WO2019007293A1

WO2019007293A1 - Compound used as alk kinase inhibitor and use thereof

Info

Publication number: WO2019007293A1
Application number: PCT/CN2018/093906
Authority: WO
Inventors: 吴豫生; 职五斌; 李敬亚; 郑茂林; 梁阿朋
Original assignee: 浙江同源康医药股份有限公司
Priority date: 2017-07-01
Filing date: 2018-06-30
Publication date: 2019-01-10
Also published as: CN108689994A

Abstract

Disclosed are a compound as shown in formula I, and a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein each symbol is as defined in the claims. The compound as shown in formula I has a good inhibitory activity on ALK kinase, and can be used to prepare a drug for regulating ALK kinase activity or treating an ALK-associated disease, especially non-small cell lung cancer.

Description

Compounds for use as ALK kinase inhibitors and their use

Technical field

The present invention relates to the field of medical technology, and in particular to a compound for use as an ALK kinase inhibitor and its use in the preparation of a medicament for modulating ALK kinase activity or treating ALK-related diseases, particularly non-small cell lung cancer.

Background technique

Malignant tumors are one of the main killers of human health. For example, according to the statistics of the International Health Organization, at present, 12 million new lung cancer patients are diagnosed every year, and 8 million people die of lung cancer every year. At present, humans have made remarkable progress in the level of understanding of tumors and treatment methods, and some tumors can be effectively controlled. However, due to the complexity of the formation mechanism of tumors, most malignant tumor cells have multiple pathways for growth, which leads to strong vitality of cancer cells. Inhibition of one or part of the pathways does not completely eliminate cancer cells. On the contrary, in addition to the usual lesion metastasis, chemotherapy often leads to mutations in cancer cell genes, resulting in drug resistance.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80% to 85% of all lung cancer patients, some of which are accompanied by genetic mutations. Two to five percent of NSCLC cases are anaplastic lymphoma kinase (ALK) rearrangements, and anaplastic lymphoma kinase is a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily. ALK was first discovered in the form of an activated fusion oncogene in anaplastic large cell lymphoma, and subsequent studies have found a fusion of ALK in a variety of cancers, including systemic tissue dysplasia, inflammation. Myofibroblastic carcinoma, non-small cell lung cancer, etc. The mutation and abnormal activity of ALK in various cancers has made it a drug target for the treatment of ALK-positive cancers.

Crizotinib, developed by Pfizer Pharmaceuticals, Inc., has been clinically validated to reduce the size of malignant tumors in patients with advanced genetically modified non-small cell lung cancer (NSCLC). However, crizotinib has the following side effects: visual impairment, gastrointestinal side effects, elevated levels of grade 3-4 liver transaminases in 16% of patients, and ALK-positive patients undergoing crizozolidine treatment at the beginning Acquired resistance is inevitable after the sensitive period. The study found that patients generally develop resistance after 1 to 2 years of treatment. At present, the second generation of ALK inhibitors, such as LDK378, alexinib and AP26113, have found that treatment improves the efficacy, but there are problems with large side effects.

Therefore, the development of new compounds with ALK kinase inhibitory activity and/or better pharmacodynamic/pharmacokinetic properties has become the key to the development of novel antitumor drugs.

Summary of the invention

The invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

among them:

n is 0 or 1;

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are each independently selected from C or N, and when N is selected, n is 0;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently selected from the group consisting of H, anthracene, halogen, cyano, nitro, ester, C _1-6 alkyl , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkoxy, C _1-6 haloalkyl, C _1‐6 Alkylthio, C _1-6 acyl, C _1-6 alkylamino or C _3-6 cycloalkylamino;

Y ₁ and Y ₂ are each independently selected from O, S, sulfoxide, sulfone, NR ₉ or R ₁₁ -C-R ₁₀ , and R ₉ , R ₁₀ and R ₁₁ are each independently selected from H, hydrazine, halogen, C. _{a 1 to 6} alkyl group, a C _3-6 cycloalkyl group or a C _{1 to 6} haloalkyl group;

R ^a is H, 氘,

Methoxy,

Cyano group,

Halogen, acetyl,

R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ are each independently selected from the group consisting of H, hydrazine, halogen, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 a haloalkyl group, R ₁₈ and R ₁₉ are each independently selected from a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _1-6 alkoxy group or a C _1-6 alkylamino group;

R ^{b is} selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 Haloalkoxy, C _3-6 cycloalkoxy, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 acyl, C _1-6 alkylamino or C _3-6 Cycloalkylamino;

R ^{c is} selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, difluoromethoxy or C _1-6 alkylthio;

R ^{d is selected} from any of the following structures:

Preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is as shown in Formula II or Formula III:

In formula III, R _{1 is} selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _{a 1 to 6} haloalkoxy group, a C _3-6 cycloalkoxy group, a C _{1 to 6} haloalkyl group, a C _{1 to 6} alkylthio group, a C _{1 to 6} acyl group, a C _{1 to 6} alkylamino group or a C _3-6 cycloalkylamino group;

In formula II or formula III,

n is 0 or 1;

X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are each independently selected from C or N, and when N is selected, n is 0;

R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _{3 -6} cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkoxy, C _1-6 haloalkyl, C _1-6 alkyl sulfide a C _{1 - 6} acyl group, a C _{1 - 6} alkylamino group or a C _3-6 cycloalkylamino group;

R ^a is H, 氘,

Methoxy,

Cyano group,

Halogen, acetyl,

R ^{c is} selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C _1-6 alkylthio;

R ^{d is selected} from any of the following structures:

Further preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is as shown in Formula IV or Formula V:

In formula V, R _{1 is} selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _{a 1 to 6} haloalkoxy group, a C _3-6 cycloalkoxy group, a C _{1 to 6} haloalkyl group, a C _{1 to 6} alkylthio group, a C _{1 to 6} acyl group, a C _{1 to 6} alkylamino group or a C _3-6 cycloalkylamino group;

In Formula IV or Formula V,

n is 0 or 1;

Y _{2 is} selected from O, S, sulfoxide, sulfone, NR ₉ or R ₁₁ -C-R ₁₀ , and R ₉ , R ₁₀ and R ₁₁ are each independently selected from the group consisting of H, hydrazine, halogen, C _{1 - 6} alkyl a C _3-6 cycloalkyl or a C _1-6 haloalkyl group;

R ^a is H, 氘,

Methoxy,

Cyano group,

Halogen, acetyl,

R ^{d is selected} from any of the following:

Further preferably, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is as shown in Formula VI or Formula VII:

Wherein: in Formula VII, R _{1 is} selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy , C _{1 - 6} haloalkoxy, C _3-6 cycloalkoxy, C _{1 - 6} haloalkyl, C _1-6 alkylthio, C _1-6 acyl, C _1-6 alkane An amino group or a C _3-6 cycloalkylamino group;

In formula VI or formula VII,

R ^a is H, 氘,

Methoxy,

Cyano group,

Halogen, acetyl,

R ^{d is selected} from any of the following structures:

R _{4 is} selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 Haloalkoxy, C _3-6 cycloalkoxy, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 acyl, C _1-6 alkylamino or C _3-6 Cycloalkylamino;

R ^{c is} selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C _1-6 alkylthio group.

More preferably, formula VII ̧ , R ₁ is halo ́.

More preferably, in Formula VI or Formula VII, R ^a is H, hydrazine, methoxy, cyano, halogen, acetyl,

R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are each independently selected from the group consisting of H, anthracene, halogen, and C _1-6 alkyl.

More preferably, in Formula VI or Formula VII, R ^{d is selected} from any of the following structures:

More preferably, in Formula VI or Formula VII, R ^{c is} selected from the group consisting of H, isopropoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy.

More preferably, in Formula VI or Formula VII, R _{4 is} selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy.

Further preferably, the compound is selected from the compounds represented by the following structural formula:

Wherein the pharmaceutically acceptable salt is a mineral or organic acid salt of the compound selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, and a hydrogen sulfate. a salt, a nitrate, a phosphate, an acid phosphate; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalic acid Salt, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylic acid Salt, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.

Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below.

"Alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. The "alkyl group" is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkoxy" refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.

"Halogen (halo)" means a fluorine, chlorine, bromine or iodine substituent.

"Haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyl groups include -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , perfluoroalkyl groups (e.g., -CF ₃ ), and the like.

"Haloalkoxy" refers to a radical of the formula -OR wherein R is haloalkyl as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

"Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms. The cycloalkyl group may be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

"Cycloalkoxy" refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Acyl" means a radical of the formula -C(O)R wherein R is alkyl as defined herein. Exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.

An ester group refers to a group of the formula -C(O)OR wherein R is alkyl as defined herein. Exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.

"Alkylthio" refers to a radical of the formula -SRa wherein Ra is H or alkyl as defined herein.

"Alkylamino" refers to a radical of the formula -NRaRb wherein Ra is H or alkyl as defined herein and Rb is alkyl as defined herein.

"Cycloalkylamino" refers to a radical of the formula -NRaRb wherein Ra is H, alkyl as defined herein or cycloalkyl as defined herein, and Rb is cycloalkyl as defined herein.

"Heteroaryl" refers to a monocyclic, bicyclic or tricyclic group of 5 to 12 ring atoms containing at least one ring heteroatom comprising 1, 2 or 3 selected from N, O or S, The remaining ring atom is the aromatic ring of C, and it should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring. The heteroaryl group is preferably specifically 5-8 ring atoms, more preferably 5-6 ring atoms. Examples of heteroaryl groups include, but are not limited to, imidazolyl,

Azolyl, different

Azyl, thiazolyl, isothiazolyl,

Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, benzofuranyl, Benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo

Azolyl, benzo

Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, decyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazoline Base, quinolizinyl, naphthyridinyl, pteridinyl, oxazolyl, aza

Base, diaza

Base, acridinyl and the like.

The solvate referred to in the present invention means a complex of the compound of the present invention and a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out. For example, a complex formed with water is referred to as a hydrate; others include an alcoholate, a ketone compound, and the like. The solvates of the present invention include the compounds of the formula I of the present invention and salts thereof, and solvates of stereoisomers.

A stereoisomer as referred to in the present invention means that the compound of formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer. The invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula I contains more than one chiral center, diastereomers may be present. Stereoisomers of the invention include resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

A prodrug as referred to in the present invention refers to a parent compound which includes a known amino protecting group and a carboxy protecting group, which are hydrolyzed under physiological conditions or released by an enzymatic reaction. Specific prodrug preparation methods can be referred to the prior art (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. ChemLett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

A compound of formula I of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which is effective for inhibiting ALK kinase activity, and ALK resistance mutants.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula I above and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier;

as well as,

A compound as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug or isotopic variation.

The use of a compound of formula I provided by the present invention or a pharmaceutical composition comprising the compound of formula I for the preparation of a medicament for modulating ALK kinase activity or for treating a disease associated with abnormal ALK kinase activity, particularly for cancer treatment, such as Small Cell Lung Cancer.

