,0.90mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium iodide (5mg,0.10eq.) was added, potassium carbonate (416mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P068-a. The yield thereof was found to be 84%.
MS(ESI):459.3[M-1]。
The second step is that: compound P068
Compound P068-a (0.23mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P068. The yield thereof was found to be 79.0%.
MS(ESI):431.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,1H,ArH),7.38(s,2H,ArH),7.30(d,J＝7.2Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),2.28(s,6H,ArCH3),1.55(s,6H,CH3)。
Example 69: compound P069
Figure BDA0002793720010000481
The first step is as follows: compound P069-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and ethyl 3-chloropropionate (123mg,0.90mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (416mg,10.00eqv.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P069-a. The yield thereof was found to be 81.6%.
MS(ESI):431.7[M-1]。
The second step is that: compound P069
Compound P069-a (0.22mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P069. The yield thereof was found to be 86.2%.
MS(ESI):403.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3),2.32(s,6H,ArCH3)。
Example 70: compound P070
Figure BDA0002793720010000482
The first step is as follows: compound P070-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (624mg,3.01mmol,10.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile, potassium carbonate (416mg,10.00eqv.) was added, and the mixture was heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P070-a. The yield thereof was found to be 29%.
MS(ESI):457.4[M-1]。
The second step is that: compound P070
Compound P070-a (0.06mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P070. The yield thereof was found to be 90.5%.
MS(ESI):443.2[M-1]。1H NMR(400MHz，CDCl3)δH＝7.84(d，J＝8.3Hz，1H，ArH)，7.40(s，2H，ArH)，7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 71: compound P071
Figure BDA0002793720010000491
The first step is as follows: compound P071-a
At room temperature, compound P061-d (100mg,0.30mmol,1.00eq.) and methyl 1-bromocyclohexanecarboxylate (666mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (416mg,10.00eqv.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P071-a. The yield thereof was found to be 19%.
MS(ESI):471.3[M-1]。
The second step is that: compound P071
Compound P071-a (0.03mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction solution was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P071. The yield thereof was found to be 90.0%.
MS(ESI):457.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.39(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),2.55(s,3H,SCH3),2.32(s,6H,ArCH3),1.94-1.50(m,10H,CH2)。
Example 72: compound P072
Figure BDA0002793720010000492
The first step is as follows: compound P072-a
Compound P061-d (100mg,0.30mmol,1.00eq.) and tert-butyl bromoacetate (588mg,3.01mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (416mg,10.00eqv.) and reaction by heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P072-a. The yield thereof was found to be 90.9%.
MS(ESI):445.2[M-1]。
The second step is that: compound P072
Compound P072-a (0.27mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL,17.24eqv.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, the solution is washed once by water, the solution is washed once by saturated saline solution, anhydrous sodium sulfate is dried, and the solution is filtered and concentrated under reduced pressure to obtain P072. The yield thereof was found to be 90.6%.
MS(ESI):389.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,1H,ArH),7.40(s,2H,ArH),7.30(d,J＝8.3Hz,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.75(s,1H,ArH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3),2.32(s,6H,ArCH3)。
Example 73: compound P073
Figure BDA0002793720010000501
The first step is as follows: compound P073-a
Compound P001-c (2.50g,13.57mmol,1.00eq.) and 3-methyl-4-hydroxybenzaldehyde (1.85g,13.57mmol,1.00eq.) were reacted at room temperature with piperidine (3.30mL,3.00eqv.) in dry methanol (55.00mL,25.11eqv.) and heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P073-a. The yield thereof was found to be 42%.
MS(ESI):301.1(M-1)。
The second step is that: compound P073-b
At room temperature, compound P073-a (0.50g,1.29mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (2.40mL,12.87mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (1.78g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P073-b. The yield thereof is 60%.
MS(ESI):445.2[M+1]。
The third step: compound P073
Compound P073-a (100mg,0.22mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL,17.24eqv.) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution is diluted by adding 4mL of dichloromethane, then 15mL of saturated sodium bicarbonate solution is added to be washed to be alkalescent, then the solution is washed to be faintly acid by saturated ammonium chloride solution, dichloromethane is used for extraction (10mL multiplied by 3), organic phases are combined, the solution is washed once by water, the solution is washed once by saturated saline solution, anhydrous sodium sulfate is dried, and the filtration and the concentration under reduced pressure are carried out to obtain P073. The yield thereof was found to be 80%.
MS(ESI):387.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.38(s,1H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.54(s,3H,SCH3),2.28(s,3H,ArCH3),1.55(s,6H,CH3)。
Example 74: compound P074
Figure BDA0002793720010000502
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and isopropyl 2-bromoisobutyrate (534. mu.L, 3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P074. The yield thereof was found to be 80%.
MS(ESI):431(M+1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,2H,ArH),7.72(d,J＝8.2Hz,1H,ArH),7.46(s,1H,ArH),7.41(d,J＝8.2Hz,2H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.99(m,1H,OCH),2.56(s,3H,SCH3),2.17(s,3H,ArCH3),1.39(s,6H,C(CH3)2),1.26(d,6H,CH3)。
Example 75: compound P075
Figure BDA0002793720010000511
The first step is as follows: compound P075-a
Compound P073-a (100mg,0.33mmol,1.00eq.) and tert-butyl 2-bromopropionate (550 μ L,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile (3.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (457mg,10.00eq.), and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P075-a. The yield thereof was found to be 80.0%.
MS(ESI):431.2[M+1]。
The second step is that: compound P075
Compound P075-a (0.24mmol,1.00eq.) is dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P0P 75. The yield thereof was found to be 96.6%.
MS(ESI):373.7[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(q,1H,OCH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.56(d,3H,CH3)。
Example 76: compound P076
Figure BDA0002793720010000512
The first step is as follows: compound P076-a
Compound P073-a (100mg,0.33mmol,1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (536 μ L,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (457mg,10.00eq.) and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P076-a. The yield thereof was found to be 20%.
MS(ESI):429.2[M+1]。
The second step is that: compound P076
Compound P076-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P076. The yield thereof was found to be 92.0%.
MS(ESI):399.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.55(s,3H,SCH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2),2.32(s,3H,ArCH3)。
Example 77: compound P077
Figure BDA0002793720010000521
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (224. mu.L, 0.99mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.032mmol,0.10eq.) and potassium carbonate (457mg,10.00eq.) were added and heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P077. The yield thereof was found to be 80.2%.
MS(ESI):487.3[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝7.3,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.92(m,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 78: compound P078
Figure BDA0002793720010000522
The first step is as follows: compound P078-a
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and tert-butyl 2-bromobutyrate (646mg,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P078-a. The yield thereof was found to be 83.2%.
MS(ESI):445.5[M+1]。
The second step is that: compound P078
Compound P078-a (0.25mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted at room temperature for 1.5 hours. The reaction solution was diluted with 4mL of dichloromethane, then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P078. The yield thereof was found to be 90.0%.
MS(ESI):387.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(t,1H,OCH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 79: compound P079
Figure BDA0002793720010000531
The first step is as follows: compound P079-a
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and ethyl 2-bromoisovalerate (693mg,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P079-a. The yield thereof was found to be 89.0%.
MS(ESI):431.5[M+1]。
The second step is that: compound P079
Compound P079-a (0.27mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P079. The yield thereof was found to be 95.3%.
MS(ESI):401.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.63(d,1H,OCH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 80: compound P080
Figure BDA0002793720010000532
The first step is as follows: compound P080-a
Compound P073-a (100mg,0.33mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (163mg,0.99mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, and potassium iodide (5mg,0.10eq.) and potassium carbonate (457mg,10.00eq.) were added, followed by heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P080-a. The yield thereof was found to be 83%.
MS(ESI):431.3[M+1]。
The second step is that: compound P080
Compound P080-a (0.25mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P080. The yield thereof was found to be 80.0%.
MS(ESI):401.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.38(s,1H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),2.28(s,3H,ArCH3),1.55(s,6H,CH3)。
Example 81: compound P081
Figure BDA0002793720010000541
The first step is as follows: compound P081-a
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and ethyl 3-chloropropionate (136mg,0.99mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.10eq.) and potassium carbonate (457mg,10.00eq.) were added, followed by heating to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to give compound P081-a. The yield thereof was found to be 89.0%.
MS(ESI):403.7[M+1]。
The second step is that: compound P081
Compound P081-a (0.27mmol,1.00eq.) is dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P081. The yield thereof was found to be 88%.