The compound of the formula I of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms include those suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, and the like).

The pharmaceutical compositions of this invention may be formulated, quantified, and administered in a manner consistent with medical practice. The "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

The pharmaceutical composition may further comprise an additional therapeutic agent, and the additional therapeutic agent is a cancer, a cardiovascular disease, an inflammation, an infection, an immune disease, a cell proliferative disease, a viral disease, a metabolic disease or an organ transplant. .

In one embodiment, the modulating ALK kinase activity or treating a disease associated with abnormal ALK kinase activity refers to treating cancer, cell proliferative diseases, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or Metabolic disease.

The cancer includes, but is not limited to, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma. , kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.

In another embodiment, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.

Detailed ways

The technical solutions of the present invention are further described below in conjunction with specific embodiments, but the scope of protection of the present invention is not limited thereto.

A series of specific compounds were prepared in each of Examples 1-9.

The reaction formula is:

The synthetic route of compound a6 is:

1) Synthesis of compound a2: 50 g of compound a1 was dissolved in 250 mL of tetrahydrofuran, 12.6 g of sodium hydroxide was dissolved in 250 mL of water, and the two solutions were mixed and stirred overnight, and tetrahydrofuran was removed by rotary evaporation, and the aqueous phase was extracted twice with dichloromethane. The aqueous phase was vacuum oven dried 45 ℃ for 16 h, to give 55g orange ^{solid, 1 H NMR (400MHz, DMSO} ): δ7.73 (t, J = 8.22,1H); 6.02 (dd, J = 2.97,13.79,1H ); 5.77 (dt, J = 2.87, 7.45, 1H).

2) Synthesis of compound a3: 14 g of compound a2 and 35 g of anhydrous potassium carbonate were added to a reaction flask, and protected with argon. To the reaction flask were added dimethylformamide (DMF, 700 mL), 140 g of hydrazine and 35 g of bromine. Ethyl fluoroacetate, gradually warmed to 55 ° C, stirred overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, added 300 mL of water, extracted three times with dichloromethane, combined with organic phase, washed with brine, dried over anhydrous magnesium sulfate, column Analysis of 15g until a pale yellow ^{oil, 1 H NMR (400MHz, CDCl} 3): δ8.01 (q, J = 5.58,3.51,1H); 7.07-7.15 (m, 2H).

3) Synthesis of compound a5: Compound a4 (7 g, 24 mmol) and anhydrous potassium carbonate (17 g, 120 mmol) were added to 200 mL of acetonitrile, stirred for 5 minutes, then compound a3 (5 g, 24 mmol) was added, and the mixture was warmed to reflux at 80 ° C overnight. cooled to room temperature, water was added, extracted with ethyl acetate twice and the combined organic phases were dried over anhydrous magnesium sulfate, concentrated and column chromatography, the resulting yellow solid was recrystallized from ether to give 3.6g yellow solid, ¹ H NMR (400MHz , CDCl ₃ ): δ 8.01 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 9.6 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 3.94 (d, J = 13.2) Hz, 2H), 3.02 (m, 2H), 2.52 (m, 8H), 2.30 (s, 3H), 1.96 (d, J = 12 Hz, 2H), 1.52 (m, 2H); MS m/z (ESI) ): 372[M+H] ⁺ .

4) Synthesis of compound a6: 3.6 g of compound a5 was dissolved in methanol, 350 mg of palladium carbon catalyst was added, hydrogen was replaced, and the mixture was stirred at room temperature overnight. TLC showed the reaction was completed, filtered over Celite, and concentrated to give 3.5 g of brown solid, ¹ H NMR (400MHz, CDCl ₃ ): δ 6.71 (m, 3H), 3.50 (m, 4H), 2.52 (m, 10H), 2.30 (s, 3H), 1.96 (d, J = 12 Hz, 2H), 1.52 ( m, 2H); MS m/z (ESI): 342 [M+H] ⁺ .

Example 1

The synthesis of compound c-1, the reaction formula is as follows:

1) Synthesis of compound b3‐1: Compound b1‐1 (0.5 g, 3 mmol) was placed in a 100 mL three-necked flask, DMF (30 mL) was added, then compound b2 (0.86 g, 4.7 mmol) and anhydrous potassium carbonate ( 1.23g, 9.5mmol), stirred at 60 ° C overnight, TLC showed that the reaction was quenched, cooled to room temperature, then added to 100 mL of water, ethyl acetate was extracted, the organic phase was washed with brine, dried over anhydrous magnesium sulfate 0.7 g of a smectite solid, ¹ H NMR (400 MHz, DMSO): δ 11.82 (s, 1H), 8.45 (m, 2H), 7.68 (m, 2H), 7.27 (m, 1H), 1.79 (d, J) =13.6 Hz, 6H); MS m/z (ESI): 316 [M+H] ⁺ .

2) Synthesis of compound c-1: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1 by volume, 8 mL total), and compound b3-1 (200 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid were added. , sealed, heated to 100 ° C, stirred overnight, cooled to room temperature, adjusted to pH 12 with 10% aqueous sodium hydroxide solution, extracted three times with dichloromethane, the organic phase was combined and dried, filtered, concentrated, sequentially with ethyl acetate, dichloromethane / methanol (volume ratio 10: 1) as the mobile phase for column chromatography to give a pale yellow solid ^{110mg, 1 H NMR (400MHz, CDCl} 3): δ10.90 (s, 1H), 8.57 (m, 1H) , 8.08 (s, 1H), 8.04 (d, J = 8.8, 1H), 7.45 (m, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 6.95 (s, 1H), 6.73 (m) , 2H), 3.67 (d, J = 12.4 Hz, 2H), 2.74 - 2.39 (m, 10H), 2.32 (s, 3H), 1.96 (d, J = 13.6 Hz, 2H), 1.84 (d, J = 12.4 Hz, 6H), 1.62 (m, 2H); MS m/z (ESI): 621[M+H] ⁺ .

Example 2

The synthesis of compound c-2, the reaction formula is as follows:

1) Synthesis of compound b3-2: Compound b1-2 (2 g, 16.3 mmol) was placed in a 100 mL three-necked flask, DMF (70 mL) was added, then compound b2 (4.65 g, 25 mmol) and anhydrous potassium carbonate (7.16) were added. g, 52 mmol), stirring at 60 ° C overnight, TLC showed that the reaction was quenched, cooled to room temperature, water (100 mL), ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate Yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.51 (d, J = 8 Hz, 1H), 8.18 (s, 1H), 8.13 (br, 1H), 7.07 (m, 2H), 6.95 ( d, J = 8 Hz 1H); MS m/z (ESI): 270 [M+H] ⁺ .

2) Synthesis of compound c-2: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3-2 (190 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 95 mg of pale yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (d, J = 6.8 Hz, 1H), 8.37 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.05 (m, 1H), 6.92 (m, 3H), 6.78 (dd, J = 9.2, 2.8 Hz, 1H), 6.72 (s, 1H).3.94(s,3H), 3.68 (d, J = 12.4 Hz, 2H), 2.75 - 2.31 (m, 14H), 1.96 (d, J = 12.8 Hz, 2H), 1.70 (m, 2H); MS m/z (ESI): 575 [M+H] ⁺ .

Example 3

The synthesis of compound c-3, the reaction formula is as follows:

1) Synthesis of compound b3‐3: Compound b1‐3 (2 g, 16.3 mmol) was placed in a 100 mL three-necked flask, DMF (70 mL) was added, then compound b2 (4.65 g, 25 mmol) and anhydrous potassium carbonate (7.16) were added. g, 52 mmol), stirring at 60 ° C overnight, TLC showed that the reaction was quenched, cooled to room temperature, water (100 mL), ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate Yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.19 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.6 Hz, 2H), 7.21. 1H), 7.17 (t, J = 7.2 Hz, 2H); MS m/z (ESI): 240 [M+H] ⁺ .

2) Synthesis of compound c-3: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3‐3 (190 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 95 mg of pale yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.05 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.16 (t, J = 7.4 Hz, 2H), 7.05 (s, 1H), 6.97 (s, 1H), 6.73 (m, 2H), 3.65 (d, J = 12.4 Hz, 2H), 2.75 - 2.31 (m, 14H), 1.96 (d, J = 12.4 Hz, 2H), 1.73 (m, 2H); MS m/z (ESI): 545 [M+H] ⁺ .

Example 4

The synthesis of compound c-4, the reaction formula is as follows:

1) Synthesis of compound b3‐4: Compound b1‐4 (1 g, 5 mmol) was placed in a 100 mL three-necked flask, added to DMF (70 mL), then NaH (0.4 g, 10.1 mmol) was added, stirred for 15 minutes, then added A solution of the compound b2 (1.83 g, 10.1 mmol) in EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.63 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 3.21 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 346 [M+H] ⁺ .

2) Synthesis of compound c-4: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3‐4 (170 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 105 mg of pale yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.60 (s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.96 (dd, J = 12.4, 8.8 Hz, 2H), 7.58 (m, 1H), 7.20 (m, 1H), 6.97 (s, 1H), 6.75 (m, 2H), 3.68 ( d, J = 12.8 Hz, 2H), 3.24 (m, 1H), 2.75 - 2.31 (m, 10H), 2.31 (s, 3H), 1.96 (d, J = 12 Hz, 2H), 1.70 (m, 2H) , 3.18 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 651 [M+H] ⁺ .

Example 5

The synthesis of compound c-5, the reaction formula is as follows:

1) Synthesis of compound b3‐5: Compound b1‐5 (2 g, 16.9 mmol) was placed in a 100 mL three-necked flask, isopropanol (70 mL) was added, then compound b2 (4.63 g, 15.5 mmol), diisopropyl Ethylethylamine (2.6 g, 20.3 mmol) was stirred at 80 ° C overnight. TLC showed EtOAc (EtOAc). through the column was concentrated, to give 0.24g yellow ^{solid, 1 H NMR (400MHz, CDCl} 3): δ8.53 (d, J = 8.4Hz, 1H), 8.33 (s, 1H), 7.80 (br, 1H), 7.66 ( m, 2H), 7.26 (m, 1 H); MS m/z (ESI): 265[M+H] ⁺ .

2) Synthesis of compound c-5: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3-5 (170 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 85 mg of pale yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.99 (s, 1H) , 6.75 (m, 2H), 3.69 (d, J = 12.4 Hz, 2H), 2.75 - 2.31 (m, 10H), 2.31 (s, 3H), 1.96 (d, J = 12.4 Hz, 2H), 1.70 ( m, 2H); MS m/z (ESI): 570 [M+H] ⁺ .