MS(ESI):373.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3),2.32(s,3H,ArCH3)。
Example 82: compound P082
Figure BDA0002793720010000542
The first step is as follows: compound P082-a
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (686mg,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P082-a. The yield thereof was found to be 29%.
MS(ESI):429.4[M+1]。
The second step is that: compound P082
Compound P082-a (0.08mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature, and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P082. The yield thereof was found to be 90.5%.
MS(ESI):413.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.96-1.56(m,8H,CH2)。
Example 83: compound P083
Figure BDA0002793720010000551
The first step is as follows: compound P083-a
At room temperature, compound P073-a (100mg,0.33mmol,1.00eq.) and methyl 1-bromocyclohexanecarboxylate (732mg,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P083-a. The yield thereof was found to be 18%.
MS(ESI):443.3[M+1]。
The second step is that: compound P083
Compound P083-a (0.04mmol,1.00eq.) is dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P083. The yield thereof was found to be 80.9%.
MS(ESI):427.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.39(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.55(s,3H,SCH3),2.32(s,3H,ArCH3),1.94-1.50(m,10H,CH2)。
Example 84: compound P084
Figure BDA0002793720010000552
The first step is as follows: compound P084-a
Compound P073-a (100mg,0.33mmol,1.00eq.) and tert-butyl bromoacetate (648mg,3.31mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (457mg,10.00eq.) and reaction at 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P084-a. The yield thereof was found to be 94%.
MS(ESI):417.2[M+1]。
The second step is that: compound P084
Compound P084-a (0.29mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P084. The yield thereof was found to be 95.0%.
MS(ESI):359.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,1H,ArH),7.40(s,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3),2.32(s,3H,ArCH3)。
Example 85: compound P085
Figure BDA0002793720010000561
The first step is as follows: compound P085-a
At room temperature, compound P001-c (2.50g,13.57mmol,1.00eq.) and P-hydroxybenzaldehyde (1.66g,13.57mmol,1.00eq.) were reacted with piperidine (3.80mL,3.00eqv.) in anhydrous methanol (55.00mL,25.11eqv.), and heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P085-a. The yield thereof was found to be 52%.
MS(ESI):287.1(M-1)。
The second step is that: compound P085-b
At room temperature, compound P085-a (0.50g,1.73mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (3.30mL,17.34mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.40g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P085-b. The yield thereof was found to be 65%.
MS(ESI):431.2[M+1]。
The third step: compound P085
Compound P085-b (100mg,0.23mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P085. The yield thereof was found to be 90%.
MS(ESI):373.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.38(d,J＝8.2Hz,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.54(s,3H,SCH3),1.55(s,6H,CH3)。
Example 86: compound P086
Figure BDA0002793720010000571
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and isopropyl 2-bromoisobutyrate (560 μ L,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (457mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen for reaction for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P086. The yield thereof was found to be 80%.
MS(ESI):417(M+1)。1H-NMR(400MHz；(CDCl3)δH＝7.79(d,J＝8.2Hz,2H,ArH),7.72(d,J＝8.2Hz,2H,ArH),7.46(d,J＝8.2Hz,2H,ArH),7.41(d,J＝8.2Hz,2H,ArH),6.84(d,J＝38.4Hz,1H,CF＝CH),4.99(m,1H,OCH),2.56(s,3H,SCH3),1.39(s,6H,C(CH3)2),1.26(d,6H,CH3)。
Example 87: compound P087
Figure BDA0002793720010000572
The first step is as follows: compound P087-a
Compound P085-a (100mg,0.35mmol,1.00eq.) and tert-butyl 2-bromopropionate (576 μ L,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile (3.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P087-a. The yield thereof was found to be 80.0%.
MS(ESI):417.2[M+1]。
The second step is that: compound P087
Compound P087-a (0.25mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P087. The yield thereof was found to be 90.6%.
MS(ESI):359.7[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(q,1H,OCH),2.55(s,3H,SCH3),1.56(d,3H,CH3)。
Example 88: compound P088
Figure BDA0002793720010000581
The first step is as follows: compound P088-a
Compound P085-a (100mg,0.35mmol,1.00eq.) and ethyl-1-bromocyclobutanecarboxylate (562 μ L,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P088-a. The yield thereof was found to be 30%.
MS(ESI):415.2[M+1]。
The second step is that: compound P088
Compound P088-a (0.09mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound P088. The yield thereof was found to be 95.0%.
MS(ESI):385.7[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.55(s,3H,SCH3),2,85-2.75(m,4H,CH2),2.52-2.62(m,2H,CH2)。
Example 89: compound P089
Figure BDA0002793720010000582
Compound P085-a (100mg,0.35mmol,1.00eq.) and isobutyl 5-chloro-2, 2-dimethylpentanoate (235 μ L,1.04mmol,3.00eq.) were dissolved in 6.00mL of anhydrous acetonitrile at room temperature, followed by addition of potassium iodide (5mg,0.10eq.) and potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P089. The yield thereof was found to be 82%.
MS(ESI):473.3[M+1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,2H,J＝8.2Hz,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,2H,OCH2),4.29(d,2H,OCH2),2.55(s,3H,SCH3),1.92(q,1H,CH),1.85(m,4H,CH2),1.32(s,6H,CH3),1.02(d,6H,CH3)。
Example 90: compound P090
Figure BDA0002793720010000591
The first step is as follows: compound P090-a
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and tert-butyl 2-bromobutyrate (677mg,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, followed by addition of potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P090-a. The yield thereof was found to be 83%.
MS(ESI):431.5[M+1]。
The second step is that: compound P090
Compound P090-a (0.27mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with a saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P090. The yield thereof was found to be 90.0%.
MS(ESI):373.3[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.65(t,1H,OCH),2.55(s,3H,SCH3),1.83(m,2H,CH2),1.56(d,3H,CH3)。
Example 91: compound P091
Figure BDA0002793720010000592
The first step is as follows: compound P091-a
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and ethyl 2-bromoisovalerate (726mg,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (480mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen protection for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P091-a. The yield thereof was found to be 85.0%.
MS(ESI):417.5[M+1]。
The second step is that: compound P091
Compound P091-a (0.28mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of saturated ammonium chloride solution, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P091. The yield thereof was found to be 90.0%.
MS(ESI):387.7[M-1]。1H NMR(400MHz，CDCl3)δH＝7.84(d，J＝8.3Hz，2H，ArH)，7.82(d，J＝8.2Hz，2H，ArH),7.40(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),4.63(d,1H,OCH),2.55(s,3H,SCH3),1.65(m,1H,CH),1.10(d,6H,CH3)。
Example 92: compound P092
Figure BDA0002793720010000601
The first step is as follows: compound P092-a
Compound P085-a (100mg,0.35mmol,1.00eq.) and ethyl 3-chloro-2, 2-dimethylpropionate (172mg,1.04mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL at room temperature, followed by addition of potassium iodide (5mg,0.10eq.) and potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P092-a. The yield thereof was found to be 86%.
MS(ESI):417.3[M+1]。
The second step is that: compound P092
Compound P092-a (0.28mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P092. The yield thereof was found to be 80.0%.
MS(ESI):387.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.38(d,J＝8.2Hz,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.45(s,2H,OCH2),2.54(s,3H,SCH3),1.55(s,6H,CH3)。
Example 93: compound P093
Figure BDA0002793720010000602
The first step is as follows: compound P093-a
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and ethyl 3-chloropropionate (143mg,1.04mmol,3.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, and potassium iodide (5mg,0.10eq.) and potassium carbonate (480mg,10.00eq.) were added, followed by heating to 70 ℃ under nitrogen for 48 hours. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P093-a. The yield thereof was found to be 80.0%.
MS(ESI):389.7[M+1]。
The second step is that: compound P093
Compound P093-a (0.27mmol,1.00eq.) was dissolved in 1.00mL of 10% sodium hydroxide solution and 1.00mL of tetrahydrofuran at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P093. The yield thereof was found to be 89%.
MS(ESI):359.3[M-1]。1H NMR(400MHz，CDCl3)δH＝7.84(d，J＝7.3，2H，ArH)，7.82(d，J＝8.2Hz，2H，ArH),7.40(s,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.65(t,2H,OCH2),4.45(t,2H,COCH2),2.55(s,3H,SCH3)。
Example 94: compound P094
Figure BDA0002793720010000611
The first step is as follows: compound P094-a
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and methyl 1-bromocyclopentanecarboxylate (719mg,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, followed by addition of potassium carbonate (480mg,10.00eq.), and heating to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P094-a. The yield thereof was found to be 30%.
MS(ESI):415.4[M+1]。
The second step is that: compound P094
Compound P094-a (0.09mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P094. The yield thereof was found to be 90.0%.