Example 6

The synthesis of compound c-6, the reaction formula is as follows:

1) Synthesis of compound b3-6: Compound b1-6 (1.5 g, 11 mmol) was placed in a 100 mL three-necked flask, DMF (70 mL) was added, then compound b2 (2.63 g, 14.4 mmol), anhydrous potassium carbonate ( 2g, stirred 14.4mmol), 80 ℃ overnight, TLC showed the reaction was substantially completed, cooled to room temperature, 100mL water was added, extracted with ethyl acetate, the aqueous phase was precipitated white solid was filtered to afford 2g as a white solid, ¹ H NMR (400MHz, DMSO): δ 8.58 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 7.88 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H); MS m/z (ESI): 283 [M+H] ⁺ .

2) Synthesis of compound c-6: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3-6 (190 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 105 mg of pale yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.22 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.56 (m, 2H), 7.11 (m, 1H), 6.96 (s, 1H), 6.75 (m, 2H), 6.05 - 5.62 ( Br, 2H), 3.69 (d, J = 12.4 Hz, 2H), 2.75 - 2.31 (m, 13H), 1.96 (d, J = 12.4 Hz, 2H), 1.70 (m, 2H); MS m/z ( ESI): 588 [M+H] ⁺ .

Example 7

The synthesis of compound c-7, the reaction formula is as follows:

1) Synthesis of compound b3-7: Compound b1-7 (2 g, 14.8 mmol) was placed in a 100 mL three-necked flask, isopropanol (70 mL) was added, then compound b2 (2.83 g, 15.5 mmol), diisopropyl Ethylethylamine (2.2 g, 18 mmol), and stirred at 60 ° C overnight. TLC EtOAc (EtOAc) EtOAc. After the column, 0.3 g of a yellow solid was obtained, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H) ), 7.65 (t, J = 8.8 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H), 2.73 (s, 3H); MS m/z (ESI): 282 [M+H] ⁺ .

2) Synthesis of compound c-7: Compound a6 (150 mg, 0.5 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3-7 (190 mg, 0.6 mmol), 3 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10:1) Column chromatography of the mobile phase gave 120 mg of pale yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.93 (s, 1H), 8.88 (d, J = 8 Hz, 1H), 8.13 ( s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.84 (m, 1H), 6.74 (s, 1H), 3.69 (d, J = 12 Hz, 2H), 2.75 - 2.31 (m, 15H), 2.31 (s, 3H) , 1.96 (d, J = 12.8 Hz, 2H), 1.70 (m, 2H); MS m/z (ESI): 587 [M+H] ⁺ .

Example 8

The synthesis of compound c-8, the reaction formula is as follows:

The compound c-7 (60 mg) was dissolved in methanol, EtOAc (EtOAc) (EtOAc) A pale yellow solid gave compound c-8.

Example 9

The synthesis of compound c-9, the reaction formula is as follows:

1) Synthesis of compound b3-9: Compound b1-9 (2 g, 9.1 mmol) was placed in a 100 mL three-necked flask, isopropanol (70 mL) was added, then compound b2 (4.63 g, 15.5 mmol), diisopropyl Ethylethylamine (2.6 g, 20.3 mmol) was stirred at 80 ° C overnight. TLC showed EtOAc (EtOAc). Concentration of the column gave 0.1 g of a yellow solid, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.36 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.42 (t, J = 8.4 Hz, 1H), 6.89 (t, J = 8.4 Hz, 1H); MS m/z (ESI): 366 [M+H] ⁺ .

2) Synthesis of compound c-9: Compound a6 (60 mg, 0.2 mmol) was dissolved in acetone/water (3:1, 8 mL), compound b3-9 (100 mg, 0.3 mmol), 2 drops of concentrated hydrochloric acid, sealed, heated Stir to 100 ° C, stir overnight, cool to room temperature, adjust the pH to 12 with 10% aqueous sodium hydroxide solution, extract three times with dichloromethane, and then dry, then filtered, concentrated, and then with ethyl acetate, dichloromethane / methanol 10: 1) as the mobile phase for column chromatography to give 35mg brown ^{solid, 1 H NMR (400MHz, CDCl} 3): δ8.27 (d, J = 8Hz, 1H), 8.10 (s, 1H), 7.95 (d , J = 9.6 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.49 (s, 1H), 7.34 (m, 1H), 6.98 (s, 1H), 6.84 (m, 1H), 6.72 ( m, 2H), 3.65 (d, J = 12.4 Hz, 2H), 2.75 - 2.31 (m, 10H), 2.31 (s, 3H), 1.96 (d, J = 11.2 Hz, 2H), 1.70 (m, 2H) MS m/z (ESI): 671 [M+H] ⁺ .

Example 10

The synthetic route of compound c-10 is as follows:

1) Synthesis of compound c10‐2:

Compound c10-1 (1 g, 3.7 mmol) was placed in a 50 mL single-mouth flask, added to ethanol (10 mL) and water (2.5 mL), then iron powder (0.82 g, 14.7 mmol), ammonium chloride (2.03 g, 38.5mmol), gradually warmed to 50 ° C, the reaction was carried out for 1 h, TLC showed that most of the starting material disappeared, cooled to room temperature, ethyl acetate was added, filtered, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate 0.72 g of a brown oily liquid was obtained. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ6.93 (s, 1H), 6.59 (s, 1H), 4.42-4.58 (m, 1H), 3.71 (s, 1H), 2.24 (s, 3H), 1.33 (d, J = 6.1 Hz, 6H); MS m/z (ESI): 244 [M+H] ⁺ .

2) Synthesis of compound c10‐3:

Compound c10-2 (0.72 g, 3.0 mmol) was placed in a 50 mL single-mouth bottle, and 1,4-dioxane (15 mL) and water (6 mL) were added, N-Boc‐1, 2, 5, 6‐4 Hydropyridine 4 - borate pinacol ester (0.92 g, 3.0 mmol), bistriphenylphosphine palladium dichloride (0.21 g, 0.3 mmol), sodium carbonate (0.64 g, 6.0 mmol), gradually warmed to 100 ° C After stirring overnight, TLC showed that the starting material c10-2 disappeared, the reaction was stopped and cooled to room temperature, 1,4-dioxane was spun out, 10 mL of water was added, ethyl acetate was extracted, and the organic phase was washed with saturated brine. Dry and concentrate the column to give 0.35 g of a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.54 (s, 2H), 5.50 (s, 1H), 4.45 - 4.48 (m, 1H), 4.01 (s, 2H), 3.58 - 3.72 (m, 4H) , 2.31 (s, 2H), 2.13 (s, 3H), 1.50 (s, 9H), 1.30 (d, J = 6.1 Hz, 6H); MS m/z (ESI): 347 [M+H] ⁺ .

3) Synthesis of compound c-10:

Compound c10-3 (140 mg, 0.6 mmol) was dissolved in ethylene glycol methyl ether (10 mL), compound b3‐4 (200 mg, 0.6 mmol), hydrogen chloride solution (0.30 mL, 5.6 M), anhydrous ethanol (0.40) (mL), gradually warmed to 120 ° C, stirred under reflux overnight, TLC showed that most of the starting material c10-3 disappeared, cooled to room temperature, 2M sodium hydroxide aqueous solution adjusted to pH 12, extracted three times with dichloromethane, dried, filtered, concentrated, Chromatography of dichloromethane/methanol (10:1) as a mobile phase gave 27 mg of product. ¹ H NMR (400 MHz, Chloroform-d) δ 9.43 (s, 1H), 8.48 (dd, J = 8.4, 1.1 Hz, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.86 (dd , J=8.0, 1.6 Hz, 1H), 7.61–7.49 (m, 2H), 7.23–7.15 (m, 2H), 6.58 (s, 1H), 5.56–5.42 (m, 1H), 4.58–4.41 (m) , 1H), 3.65 (t, J = 2.8 Hz, 3H), 3.22 (dt, J = 24.0, 6.3 Hz, 4H), 2.47 (s, 2H), 2.06 (s, 3H), 1.30 (d, J = MS Hz (ESI): 556 [M+H] ⁺ .

Example 11

The synthetic route of compound c-11 is as follows:

1) Synthesis of compound c11‐2:

Compound c11‐1 (12.3 g, 100 mmol) was placed in a 250 mL three-necked flask, tetrahydrofuran (120 mL) was added, and di-tert-butyl dicarbonate (21.8 g, 100 mmol) was slowly added and stirred overnight. TLC showed most of the material. After disappearing, the reaction was stopped, tetrahydrofuran was spun off, the column was passed (PE: EA = 10:1), the crude product was spun, and petroleum ether was beaten for 20 min, and filtered to obtain 18.6 g of a white solid solid. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.80 (s, 1H), 6.95 (s, 1H), 6.81-6.86 (m, 1H), 6.65 (s, 1H), 2.24 (s, 3H), 1.52 (s, 9H); MS m/z (ESI): 246[M+Na] ⁺ .

2) Synthesis of compound c11‐3:

Compound c11‐3 (5.0 g, 22.5 mmol) was placed in a 250 mL three-necked flask, anhydrous tetrahydrofuran (100 mL) was added, cooled to -15 ° C, sodium hydride (9 g, 225 mmol) was added in portions, and kept below -5 °C. After 30 min, hydrazine (22.5 g, 1125 mmol) was slowly added dropwise. After 30 min dropwise, diethyl bromodifluoromethyl phosphate (12.0 g, 45 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. 100 mL of a mixed solvent (petroleum ether: ethyl acetate = 10:1) was added, and the mixture was separated, dried and purified by column chromatography (ethyl ether: ethyl acetate = 10:1) to give 6.6 g of pale yellow oily liquid. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.99 (s, 1H), 6.96 (d, J = 8.3Hz, 1H), 6.84 (s, 1H), 6.77-6.79 (m, 1H) 2.33 (s, 3H), 1.53 s, 9H); MS m/z (ESI): 297 [M+Na] ⁺ .

3) Synthesis of compound c11‐4:

Compound c11‐3 (5.6 g, 20.4 mmol) was placed in a 250 mL three-necked flask, dichloromethane (100 mL) was added, excess trifluoroacetic acid was added, and the reaction was carried out overnight at room temperature, and the pH was adjusted to 8 with potassium carbonate solution. The ester was extracted, dried and dried over EtOAc (EtOAc:EtOAc:EtOAc) ^{1 H NMR (400MHz, DMSO)} : δ6.83 (d, J = 8.1Hz, 1H), 6.56 (d, J = 1.4Hz, 1H), 6.32-6.34 (m, 1H) 4.93 (s, 2H), 2.15 (s, 3H); MS m/z (ESI): 195 [M+H] ⁺ .

4) Synthesis of compound c11‐5:

Compound c11‐4 (2.6 g, 15.0 mmol) was placed in a 100 mL three-necked flask, and N,N-dimethylformamide (20 mL) was added to an ice salt bath to below -0 ° C to give N-bromosuccinimide. (2.66g, 15.0mmol) dissolved in N,N-dimethylformamide (10mL) was added to the reaction, slowly rose to room temperature for 3h, TLC showed the disappearance of the starting material c11‐4, stop the reaction, add ethyl acetate (100mL ), washed three times with water, dried organic phase, and dried over a column (petroleum ether: ethyl acetate = 6:1). 2.12 g of a brown oily liquid were obtained. ¹ H NMR (400 MHz, DMSO): δ 7.14 (s, 1H), 6.73 (s, 1H), 5.18 (s, 2H), 2.18 (s, 3H); MS m/z (ESI): 253 [M +H] ⁺ .