MS(ESI):399.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,J＝8.2Hz,1H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.55(s,3H,SCH3),1.96-1.56(m,8H,CH2)。
Example 95: compound P095
Figure BDA0002793720010000612
The first step is as follows: compound P095-a
At room temperature, compound P085-a (100mg,0.35mmol,1.00eq.) and methyl 1-bromocyclohexanecarboxylate (768mg,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile 6.00mL, potassium carbonate (480mg,10.00eq.) was added, and the mixture was heated to 70 ℃ under nitrogen for 4 days. The reaction solution was concentrated under reduced pressure, diluted with 20mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using preparative chromatography plates (petroleum ether: dichloromethane ═ 1:10) to afford compound P095-a. The yield thereof was found to be 20%.
MS(ESI):387.3[M+1]。
The second step is that: compound P095
Compound P095-a (0.05mmol,1.00eq.) was dissolved in 10% sodium hydroxide solution 1.00mL and tetrahydrofuran 1.00mL at room temperature and reacted for 3 hours at room temperature. The reaction mixture was added with 30mL of a saturated solution of ammonium chloride, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P095. The yield thereof was found to be 80.0%.
MS(ESI):371.2[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.39(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),2.55(s,3H,SCH3),1.55(m,4H,CH2)。
Example 96: compound P096
Figure BDA0002793720010000621
The first step is as follows: compound P096-a
Compound P085-a (100mg,0.35mmol,1.00eq.) and tert-butyl bromoacetate (677mg,3.47mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.) at room temperature, followed by addition of potassium carbonate (480mg,10.00eq.) and heating to 70 ℃ under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:10) to give compound P096-a. The yield thereof was found to be 94%.
MS(ESI):403.2[M+1]。
The second step is that: compound P096
Compound P096-a (0.30mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 hours at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P096. The yield thereof was found to be 91.0%.
MS(ESI):345.4[M-1]。1H NMR(400MHz,CDCl3)δH＝7.84(d,J＝8.3Hz,2H,ArH),7.82(d,J＝8.2Hz,2H,ArH),7.40(d,J＝8.2Hz,2H,ArH),7.30(d,J＝8.3Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),6.58(d,J＝8.2Hz,1H,ArH),4.89(s,2H,OCH2CO),2.55(s,3H,SCH3)。
Example 97: compound P097
Figure BDA0002793720010000622
The first step is as follows: compound P097-a
Compound P001-c (2.00g,10.86mmol,1.00eq.) and 3, 5-dichloro-4-hydroxybenzaldehyde (2.08g,10.86mmol,1.00eq.) were reacted at room temperature with piperidine (3.00mL,3.00eqv.) in dry methanol (50.00mL,25.11eqv.) under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P097-a. The yield thereof was found to be 38%.
MS(ESI):356.1(M-1)。
The second step is that: compound P097-b
At room temperature, compound P097-a (0.50g,1.40mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (2.70mL,14.00mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (1.94g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P097-b. The yield thereof is 60%.
MS(ESI):500.2[M+1]。
The third step: compound P097
Compound P097-b (200mg,0.40mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P097. The yield thereof was found to be 79%.
MS(ESI):442.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝8.10(s,2H,ArH),7.85(d,J＝7.2Hz,2H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.54(s,3H,SCH3),1.55(s,6H,CH3)。
Example 98: compound P098
Figure BDA0002793720010000631
The first step is as follows: compound P098-a
Compound P001-c (2.00g,10.86mmol,1.00eq.) and 2-methyl-4-hydroxybenzaldehyde (1.48g,10.86mmol,1.00eq.) were reacted at room temperature with piperidine (3.00mL,3.00eqv.) in dry methanol (50.00mL,25.11eqv.) and heated to room temperature under nitrogen for 96 hours. The reaction solution was concentrated under reduced pressure, mixed with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 3:1) to give compound P098-a. The yield thereof was found to be 37%.
MS(ESI):301.1(M-1)。
The second step is that: compound P098-b
At room temperature, compound P098-a (0.50g,1.65mmol,1.00eq.) and tert-butyl 2-bromoisobutyrate (3.10mL,16.54mmol,10.00eq.) were dissolved in anhydrous acetonitrile (15.00mL,30.00eqv.), added with potassium carbonate (2.29g,10.00eqv.), and heated to 70 ℃ under nitrogen protection for 96 hours. The reaction solution was concentrated under reduced pressure, diluted with 40mL of water and mixed well, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with water to neutrality, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: dichloromethane ═ 1:1) to give compound P098-b. The yield thereof is 60%.