5) Synthesis of compound c11‐6:

Compound c11‐5 (1 g, 4.0 mmol) was placed in a 50 mL vial, added to 1,4-dioxane (20 mL) and water (8 mL), then N-Boc‐1, 2, 5, 6 Tetrahydropyridine-4-boronic acid pinacol ester (1.29 g, 4.16 mmol), bistriphenylphosphine palladium dichloride (0.28 g, 0.40 mmol), sodium carbonate (0.85 g, 8.0 mmol), gradually warmed to The mixture was stirred at reflux for 4 h. TLC showed that most of the material was evaporated. The mixture was cooled to room temperature, and then evaporated to EtOAc. The column was concentrated (petroleum ether: ethyl acetate = 10:1) to yield 0.9 g. ^{1 H NMR (400MHz, DMSO)} : δ6.70 (s, 1H), 6.57 (s, 1H), 5.49 (s, 1H), 4.93 (s, 2H), 3.92 (s, 2H), 3.49 (t, J = 5.5 Hz, 2H), 2.22 (d, J = 1.6 Hz, 2H), 2.09 (s, 3H), 1.43 (s, 9H); MS m/z (ESI): 356 [M+H] ⁺ .

6) Synthesis of compound c-11:

Compound c11‐6 (142 mg, 0.53 mmol) was dissolved in ethylene glycol monomethyl ether (10 mL), and compound b3‐4 (180 mg, 0.53 mmol), ethanol hydrogen chloride solution (0.21 mL, 5.6 M), ethanol (0.32 mL) ), heated to 120 ° C, stirred and refluxed overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide solution, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol (10:1) Column chromatography of the mobile phase gave 19 mg of product. ^{1 H NMR (400MHz, DMSO)} : δ9.54 (s, 1H), 8.78 (s, 1H), 8.49 (d, J = 8.2Hz, 1H), 8.24 (s, 1H), 7.81-7.84 (m, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.44 (s, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.70 (s, 1H), 4.45 (s, 1H), 3.39- 3.46 (m, 5H), 2.97-3.02 (m, 3H), 2.25 (s, 3H), 1.82 (s, 5H), 1.16 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 565[M+H] ⁺ .

Example 12

The synthetic route of compound c-12 is as follows:

1) Synthesis of compound c12‐1:

Compound c11-6 (0.2 g, 0.56 mmol) was dissolved in methanol, then 20 mg of palladium-carbon catalyst was added, and the hydrogen was replaced. The mixture was stirred at room temperature for 3 h. ^{1 H NMR (400MHz, DMSO)} : δ6.76 (s, 1H), 6.55 (s, 1H), 4.77 (s, 2H), 4.04 (s, 2H), 2.78 (s, 2H), 2.66-2.72 ( m, 2H), 2.15 (s, 3H), 1.41 (s, 9H); MS m/z (ESI): 358 [M+H] ⁺ .

2) Synthesis of compound c-12:

Compound c12-1 (190 mg, 0.4 mmol) was dissolved in ethylene glycol methyl ether (10 mL). Compound b3-4 (138 mg, 0.4 mmol), hydrogen chloride solution (0.21 mL, 5.6 M), ethanol (0.32 mL) Heat to 120 ° C, stir and reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide solution, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol ( 10:1) Column chromatography for the mobile phase gave 19 mg of product. ^{1 H NMR (400MHz, DMSO)} : δ9.53 (s, 1H), 8.73 (s, 1H), 8.49 (d, J = 8.2Hz, 1H), 8.25 (s, 1H), 7.81-7.84 (m, 1H), 7.57 (t, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J = 7.2 Hz, 1H), 6.90 (s, 1H), 5.63 (s, 1H), 3.41 - 3.47 (m, 2H), 2.95 (t, J = 5.5 Hz, 1H), 2.20 (s, 2H), 2.17 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H); MS m/z ( ESI): 567 [M+H] ⁺ .

Example 13

The synthetic route of compound c-13 is as follows:

1) Synthesis of compound c13‐2:

Compound c13‐1 (0.4 g, 2.2 mmol) was placed in a 100 mL three-necked flask, added to N,N-dimethylformamide (10 mL), ice-salted bath to below -0 °C, then sodium hydride (0.16 g) , 4.4 mmol), stirring for 15 minutes, then adding a solution of compound b2 (0.8 g, 4.4 mmol) in N,N-dimethylformamide, stirring at room temperature overnight, adding 10 mL of water, ethyl acetate extraction, the organic phase with saturated salt It was washed with water, dried over anhydrous magnesium sulfate and evaporated. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ9.62 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.28 (s, 1H), 7.95 (dd, J1 = 1.5Hz, J2 = 6.4 Hz 1H), 7.65‐7.69 (m, 1H), 7.27‐7.31 (m, 1H) 4.75 (d, J=5.3 Hz, 1H), 2.65 (d, J=5.3 Hz, 1H) 1.61 (s, 6H) MS m/z (ESI): 333 [M+H] ⁺ .

2) Synthesis of compound c‐13:

Compound c13-2 (100 mg, 0.3 mmol) was dissolved in ethylene glycol monomethyl ether (10 mL), and compound a6 (140 mg, 0.41 mmol), hydrogen chloride solution (0.21 mL, 5.6 M), ethanol (0.32 mL), Heat to 120 ° C, stir and reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, 2M aqueous sodium hydroxide solution adjusted to pH 12, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol (10 :1) Column chromatography for the mobile phase gave 25 mg of product. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ9.14 (s, 1H), 8.45 (d, J = 8.2Hz, 1H), 8.09 (s, 1H), 7.92-7.96 (m, 2H), 7.52-7.56 (m, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.72 (s, 2H), 4.74 (s, 1H), 3.66 (d, J = 12.2 Hz, 2H) , 2.38 - 2.74 (m, 14H) 2.31 (s, 3H), 1.95 - 1.98 (m, 2H), 1.62 - 1.69 (m, 4H); MS m/z (ESI): 638 [M+H] ⁺ .

Example 14

The synthetic route of compound c-14 is as follows:

1) Synthesis of compound c14‐3:

Compound c14‐1 (15 g, 75.4 mmol) was placed in a 1000 mL three-necked flask, methanol (300 mL) was added, and compound c14-2 (17.4 g, 79.1 mmol) was added to the reaction, and sodium cyanoborohydride (9.45 g, 150.7mmol) was slowly added to the reaction and stirred overnight. TLC showed that most of the starting material c14‐1 disappeared, the reaction was stopped, the methanol was spun off, dissolved in dichloromethane, washed twice with water, twice with saturated brine, dichloromethane/methanol (10:1) Column chromatography of the mobile phase gave 12.2 g of solid.

^{_{1 H NMR (400MHz, CDCl 3}} ): δ7.36-7.31 (m, 5H), 5.13 (s, 2H), 4.13 (s, 2H), 3.81-3.86 (m, 4H), 3.51 (t, J = 5.0 Hz, 4H), 3.06‐2.99 (m, 2H), 2.69 (t, J=12 Hz, 2H), 2.51 (s, 3H), 2.43‐2.37 (m, 1H), 1.95‐1.74 (m, 6H) , 1.46 (s, 9H); MS m/z (ESI): 404 [M+H] ⁺ .

2) Synthesis of compound c14‐4:

Compound c14‐3 (11.2 g, 27.8 mmol) was placed in a 250 mL three-necked flask, methanol (100 mL) was added, dry palladium carbon (1 g, 10%) was added, and the reaction was carried out overnight under a hydrogen atmosphere. The reaction disappeared, the reaction was quenched, filtered, dried and purified elute ^{_{1 H NMR (400MHz, CDCl 3}} ): δ4.14 (s, 2H), 2.94 (t, J = 4.8Hz, 4H), 2.69 (t, J = 11.5Hz, 2H), 2.58 (m, 6H), 2.40‐2.32 (m, 1H), 1.80 (d, J=11.6 Hz, 2H) 1.45 (s, 9H), 1.42‐1.35 (m, 2H); MS m/z (ESI): 270 [M+H] ⁺ .

3) Synthesis of compound c14‐5:

Compound c14‐4 (3 g, 11.2 mmol) was placed in a 250 mL three-necked flask, N,N-dimethylformamide (100 mL) was added, and the ice salt bath was taken below ‐0 ° C, and sodium hydride (0.63 g, 15.6mmol) After 30 minutes, deuterated iodomethane (1.62 g, 11.2 mmol) was added. After 1 h, TLC showed the disappearance of starting material c14‐4, quenched and quenched, extracted with ethyl acetate, dried and then dried. Methyl chloride:methanol = 10:1) gave 1.15 g of a solid. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ4.15 (s, 2H), 2.88 (s, 6H), 2.70 (t, J = 12.0Hz, 2H), 2.56-2.49 (m, 1H), 1.84 (d , J = 12.7 Hz, 2H) 1.45 (s, 9H), 1.41 - 1.40 (m, 2H); MS m/z (ESI): 287 [M+H] ⁺ .

4) Synthesis of compound c14‐6:

Compound c14-5 (1.15 g, 4 mmol) was placed in a 100 mL three-necked flask, and then added to a solution of 1,4-dioxane in HCl, stirred, and filtered to give a white solid. ¹ H NMR (400 MHz, D ₂ O): δ 3.86 - 3.86 (m, 14H), 3.04 (t, J = 12.9 Hz, 2H), 2.40 (d, J = 13.3 Hz, 2H) 1.96 - 1.86 (m) , 2H); MS m/z (ESI): 295 [M+H] ⁺ .

5) Synthesis of compound c14‐7:

Compound c14-6 (1 g, 4.5 mmol) and anhydrous potassium carbonate (1.37 g, 9.9 mmol) were added to 20 mL of N,N-dimethylformamide, and a3 (0.937 g, 4.5 mmol) was added to warm to 120 ° C and reflux overnight. , TLC showed that most of the starting material c14-6 disappeared, the reaction was stopped and cooled to room temperature, water was added, ethyl acetate was extracted twice, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 10:1) 0.86 g of a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (d, J = 9.4 Hz, 1H), 6.68 (d, J = 9.4 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 3.93 ( d, J = 13.1 Hz, 2H), 3.00 (t, J = 11.0 Hz, 2H), 2.63 (m, 8H), 1.98 (d, J = 12.4 Hz, 2H), 1.72 - 1.55 (m, 2H); MS m/z (ESI): 355 [M+H] ⁺ .

6) Synthesis of compound c14‐8:

0.86 g of the compound c14-7 was dissolved in methanol, 86 mg of palladium carbon catalyst was added, and the hydrogen was replaced, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was completed, filtered over Celite, and evaporated. ^{_{1 H NMR (400MHz, CDCl 3}} ): δ6.69 (m, 3H), 3.50 (m, 4H), 2.65-2.48 (m, 9H), 2.36-2.29 (m, 1H), 1.92 (d, J = 12 Hz, 2H), 1.69 (m, 2H); MS m/z (ESI): 345 [M+H] ⁺ .

7) Synthesis of compound c-14:

Compound c14-8 (240 mg, 0.7 mmol) was dissolved in ethylene glycol methyl ether (10 mL). Compound b3-4 (172 mg, 0.50 mmol), hydrogen chloride solution (0.21 mL, 5.6 M), ethanol (0.33 mL) Heat to 120 ° C, stir and reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide solution, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol ( 10:1) Column chromatography of the mobile phase gave 39 mg of solid. ^{1 H NMR (400MHz, DMSO)} : δ9.60 (s, 1H), 8.54 (d, J = 8.3Hz, 1H), 8.13 (s, 1H), 7.96 (d, J = 14.1Hz, 1H) 7.90 ( m,1H), 7.58 (t, J = 14.4 Hz, 1H), 7.23 (m, 1H) 6.98 (s, 1H), 6.76 (m, 2H), 3.67 (d, J = 12.3 Hz, 2H), 3.24 (m, 1H), 2.76‐2.41 (m, 10H), 1.97 (d, J = 12.0 Hz, 2H) 1.68 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H); MS m/z ( ESI): 654 [M+H] ⁺ .

Example 15

The synthetic route of compound c-15 is as follows:

1) Synthesis of compound c15‐2:

Compound c15‐1 (5.0 g, 31.8 mmol) was placed in a 250 mL three-necked flask, re-distilled tetrahydrofuran (100 mL) was added, cooled to -15 ° C, sodium hydride (16 g, 400 mmol) was added in portions, maintaining -5 ° C throughout After 30 minutes, water (40 g, 2 mol) was slowly added dropwise, and after 30 minutes of dropwise addition, diethyl bromodifluoromethyl phosphate (17 g, 63 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed by TLC. 100 mL of a mixed solvent (petroleum ether: ethyl acetate = 10:1), liquid separation, dried, and column chromatography ( petroleum ether: ethyl acetate = 10:1) afforded 3.5 g of pale yellow oily liquid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.03 (m, 1H), 7.15 - 7.08 (m, 2H), 7.83 - 7.46 (m, 1H); MS m/z (ESI): 208 [M+H ] ⁺ .

2) Synthesis of compound c15‐4:

Compound c15-2 (2.5 g, 8.6 mmol) and anhydrous potassium carbonate (3.5 g, 25.4 mmol) were added to 20 mL of acetonitrile, and c15-3 (2 g, 9.7 mmol) was added and the mixture was warmed to reflux at 120 ° C overnight. Most of the disappearance was carried out, and the reaction was cooled to room temperature. Water was added, and ethyl acetate was evaporated and evaporated. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 9.8 Hz, 1H), 6.68 (dd, J = 6.8, 1.8 Hz, 1H), 6.61 (s, 1H), 6.80-6.41 (t , J=85.1 Hz, 1H) 3.93 (d, J = 12.4 Hz, 2H), 3.04 - 2.96 (m, 2H), 2.75 - 2.33 (m, 9H), 2.29 (s, 3H), 1.98 (d, J) =11.7 Hz, 2H), 1.59 (qd, J = 12.1, 4.0 Hz, 2H); MS m/z (ESI): 371 [M+H] ⁺ .

3) Synthesis of compound c15‐5:

0.8 g of the compound c15-4 was dissolved in methanol, 80 mg of a palladium carbon catalyst was added, and the hydrogen was replaced, and the mixture was stirred at room temperature overnight. TLC showed that the reaction was completed. ¹ H NMR (400 MHz, Chloroform-d): δ 6.81 - 6.64 (m, 3H), 6.44 (t, J = 74.6 Hz, 1H), 3.69 - 3.40 (m, 5H), 2.76 - 2.25 (m, 13H) ), 1.93 (dt, J = 12.8, 2.9 Hz, 2H), 1.68 (qd, J = 12.1, 3.9 Hz, 2H); MS m/z (ESI): 341 [M+H] ⁺ .

4) Synthesis of compound c-15:

Compound c15-5 (170 mg, 0.7 mmol) was dissolved in ethylene glycol methyl ether (10 mL). Compound b3‐4 (240 mg, 0.50 mmol), hydrogen chloride solution (0.21 mL, 5.6 M), ethanol (0.33 mL) Heat to 120 ° C, stir and reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide solution, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol ( 10:1) Column chromatography of the mobile phase gave 39 mg of solid. ¹ H NMR (400 MHz, Chloroform-d): δ 9.60 (s, 1H), 8.58 - 8.49 (m, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.90 ( Dd, J = 8.0, 1.6 Hz, 1H), 7.58 (td, J = 8.4, 7.9, 1.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.97 (s, 1H), 6.80 - 6.68 (m, 2H), 6.48 (t, J = 73.8 Hz, 2H), 3.67 (d, J = 12.3 Hz, 2H), 3.29 - 3.17 (m, 1H), 2.78 - 2.33 (m, 10H), 2.31 (s, 3H) ), 1.97 (d, J = 12.5 Hz, 2H), 1.76 - 1.51 (m, 3H), 1.31 (d, J = 6.9 Hz, 6H); MS m/z (ESI): 650 [M+H] ⁺ .

Example 16

The synthetic route of compound c-16 is as follows:

1) Synthesis of compound c16‐3:

Compound c16‐1 (10.0 g, 50 mmol) was placed in a 250 mL three-necked flask, anhydrous methanol (100 mL) was added, acetic acid and morpholine (4.78 g, 55 mmol) were slowly added, and palladium carbon (1 g. 10%) was added. The reaction was carried out overnight under an atmosphere, the temper was taken to give a reaction, and the solvent was evaporated. The solvent was dissolved in methylene chloride. The mixture was washed with a small amount of water, and the mixture was separated, and dried and purified by column chromatography (dichloromethane:methanol = 20:1). ¹ H NMR (400 MHz, Chloroform-d) δ 4.30 - 4.00 (m, 2H), 3.79 - 3.64 (m, 4H), 2.71 (t, J = 12.5 Hz, 2H), 2.60 - 2.47 (m, 4H) , 2.31 (ddt, J = 11.2, 7.3, 3.7 Hz, 1H), 1.81 (dt, J = 13.1, 2.7 Hz, 2H), 1.45 (s, 11H); MS m/z (ESI): 270 (GC- MS).

2) Synthesis of compound c16‐4:

Compound c16-3 (9.0 g, 33 mmol) was placed in a 100 mL three-necked flask, and then added to a solution of 1,4-dioxane in HCl, stirred, and filtered to give 9.2 g of white solid. ^{1 H NMR (400MHz, Deuterium Oxide} ) δ4.09 (s, 2H), 3.79 (s, 2H), 3.57 (dddd, J = 22.3,18.3,7.7,4.5Hz, 5H), 3.24 (s, 2H), 3.06 (td, J = 13.4, 2.9 Hz, 2H), 2.50 - 2.29 (m, 2H), 1.90 (qd, J = 13.2, 4.2 Hz, 2H).

3) Synthesis of compound c16‐7:

7.6 g of compound c16‐4 was dissolved in N,N-dimethylformamide, 6 g of c16‐5 and 7.2 g of potassium carbonate were added, heated to 120 ° C overnight, cooled to room temperature and stirred, TLC showed complete reaction, diatom The soil was filtered and concentrated to give 8 g of a white solid. This crude product was dissolved in methanol, then 500 mg of wet palladium on carbon was added, and the reaction was allowed to stand overnight under a hydrogen atmosphere. The next day, filtration, and spin-drying the column gave 6.1 g of product. ¹ H NMR (400 MHz, Chloroform-d) δ 6.82 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.81 - 3.64 (m, 4H), 3.60 - 3.21 (m) , 4H), 2.59 (dt, J = 6.7, 2.6 Hz, 6H), 2.29 (tt, J = 11.4, 3.7 Hz, 1H), 1.92 (dt, J = 12.7, 2.9 Hz, 2H), 1.68 (qd, J = 12.1, 4.0 Hz, 2H); MS m/z (ESI): 262 [M+H] ⁺ .

4) Synthesis of compound c-16:

Compound c16-7 (400 mg, 1.53 mmol) was dissolved in ethylene glycol methyl ether (10 mL). Compound b3‐4 (340 mg, 0.7 mmol), hydrogen chloride solution (0.42 mL, 5.6 M), ethanol (0.66 mL) Heating to 120 ° C, stirring under reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, 2 moles per liter of aqueous sodium hydroxide solution adjusted to pH 12, extracted three times with dichloromethane, dried, filtered, concentrated, dichloro Methanol/methanol (10:1) was subjected to column chromatography on a mobile phase to yield 110 mg of solid. ^{1 H NMR (400MHz, Chloroform-} d) δ9.61 (s, 1H), 8.61 (dd, J = 8.5,1.1Hz, 1H), 8.11 (s, 1H), 7.89 (dd, J = 8.0,1.7Hz , 1H), 7.59 - 7.52 (m, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.96 - 6.81 (m, 3H), 3.75 (t, J = 4.7 Hz, 4H), 3.69 (d, J = 12.5 Hz, 2H), 3.24 (p, J = 6.9 Hz, 1H), 2.71 (td, J = 12.3, 2.4 Hz, 2H), 2.60 (t, J = 4.7 Hz, 4H), 2.39 - 2.26 (m, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.76 - 1.51 (m, 2H), 1.31 (d, J = 6.9 Hz, 6H); MS m/z (ESI): 571 [M+H] ⁺ .

Example 17

The synthetic route of compound c-17 is as follows:

1) Synthesis of compound c17‐1:

Compound c16‐4 (2 g, 8.3 mmol) and anhydrous potassium carbonate (3.8 g, 37.5 mmol) were added to 30 mL of acetonitrile, and a3 (1.87 g, 9 mmol) was added and the mixture was heated to 100 ° C and refluxed overnight. The reaction was quenched to rt. EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 9.4 Hz, 1H), 6.69 (d, J = 9.4 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 3.92 ( Dd, J = 13.3, 3.1 Hz, 2H), 3.79 - 3.65 (m, 4H), 3.01 (ddd, J = 13.2, 11.7, 2.8 Hz, 2H), 2.62 - 2.51 (m, 4H), 2.51 - 2.40 ( m, 1H), 1.98 (dd, J = 13.9, 3.4 Hz, 2H), 1.72 - 1.51 (m, 2H); MS m/z (ESI): 359 [M+H] ⁺ .