MS(ESI):445.2[M+1]。
The third step: compound P098
Compound P098-b (200mg,0.45mmol,1.00eq.) was dissolved in 25% trifluoroacetic acid in dichloromethane (4.00mL) at room temperature and reacted for 1.5 h at room temperature. The reaction solution was diluted with 4mL of dichloromethane, and then washed with 15mL of saturated sodium bicarbonate solution to weak alkalinity, then washed with saturated ammonium chloride solution to weak acidity, extracted with dichloromethane (10 mL. times.3), the organic phases were combined, washed with water once, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give P098. The yield thereof was found to be 75%.
MS(ESI):387.7[M-1]。1H-NMR(400MHz；(CDCl3)δH＝7.85(d,J＝7.2Hz,2H,ArH),7.58(d,J＝8.2Hz,1H,ArH),7.30(d,J＝7.2Hz,2H,ArH),6.85(d,J＝8.2Hz,1H,ArH),6.82(s,1H,ArH),6.77(d,J＝36.8Hz,1H,CF＝CH),2.54(s,3H,SCH3),2.32(s,3H,ArCH3),1.55(s,6H,CH3)。
EXAMPLE 99 PPAR activity of the Compounds of the invention
Plasmid vectors containing PPAR α (Kanamycin +), PPAR δ (Kanamycin +), pPPRE3-TK _ Luciferase (Kanamycin +) were introduced into DH5a competent cells, respectively, and the objective plasmids were obtained by monoclonal and amplification culture. The Plasmid of interest was extracted using the Plasmid Miniprep Kit, and luciferase and PPAR expression vectors were transfected into Hela cells. 24h after transfection, cells were plated at 5 x 105The mixture was inoculated in a 96-well plate per ml and after 12 hours the compounds of the invention and the positive compounds were added. The initial concentration of the compound was 10000nM, ShuitongDiluted to 10 concentration gradients in a 1:2 ratio. Adding luciferase detection reagent after culturing in the incubator for 24h, detecting the luminous intensity by a Tecan Spark microplate reader, and calculating EC50The values, results are shown in Table 1.
TABLE 1 agonistic activity (EC) of the compounds of the invention on PPAR α, δ50Value, nM)
Compound numbering PPARα PPARδ
GFT-505 +++ +
P001 ++++ ++
P002 ++++ ++
P003 ++++ +++
P004 +++ ++
P006 +++ ++
P007 +++ ++
P008 +++ ++
P010 +++ +
P013 +++ ++
P015 +++ ++
P018 +++ +
P025 ++ +
P030 ++ +
P037 +++ ++
P039 +++ ++
P045 +++ +
P049 ++ +
P051 +++ +
P057 +++ +
P061 +++ ++
P063 +++ ++
P073 +++ ++
P085 +++ +
P087 ++++ +
P090 +++ ++
P092 ++ +
P097 +++ +
P098 +++ +
[ note ] + + + + + +: represents EC50Values less than 10 nM;
+++: represents EC50The value is greater than or equal to 10nM and less than 50 nM;
++: represents EC50The value is greater than or equal to 50nM and less than 100 nM;
+: represents EC50The values are greater than or equal to 100nM and less than 500 nM.
The experimental results show that: EC of the Compounds of the invention on PPAR alpha and PPAR delta agonism50The value is superior to that of a positive control drug, and the compound of the invention has stronger activity.
EXAMPLE 100 animal bioavailability of Compounds of the invention
Rats were fasted for 12h without water deprivation. After administration, about 400. mu.L of blood, EDTA-Na, was drawn from the orbit after each animal was administered2The collection time points of the anticoagulant and intravenous injection administration group are as follows: 2min, 10min, 30min, 1h, 2h, 4h, 6h, 8h, 24h and 30h after the test substance is administered; the collection time points of the gavage administration group are as follows: 5min, 10min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 24h and 30h after administration of the test substance. After collection, the plasma was separated by placing in an ice bath and centrifuging within 1 hour (centrifugation: 6000rpm, 8min, 4 ℃). Vortex at 2500rpm, mix well for 1min, collect 100.0 μ L of bloodThe slurry sample is added with 10.0 mu L of internal standard working solution (1.000 mu g/mL) in a 1.5mL centrifuge tube, vortexed at 2500rpm for 1min, then centrifuged at 17000 Xg and 4 ℃ for 15min, and the supernatant is taken and analyzed by UHPLC-MS/MS injection, and the injection amount is 2.0 mu L. Data were analyzed using winnonlin7.0 pharmacokinetic software.
The results of the in vivo pharmacokinetic studies of compound P001 in SD rats (n ═ 3) showed that the half-life T of compound P001 in rats was half-life T after intravenous administration (dose 1.0mg/kg)1/21.63 +/-0.15 h, CmaxIs 5115.19 +/-269.84 ng/mL. half-Life T in rats after intragastric administration of Compound P001 (dose 10.0mg/kg)1/21.46 +/-0.37 h, Cmax4603.24 + -1048.8 ng/mL, absolute bioavailability of 40.88%.
The document CN108658908A reports that 20mg/kg is administrated by gastric lavage, and the Cmax of GFT-505 is 1138ng/mL, which shows that the compound P001 blood concentration of the invention is higher and the effect is better than GFT-505.
EXAMPLE 101 Effect of Compounds of the invention on the expression of collagen I protein
Laying 6-well plates 5 x 10 per well by setting blank control group, TGF beta 1 model group, GFT-505 positive control group and compound group of the invention, LX-2 (hepatic stellate cell)5After 12h, the original culture medium is discarded, culture medium containing 2% serum is added, GFT-505 and the compounds P001, P002 and P003 of the invention are added respectively, the final concentration is 10 μ M, and the blank control group is replaced by the same amount of culture medium. After 1h, the blank was replaced with an equal amount of medium and the other groups were supplemented with TGF β 1 to a final concentration of 1 ng/ml. After 48h, cells were trypsinized and the expression of Collagen I protein was detected by Western Blot. The relative expression levels of the Collagen I proteins in each group are shown in Table 2.
TABLE 2 relative expression levels of the Collagen I proteins in each group
Group of Sample (I) Relative expression level of protein
Blank control group Culture medium 0.18
Model set TGFβ1 0.71
Positive control group GFT-505 0.52
Inventive example 1 P001 0.38
Inventive example 2 P002 0.33
Inventive example 3 P003 0
The compounds P001, P002 and P003 can effectively reduce the expression level of the Collagen I protein, have obvious effect, and have stronger activity compared with a positive control drug GFT-505, wherein the compound P003 has the best effect.

Claims (16)

1. An alpha-fluoro chalcone derivative is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002793718000000011
wherein:
R1、R2each independently selected from H, halogen, CF3、-CN、C1-6Alkoxy, CF3O、CHF2O、C1-6Alkylthio, CF3S、CHF2S、C1-6Alkyl radical, C1-6Alkyl sulfoxide radical-, CF3SO、C1-6Alkyl sulfone group or CF3SO2Or selected from optionally substituted with 1, 2 or 3R: c1-6Alkyl radical, C1-6alkyl-S (═ O) -, C1-6alkyl-S (═ O)2-、C1-6Alkyl- (═ O)2-、C1-6Alkoxy or C1-6An alkylthio group;
R3、R4are respectively and independently selected from H, halogen and C1-4Alkyl radical, C1-4Alkoxy, including but not limited to Cl, Br, I, CH3、Et、CH3O；
R5、R6Each independently selected from H, C1-6Alkyl radical, C1-6Heteroalkyl, phenyl, 5-to 6-membered heteroaryl, R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl; wherein R is5、R6Including but not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl, or pyridyl; r5、R6The ring formation is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure FDA0002793718000000012
Figure FDA0002793718000000013
R7Is selected from H or C1-6An alkyl group;
n is selected from 0, 1, 2, 3,4, 5 or 6;
r is selected from H,F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2、Me、Et、CF3、CHF2、CH2F、NHCH3Or N (CH)3)2。
2. The α -fluorochalcone derivative according to claim 1, wherein in the compound of formula i, R is1,R2Selected from H, halogen, CF3、-CN、C1-6Alkoxy, CF3O、CHF2O、C1-6Alkylthio, CF3S、CHF2S、C1-6Alkyl radical, C1-6Alkyl sulfoxide radical-, CF3SO、C1-6Alkyl sulfone group or CF3SO2(ii) a Wherein R is1、R2Preferably selected from Cl, Me, Et, CH3O、EtO、n-Pr-O、i-PrO、CH3S、EtS、n-PrS、i-PrO、CH3SO、CH3SO2、CF3O、CHF2O、CF3S、CHF2S、CF3SO or CF3SO2。
3. The α -fluorochalcone derivative according to claim 1, wherein in the compound of formula i, R is3、R4Each independently selected from H, halogen, C1-4Alkyl or C1-4Alkoxy, or each is independently selected from C optionally substituted with 1, 2 or 3R1-4Alkyl radical, C1-4An alkoxy group.