2) Synthesis of compound c17‐2:

1.46 g of the compound c17-1 was dissolved in methanol, 146 mg of palladium carbon catalyst was added, and the hydrogen was replaced, and the mixture was stirred at room temperature overnight. TLC showed the reaction was completed, filtered over Celite, and evaporated. ¹ H NMR (400 MHz, Chloroform-d) δ 6.76 - 6.61 (m, 3H), 3.81 - 3.65 (m, 4H), 3.57 (s, 2H), 3.51 (d, J = 12.4 Hz, 2H), 2.68 – 2.49 (m, 6H), 2.33–2.22 (m, 1H), 1.93 (dt, J = 12.8, 2.9 Hz, 2H), 1.66 (qd, J = 12.1, 4.0 Hz, 2H); MS m/z ( ESI): 329 [M+H] ⁺ .

3) Synthesis of compound c-17:

Compound c17‐2 (280 mg, 0.85 mmol) was dissolved in ethylene glycol methyl ether (10 mL), and compound b3‐4 (200 mg, 0.58 mmol), ethanol hydrogen chloride solution (0.4 mL, 5.6 M), ethanol (0.6 mL) Heat to 120 ° C, stir and reflux overnight, TLC showed that most of the starting material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide solution, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol ( 10:1) Column chromatography of the mobile phase gave 110 mg of solid. ^{1 H NMR (400MHz, Chloroform-} d) δ9.60 (s, 1H), 8.54 (dd, J = 8.5,1.1Hz, 1H), 8.13 (s, 1H), 7.96 (d, J = 8.9Hz, 1H ), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (ddd, J = 8.7, 7.4, 1.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.98 (s, 1H), 6.80 - 6.69 (m, 2H), 3.75 (t, J = 4.7 Hz, 4H), 3.67 (d, J = 12.3 Hz, 2H), 3.24 (p, J = 6.8 Hz, 1H), 2.74 (td, J = 12.3) , 2.5 Hz, 2H), 2.59 (t, J = 4.7 Hz, 4H), 2.38 - 2.27 (m, 1H), 1.97 (d, J = 12.4 Hz, 2H), 1.68 (td, J = 12.0, 3.9 Hz , 2H), 1.32 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 638 [M+H] ⁺ .

Example 18

The synthetic route of compound c-18 is as follows:

1) Synthesis of compound c18‐2:

Compound c18-1 (15 g, 68 mmol) and anhydrous sodium carbonate (10.76 g, 102 mmol) were added to 100 mL of 1,4-dioxane, and 21 mL of N,N-dimethylamine in ethanol was added (3M). After stirring at room temperature overnight, TLC showed that most of the material c18-1 disappeared, the reaction was stopped, the solvent was evaporated, ethyl acetate was dissolved, washed three times with water, dried over anhydrous magnesium sulfate, concentrated, and column chromatography ( petroleum ether: ethyl acetate = 2 :1), gave 12.6 g of solid. ¹ H NMR (400 MHz, Chloroform-d) δ 8.01 - 7.94 (m, 1H), 7.75 - 7.66 (m, 2H), 7.65 - 7.57 (m, 1H), 2.92 (s, 6H); MS m/z (ESI): 231 [M+H] ⁺ .

2) Synthesis of compound c18‐3:

1.8 g of the compound c18-2 was dissolved in methanol, 180 mg of a palladium-carbon catalyst was added, and the hydrogen was replaced. The mixture was stirred at room temperature overnight. TLC showed the reaction was completed, filtered and evaporated. ^{1 H NMR (400MHz, DMSO-} d 6) δ7.39 (d, J = 7.8Hz, 1H), 7.31 (t, J = 8.4Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 6.66 (t, J = 7.8 Hz, 1H), 6.05 (s, 2H), 2.64 (s, 6H); MS m/z (ESI): 201 [M+H] ⁺ .

3) Synthesis of compound c18‐4:

Compound c18‐3 (1 g, 5 mmol) was placed in a 100 mL three-necked flask, added to N,N-dimethylformamide (20 mL), ice-salt bath below 0 ° C, then sodium hydride (0.4 g, 10 mmol). After stirring for 15 minutes, a solution of the compound b2 (0.86 mL, 10 mmol) in N, N-dimethylformamide was added, and the mixture was stirred at room temperature overnight, then 10 mL of water, ethyl acetate was evaporated, and the organic phase was washed with saturated brine. The magnesium was dried and concentrated to give a white solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.86 (s, 1H), 8.60 (dd, J = 8.5, 1.1 Hz, 1H), 8.28 (s, 1H), 7.87 (dd, J = 8.0, 1.6 Hz , 1H), 7.75 - 7.61 (m, 1H), 7.29 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 2.74 (s, 6H); MS m/z (ESI): 347 [M+H] ⁺ .

4) Synthesis of compound c-18:

Compound c18-4 (170 mg, 0.5 mmol) was dissolved in ethylene glycol methyl ether (10 mL), and compound a6 (248 mg, 7.3 mmol) was added, and hydrogen chloride solution (0.3 mL, 5.6 M), ethanol (0.3 mL), and heated. After stirring to reflux at 120 ° C, TLC showed that most of the material disappeared, cooled to room temperature, adjusted to pH 12 with 2M aqueous sodium hydroxide, extracted three times with dichloromethane, dried, filtered, concentrated, dichloromethane / methanol (10: 1) Column chromatography for the mobile phase gave 25 mg of product. ^{1 H NMR (400MHz, Chloroform-} d) δ9.44 (s, 1H), 8.51 (dd, J = 8.4,1.2Hz, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.8Hz, 1H ), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 - 7.47 (m, 1H), 7.22 (ddd, J = 8.4, 7.4, 1.2 Hz, 1H), 6.98 (s, 1H), 6.80 - 6.68 (m, 2H), 3.67 (d, J = 12.2 Hz, 2H), 2.74 (s, 14H), 2.42 - 2.35 (m, 1H), 2.31 (s, 3H), 1.97 (d, J = 12.4 Hz) , 2H), 1.68 (dd, J = 11.9, 3.9 Hz, 4H); MS m/z (ESI): 652 [M+H] ⁺ .

Example 19

The synthetic route of compound c-19 is as follows:

1) Synthesis of compound c19‐2:

Compound c19-1 (710 mg, 1.82 mmol) was dissolved in 20 ml of ethanol, and the compound c19-a (1.06 g, 9.1 mmol) was added with stirring at room temperature, then cooled to 0 ° C, acetic acid (1.09 g, 18.2 mmol) After reacting at 0 ° C for 30 minutes, sodium cyanoborohydride (229 mg, 3.64 mmol) was added, and the reaction was allowed to stand at room temperature overnight. TLC showed the reaction was completed, diluted with water, ethyl acetate was evaporated, and the organic phase was washed with brine. Dry over anhydrous sodium sulfate and concentrate to give a crude material. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.39-7.23 (m, 5H), 6.94 (s, 1H), 6.80 (s, 1H), 5.49 (s, 1H), 5.14 ( s, 2H), 3.20 (d, J = 3.1 Hz, 2H), 2.96 (dd, J = 11.9, 4.0 Hz, 2H), 2.70 (t, J = 5.5 Hz, 2H), 2.36 (t, J = 3.7) Hz, 1H), 2.32 - 2.26 (m, 2H), 2.20 (s, 3H), 2.01 - 2.14 (m, 2H), 1.89 - 1.82 (m, 2H), 1.77 - 1.66 (m, 2H).

2) Synthesis of compound c19‐3:

The compound c19-2 (945 mg, 1.93 mmol) was dissolved in 20 ml of methanol, and palladium carbon (472 mg, 10%) was added with stirring at room temperature, then hydrogen was replaced three times, and reacted at room temperature overnight at 0.2-0.4 MPa, TLC showed The reaction was completed, filtered, and concentrated to give a crude benzyl benzene (yield: 596 mg). The crude product was then dissolved in 20 ml of methanol. Palladium hydroxide carbon (500 mg) was added with stirring at room temperature, three times with hydrogen, and reacted at room temperature at 0.2-0.4 MPa. After overnight, TLC showed the reaction was completed, filtered and concentrated to EtOAc EtOAc ^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.84 (s, 1H), 6.50 (s, 1H), 3.63 (s, 2H), 3.01-2.92 (m, 2H), 2.92-2.82 (m, 2H), 2.49 (tt, J = 11.6, 4.1 Hz, 1H), 2.26 (m, 4H), 2.14 (s, 3H), 1.93 (td, J = 11.9, 2.4 Hz, 2H), 1.76 (dt, J = 12.9, 2.8 Hz, 2H), 1.71 - 1.55 (m, 7H), 0.84 - 0.73 (m, 2H).

3) Synthesis of compound c19‐4:

Compound c18-3 (200 mg, 1.0 mmol) was dissolved in 2 ml of N,N-dimethylformamide, sodium hydride (80 mg, 2.0 mmol, 60% in oil) was added at 0 ° C and reacted for 30 minutes. Compound 8 (334 mg, 2.0 mmol) was added, and the reaction was stirred at room temperature overnight. EtOAc was evaporated. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.66 (s, 1H), 8.60 (dd, J = 8.4, 1.1 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (m, 1H), 7.24 - 7.18 (m, 1H), 2.68 (s, 6H).

4) Synthesis of compound c-19:

Compound c19‐3 (200 mg, 0.56 mmol) was dissolved in 10 ml of ethylene glycol mono-tert-butyl ether, and then compound c19‐4 (222 mg, 0.67 mmol), dioxane hydrochloride solution (4M) was added with stirring at room temperature. The reaction was carried out at 120 ° C. The reaction was completed with EtOAc (EtOAc). ‐19, 23 mg.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.35 (d, J = 3.1Hz, 1H), 8.64 (d, J = 8.4Hz, 1H), 8.11 (s, 1H), 8.07 (d, J = 2.7Hz , 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.20 (s, 1H), 7.08 (s, 1H), 3.23 (t, J = 14.2 Hz, 4H), 2.78 (s, 6H), 2.51 (m, 4H), 2.30 (s, 3H), 2.05 (m, 7H), 1.87 (d, J = 12.8 Hz, 2H). MS [M+H] ⁺ 652.4.

The compounds were synthesized according to Examples 18 and 19:

Example 24

The synthetic route of compound c-24 is as follows:

1) Synthesis of compound c24‐5:

Compound c24-2 (624mg, 3mmol) was dissolved in 10ml of DMF, and then stirred at room temperature was added K2CO ₃ (1.04g, 7.5mmol), compound c24-4 (447mg, 3.3mmol), the reaction was placed at 90 deg.] C After the reaction was completed, TLC showed EtOAc (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 9.4 Hz, 1H), 6.65 (dd, J = 9.3, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 3.73 (t, J = 6.2 Hz, 4H), 2.58 (t, J = 6.2 Hz, 4H).

2) Synthesis of compound c24‐7:

Compound c24‐6 (3.73 g, 20 mmol) was dissolved in 20 mL of MeCN, then K ₂ CO ₃ (6.9 g, 50 mmol), CD ₃ OTs (4.16 g, 22 mmol), and the reaction was placed at 60 ° C under stirring at room temperature. After the reaction was completed overnight, TLC showed that the reaction was completed, diluted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated. oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.37 (t,J=5.1 Hz, 4H), 2.27 (t,J=5.1 Hz, 4H), 1.39 (s, 9H).

3) Synthesis of compound c24‐8:

Compound c24-7 (2.4 g, 11.8 mmol) was dissolved in 20 ml of DCM, and 10 ml of 4M hydrochloric acid dioxane solution was added dropwise with stirring at room temperature, then stirred at room temperature for 3 h, TLC showed the reaction was complete, and a white solid precipitated, filtered, DCM The filter cake was washed and the filter cake was dried to give the title compound, m.

4) Synthesis of compound c24‐9:

Compound c24-8 (1.26 g, 9 mmol) was dissolved in 20 ml of ethanol, then triethylamine (1.36 g, 13.5 mmol) was added with stirring at room temperature, stirred at room temperature for 10 min, then cooled to 0 ° C, and compound c24 was added. 1-5 (862 mg, 3 mmol), acetic acid (1.8 g, 30 mmol), EtOAc (EtOAc, EtOAc (EtOAc) The mixture was diluted with EtOAc. EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 9.4 Hz, 1H), 6.61 (dd, J = 9.5, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 3.86 (d, J = 13.5 Hz, 2H), 3.00 - 2.87 (m, 2H), 2.64 - 2.41 (m, 8H), 2.21 - 2.36 (m, 1H), 1.94 - 1.86 (m, 2H), 1.59 - 1.46 (m, 2H).

5) Synthesis of compound c24‐10:

The compound c24-9 (583 mg, 1.56 mmol) was dissolved in 25 ml of methanol, then 5% palladium carbon (292 mg) was added with stirring at room temperature, and the mixture was stirred with hydrogen, and stirred at room temperature for 4 h. Crude c24‐10, 494 mg, yellow oil. MS [M+H] ⁺ 345.3; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.67 - 6.56 (m, 3H), 3.48 - 3.38 (m, 2H), 3.17 (br, 2H), 2.72 - 2.37 (m , 10H), 2.30 (tt, J = 11.4, 3.6 Hz, 1H), 1.90 - 1.80 (m, 2H), 1.61 (qd, J = 12.1, 4.0 Hz, 2H).

6) Synthesis of compound c-24:

Compound c24-10 (200 mg, 0.58 mmol) was dissolved in 18 ml of ethylene glycol monobutyl ether, and then compound b3‐1 (237 mg, 0.75 mmol), hydrochloric acid ethanol solution (5.6 M) 0.36 ml was added under stirring at room temperature. The reaction was carried out at 120 ° C, and the mixture was evaporated. EtOAc EtOAc m. MS [M+H] ⁺ 624.3; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.82 (s, 1H), 8.49 (dd, J = 8.5, 4.4 Hz, 1H), 8.01 (s, 1H), 7.96 ( d, J=8.9 Hz, 1H), 7.38 (dd, J=8.7, 7.2 Hz, 1H), 7.25–7.19 (m, 1H), 7.02–7.08 (m, 1H), 6.88 (s, 1H), 6.72 –6.61(m,2H),3.59(d,J=12.2Hz,2H), 2.69–2.40(m,10H),2.36–2.29(m,1H),1.89(d,J=12.7Hz,2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.63–1.68 (m, 2H).

Example 25

The synthetic route of compound c-25 is as follows:

1) Synthesis of compound c25‐5: 10 g of compound c25‐4 was dissolved in 20 mL of 1,4-dioxane, 4M hydrogen chloride in 1,4-dioxane solution (80 mL), and stirred at room temperature for 4 hours. After the reaction was completed, 50 mL of methyl tert-butyl ether was added to the system, stirred for 5 minutes, filtered, and the filter cake was washed with 50 mL of methyl t-butyl ether, and the filter cake was dried to obtain 6.5 g of compound c25-5; ¹ H NMR (400 MHz) , DMSO): δ 9.64 (br, 1H), 3.41 - 3.38 (m, 4H), 2.61 - 2.58 (m, 4H).

2) Synthesis of compound c25‐6: 6.5 g of compound c25‐5, 9.9 g of compound 5A, 16.8 g of potassium carbonate were added to acetonitrile, and the temperature was raised to 80° C. and reacted overnight; after the reaction was completed, the system was cooled to room temperature, and the filtrate was filtered. Concentration, column chromatography (petroleum ether: ethyl acetate = 10:1, ethyl acetate) afforded 1 g of compound C25-6; ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.74 (m, 4H), 2.50‐2.47 (m, 4H).

3) Synthesis of compound c25‐8: 6.5 g of compound c25‐7 was dissolved in 240 ml of THF, 12 g of NaH was added at 0 degree, stirred for half an hour, and 30 g of heavy water was added dropwise to the reaction at 0 degree, plus, 0 degree The reaction was half an hour. 16 g of diethyl bromofluoromethylphosphonate was added dropwise to the reaction system at 0 °C, and the mixture was stirred for 2 hours. TLC showed the reaction was completed, extracted with ethyl acetate (300 ml), the organic phase was dried, concentrated, and 6.5 g C25‐8. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.85 - 7.83 (d, 1H, J = 8.68 Hz), 7.58 - 7.58 (m, 1H), 7.55 - 7.53 (m, 1H).

4) Synthesis of compound c25‐9: 6.5 g of compound c25‐8, 7.6 g of compound 8A, 268 mg of palladium acetate, 672 mg of tricyclohexylphosphine, 9.9 g of potassium carbonate were added to a mixture of 180 mL of 1,4-dioxane and 18 mL of water. The solution was reacted under argon for 15 h at 95 °C. TLC showed the reaction was complete. After concentration, water was added, ethyl acetate was extracted, and the organic phase was washed with brine, dried and concentrated to give 6.56 g of compound c25-9. The NMR information of compound c25-9 was: ¹ H NMR (400MHz, CDCl ₃ ): δ 7.95 - 7.93 (d, 1H, J = 8.44 Hz), 7.37 - 7.34 (m, 2H), 6.23 (br, 1H), 4.13 - 4.12 (m, 2H), 3.67 - 3.64 (m, 2H), 2.51 (br, 2H), 1.49 (s, 9H).

5) Synthesis of compound c25‐10: 3.5 g of compound c25‐9 was dissolved in 10 mL of 1,4-dioxane, and 4 mL of hydrogen chloride in 60 mL of 1,4-dioxane solution was added. The reaction was carried out for 4 hours at room temperature, and the reaction was completed by TLC. Add 30 mL of methyl tert-butyl ether, filter, filter cake washed with 60 mL of methyl tert-butyl ether, and dry to obtain 3.1 g of compound c25‐10; the nuclear magnetic resonance information of compound c25‐10 is: ¹ H NMR (400 MHz, DMSO) ): δ 9.57 (br, 2H), 8.11 - 8.09 (d, 1H, J = 8.56 Hz), 7.61 - 7.58 (dd, 1H, J1 = 8.56 Hz, J2 = 1.8 Hz), 7.56 (s, 1H) , 6.52 (s, 1H), 3.79 (s, 2H), 3.31 (s, 2H), 2.74 - 2.73 (m, 2H).

6) Synthesis of compound c25-11: 307 mg of compound c25-10 was added to 8 mL of anhydrous THF, 0.2 mL of triethylamine was added, stirred for 5 minutes, 232 mg of compound 6 and 0.9 g of acetic acid were added under ice bath, and stirred for half an hour. Under ice cooling, 636 mg of sodium triacetoxyborohydride was added to the reaction, and the mixture was naturally stirred to room temperature overnight. Add 10 mL of water, sodium carbonate to pH = 9, extract with ethyl acetate, dry, concentrate, column chromatography to give 268 mg of compound c25-11; NMR information: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93-7.91 (d, 1H, J = 8.4 Hz), 7.37 - 7.35 (m, 2H), 6.30 - 6.29 (m, 1H), 3.36 - 3.34 (m, 2H), 2.97 - 2.94 (m, 2H), 2.83 - 2.80 (m, 2H), 2.55‐2.54 (m, 2H), 2.45‐2.37 (m, 1H), 2.04‐1.97 (m, 2H), 1.88‐1.85 (m, 2H), 1.74‐1.64 (m, 2H) .

8) Synthesis of compound c25‐12: 268 mg of compound c25‐11, 20 mg of Pd/C, added to 8 mL of anhydrous methanol, stirred under a hydrogen atmosphere for 24 hours, LC-MS showed the reaction was complete, filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give 238 mg of the yellow solid compound c25-12; the NMR information of the compound c25-12 was: ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.89 - 6.87 (m, 2H), 6.72 - 6.70 (d, 2H, J = 8.6 Hz), 3.73 (br, 2H), 3.04 - 2.93 (m, 4H), 2.41 - 2.26 (m, 4H), 2.01 - 1.96 (m, 2H), 1.80 - 1.62 (m, 8H).

9) Synthesis of compound c-25: 171 mg of compound c25-12 and 165 mg of compound b3‐1, dissolved in 13 mL of ethylene glycol monomethyl ether and 0.43 mL of ethanol, and added 0.26 mL of hydrogen chloride in ethanol (5.6 M). 120 degree reaction for 18h. The solvent was removed under reduced pressure, water was added, water was added, and the mixture was adjusted to pH 9 with methylene chloride, extracted with methylene chloride, dried, concentrated, and purified by column chromatography to give 24 g of compound c-25. The NMR information of compound c-25 was: ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.86 (s, 1H), 8.55 - 8.52 (m, 1H), 8.26 - 8.24 (d, 1H, J = 8.00 Hz), 8.11 (s, 1H), 7.49 - 7.45 (t, 1H) ), 7.32 - 7.28 (m, 1H), 7.21 (s, 1H), 7.16 - 7.12 (m, 1H), 7.04 - 7.00 (m, 2H), 3.06 - 3.03 (m, 2H), 2.96 - 2.93 (m , 2H), 2.49‐2.41 (m, 1H), 2.37‐2.26 (m, 3H), 2.9‐1.95 (m, 2H), 1.85‐1.65 (m, 14H).

Example 26

The synthetic route of compound c-26 is as follows:

1) Synthesis of compound c26‐16: 1 g of compound c26‐10 was added to 30 mL of anhydrous THF, 0.68 mL of triethylamine was added, stirred for 5 minutes, 3.24 g of N‐BOC‐4 piperidone and 2.9 g of acetic acid in an ice bath. After the addition, the mixture was stirred for half an hour, and 2.07 g of sodium triacetoxyborohydride was added to the reaction under ice cooling, and the mixture was naturally stirred at room temperature overnight. Add 30 mL of water, sodium carbonate to pH = 9, extract with ethyl acetate, dry, concentrate, and then chromatographed to give 1.2 g of compound c26-16; NMR information: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93 - 7.91 (d, 1H, J = 8.36 Hz), 7.37 - 7.34 (m, 2H), 6.28 (br, 1H), 4.17 (br, 2H), 3.35 - 3.34 (m, 2H), 2.82 - 2.79 (m, 2H), 2.77‐2.71 (m, 2H), 2.55‐2.51 (m, 3H), 1.87‐1.84 (m, 2H), 1.54‐1.45 (m, 11H).