4. The α -fluorochalcone derivative according to claim 1, wherein in the compound of formula i, R is5、R6Each independently selected from H, C1-6Alkyl radical, C1-6Heteroalkyl, phenyl or 5-to 6-membered heteroaryl, R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl, R5、R6Including but not limited to methyl, ethyl, isopropyl, phenyl, pyrazolyl, or pyridyl; or R5、R6The ring formation is cyclopropyl and cyclobutylA group consisting of cyclopentyl, cyclohexyl,
Figure FDA0002793718000000014
5. The α -fluorochalcone derivative according to claim 1, wherein in the compound of formula I,
Figure FDA0002793718000000021
selected from:
Figure FDA0002793718000000022
Figure FDA0002793718000000023
6. the α -fluorochalcone derivative according to claim 1, wherein in the compound of formula I,
Figure FDA0002793718000000024
selected from:
Figure FDA0002793718000000025
7. the α -fluorochalcone derivative according to claim 1, which is a compound represented by the formula ii:
Figure FDA0002793718000000026
wherein:
when R is1Selected from H or-XR, wherein X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2(ii) a Then R is2Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl or halo C1-6An alkoxy group; or
When R is2Selected from H or-XR, wherein X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2(ii) a Then R is1Selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl or halo C1-6An alkoxy group;
R3、R4are respectively and independently selected from H, halogen and C1-4Alkyl or C1-6An alkoxy group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
n is selected from 0, 1, 2, 3 or 4;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
8. The α -fluorochalcone derivative according to claim 7, which is a compound represented by the formula IIa:
Figure FDA0002793718000000027
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4are respectively and independently selectedFrom H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
9. The α -fluorochalcone derivative according to claim 7, which is a compound represented by the formula IIb:
Figure FDA0002793718000000031
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
10. The α -fluorochalcone derivative according to claim 7, which is a compound represented by the formula IIc:
Figure FDA0002793718000000032
wherein R is selected from Me, Et and CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, or R5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
11. The α -fluorochalcone derivative according to claim 7, which is a compound represented by the formula iid:
Figure FDA0002793718000000033
wherein R is1Selected from H or-XR, X is selected from S, S (O), S (O)2Or O, R is selected from Me, Et, CF3、CHF2、CH2F、NHCH3Or N (CH)3)2；
R2Selected from H, halogen or C1-6An alkyl group;
R3、R4each independently selected from H, halogen or C1-4An alkyl group;
R5、R6each independently selected from H, C1-6Alkyl, phenyl or 5-to 6-membered heteroaryl, orR5、R6Can also be cyclized to C3-6Cycloalkyl or 3-to 6-membered heterocycloalkyl;
R7is selected from H or C1-6An alkyl group;
the heteroaryl and the heterocycloalkyl contain at least one heteroatom, and the heteroatom is selected from one or more of N, O, S.
12. An alpha-fluoro chalcone derivative is a compound with the following structure or a pharmaceutically acceptable salt thereof:
Figure FDA0002793718000000041
Figure FDA0002793718000000051
13. a pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers.
14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 in the manufacture of a medicament for the treatment of a PPAR receptor associated disease.
15. The use according to claim 14, wherein the PPAR receptor associated disease is: non-alcoholic steatohepatitis, liver fibrosis, insulin resistance, primary biliary cholangitis, dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, cardiovascular disease, obesity, kidney disease, or degenerative brain disease.
16. The use according to claim 15, wherein the kidney disease is selected from chronic kidney disease, renal failure, and the cerebral degenerative disease is selected from alzheimer's disease.
CN202011323949.7A 2019-11-21 2020-11-23 Alpha-fluoro chalcone derivative and application thereof Pending CN112824380A (en)

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