2) Synthesis of compound c26-17: 1.2 g of compound c26-16, 200 mg of Pd/C was taken, added to 50 mL of anhydrous methanol, and stirred under a hydrogen atmosphere for 24 hours. LC-MS showed the reaction was complete, filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give 1.1 g of a yellow solid compound c26-17; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.90 - 6.88 (m, 2H), 6.72 - 6.70 (d, 2H, J = 8.16 Hz), 4.16 ( Br, 2H), 3.74 (s, 2H), 3.02 - 3.00 (m, 2H), 2.73 - 2.66 (m, 2H), 2.46 - 2.34 (m, 2H), 2.29 - 2.24 (m, 2H), 1.83 - 1.80 (m, 4H), 1.72‐1.66 (m, 2H), 1.50‐1.40 (m, 11H).

3) Synthesis of compound c-26: 365 mg of compound c26-17 and 365 mg of compound b3‐4, dissolved in 22 mL of ethylene glycol monomethyl ether and 0.74 mL of ethanol, and added 0.45 mL of hydrogen chloride in ethanol (5.6 M). 120 degree reaction for 18h. The solvent was removed under reduced pressure, water was added, water was added, and the mixture was adjusted to pH 9 with methylene chloride, extracted with dichloromethane, dried and concentrated to give 15 g of compound c-26. The NMR information of compound c-26 was: ¹ H NMR (400 MHz, CD ₃ OD): δ 8.36 - 8.33 (d, 1H, J = 8.36 Hz), 8.04 (s, 1H), 7.79 - 7.77 (dd, 1H, J1 = 7.96 Hz, J2 = 1.48 Hz), 7.71 - 7.68 (d,1H,J=8.16Hz), 7.51‐7.46(m,1H), 7.24‐7.20(m,1H),6.99‐6.96(m,2H),3.32‐3.28(m,2H),3.23‐3.21 (m, 1H), 3.05‐3.02 (m, 2H), 2.86‐2.80 (m, 2H), 2.61‐2.48 (m, 2H), 2.36‐2.31 (m, 2H), 2.01‐1.98 (m, 2H) , 1.81 (br, 2H), 1.72 - 1.58 (m, 4H), 1.15 - 1.13 (d, 6H, J = 6.84 Hz).

Example 27

The synthetic route of compound c-27 is as follows:

1) Synthesis of compound c27‐2: The crude compound c27‐1 (21.7 g, 61.13 mmol) was dissolved in 400 ml of tetrahydrofuran, sodium hydrogencarbonate (5.65 g, 67.24 mmol) was added, the temperature was kept at 0 ° C, and chloroformic acid was added dropwise. Benzyl ester (9.5 ml, 67.24 mmol) was stirred at room temperature for 3 h. The reaction mixture was diluted with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.98 (s, 1H), 7.43-7.35 (m, 5H), 7.01 (s, 1H), 6.82 (s, 1H), 5.55 (br, 1H), 5.21 ( s, 2H), 4.02 (s, 2H), 3.51 - 3.59 (t, 2H), 2.30 (s, 1H), 2.25 (s, 3H), 1.50 (s, 9H).

2) Synthesis of compound c27‐3: Compound c27‐2 (24.9 g, 0.05 mol) was dissolved in 200 ml of 4M hydrochloric acid dioxane solution, then stirred at room temperature overnight, TLC showed the reaction was complete, concentrated under reduced pressure, and saturated. The sodium hydrogencarbonate solution was extracted with EtOAc (EtOAc). MS [M+H] ⁺ 390.2; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.34 - 7.28 (m, 5H), 6.95 (s, 1H), 6.77 (s, 1H), 5.53‐5.52(t,1H), 5.14(s,2H), 3.44‐3.43(d,2H,J=2.71Hz), 3.04‐3.01(t,2H), 2.20‐2.18(m,5H).

3) Synthesis of compound c27‐4: The crude compound c27‐3 (1.86 g, 4.78 mmol) was dissolved in 200 ml of acetonitrile, followed by methyl bromoacetate (0.46 ml, 4.83 mmol), potassium iodide (79 mg, 0.478 mmol). And triethylamine (0.66 ml, 4.83 mmol), EtOAc. MS [M+H] ⁺ 462.2; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.43 - 7.34 (m, 5H), 7.02 (s, 1H), 6.85 (s, 1H), 5.54‐5.53(t,1H), 5.20(s,2H), 3.75(s,3H), 3.39(s,2H), 3.29‐3.27(q,2H),2.84‐2.81(t,2H), 2.39‐ 2.38 (t, 3H), 2.27 (s, 3H).

4) Synthesis of compound c27‐5: Compound c27‐4 (3.0 g) was dissolved in 100 ml of anhydrous methanol, then 50% wet palladium carbon (1.5 g) was added, and hydrogenation reaction was carried out for 24 h with stirring at room temperature, LC‐MS tracking After the reaction was completed, the mixture was filtered through Celite, washed with methanol, and evaporated. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.89 (s, 1H), 6.57 (s, 1H), 3.74 (s, 3H), 3.68 (s, 2H), 3.26 (s, 2H), 3.05-3.02 ( d, 2H, J = 10.58 Hz), 2.61 - 2.54 (m, 1H), 2.32 - 2.25 (m, 2H), 2.21 (s, 3H), 1.80 - 1.69 (m, 4H).

5) Synthesis of compound c-27: Compound c27-5 (505 mg, 1.54 mmol) and compound b3‐4 (558 mg, 1.61 mmol) were dissolved in 40 ml of ethylene glycol monomethyl ether, followed by 7 M hydrochloric acid ethanol solution. (0.82 ml) and 1.33 ml of absolute ethanol were heated to 120 ° C and stirred for 24 h. After the completion of the reaction, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, MS [M+H] ⁺ 639.3; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 8.46 - 8.44 (d, 2H, J = 8.30 Hz), 8.09 (s, 1H), 7.94 ( s, 1H), 7.87‐7.84 (dd, 1H, J1=7.92Hz, J2=1.50Hz), 7.55‐7.51(m,1H), 7.21‐7.17(m,3H),7.13(s,1H),6.96 (s, 1H), 3.68 (s, 3H), 3.22 - 3.17 (m, 3H), 3.02 - 2.99 (m, 2H), 2.63 - 2.57 (m, 1H), 2.29 - 2.23 (m, 2H), 2.15 (s, 3H), 1.78 - 1.67 (m, 4H), 1.26 - 1.24 (d, 6H, J = 6.85 Hz).

Example 28

The synthetic route of compound c-28 is as follows:

The compound c-27 (60 mg, 0.09 mmol) was dissolved in 20 ml of anhydrous ethanol, and then sodium borohydride (14 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. MS [M+H] ⁺ 611.3; ¹ H NMR (400 MHz, CDCl ₃ + D ₂ O) δ 8.54 - 8.52 (d, 1H, J = 8.60 Hz), 8.16 (s, 1H), 8.04 (s, 1H) ), 7.93 - 7.91 (d, 1H, J = 7.59 Hz), 7.62 - 7.58 (m, 1H), 7.24 - 7.17 (m, 1H), 7.03 (s, 1H), 3.78 (br, 2H), 3.65 ( Br, 1H), 3.30 (br, 2H), 2.79 (br, 3H), 2.44 (br, 2H), 2.23 (s, 3H), 1.97 - 1.79 (m, 4H), 1.32 - 1.31 (d, 6H, J = 6.58 Hz).

Example 29

The synthetic route of compound c-29 is as follows:

The compound c-27 (50 mg) was dissolved in 10 ml of anhydrous methanol, and then ammonia gas was passed to cool in an ice salt bath to be saturated, and then transferred to a humidified tank at 100 ° C overnight, and then concentrated by cooling to obtain 20 mg of a c-29 product. MS [M+H] ⁺ 624.3; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 8.53 - 8.51 (d, 2H, J = 8.59 Hz), 8.16 (s, 1H), 8.02 ( s,1H), 7.93-7.91 (d,1H,J=7.86Hz), 7.61‐7.57(t,1H), 7.27‐7.23(m,3H),7.13(br,1H),6.99(s,1H) , 5.71 (br, 1H), 3.28 - 3.26 (m, 2H), 3.11 - 3.02 (m, 5H), 2.72 - 2.64 (m, 1H), 2.35 - 2.30 (t, 2H), 2.20 (s, 3H) , 1.80‐1.69 (m, 4H), 1.32‐1.30 (d, 6H, J=6.62 Hz).

Example 30

The synthetic route of compound c-30 is as follows:

1) The compound c31‐5 (600 mg) was dissolved in 20 ml of anhydrous methanol, and then ammonia gas was passed through the ice salt bath to be saturated, and then transferred to a smoldering pot at 100 ° C for 8 hours. The LCMS detected the reaction completely and concentrated. The crude product is purified by column chromatography to give the product as a yellow solid ^{334mg; MS [M + H] +} 315.2.

2) Compound c31‐6 (100 mg, 0.32 mmol) and compound b3‐4 (116 mg, 0.33 mmol) were dissolved in 8.2 ml of ethylene glycol monomethyl ether, and then 5.6 M hydrochloric acid ethanol solution (0.17 ml) was added in sequence, Ethanol (0.27 ml), warmed to 120 ° C, stirred overnight, concentrated under reduced pressure, EtOAc (EtOAc m. The crude product was obtained and purified by column chromatography to give 36 mg. MS [M+H] ⁺ 683.2; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 8.46 - 8.44 (d, 2H, J = 8.30 Hz), 8.09 (s, 1H), 7.94 ( s, 1H), 7.87‐7.84 (dd, 1H, J1=7.92 Hz, J2=1.50 Hz), 7.55‐7.51 (m, 1H), 7.21‐7.14 (m, 3H), 6.96 (s, 1H), 4.25 ‐4.22(t,2H), 3.56‐3.54(t,2H), 3.33(s,3H), 3.28‐3.26(m,2H), 3.20‐3.15(q,2H),3.03‐3.10(d,2H, J=11.32Hz), 2.64‐2.55(m,1H), 2.35‐2.29(t,3H), 2.15(s,3H),1.78‐1.67(m,6H),1.26‐1.24(d,6H,J= 6.85Hz).

Effect test: Determination of biological activity

The compounds prepared in Examples 1-9 were screened for activity against anaplastic lymphoma kinase (ALK) using the Caliper Mobility Shift Assay method at ATP Km concentrations.

The in vitro activity of each compound on anaplastic lymphoma kinase (ALK) was screened at Km concentration using the Caliper Mobility Shift Assay method, and Staurosporine was used as a control. The bioactivity screening of the compound will be performed at 10 concentrations. Repeat the assay.

Experimental Materials:

Anaplastic lymphoma kinase (ALK) (Carna, Cat. No. 08-105, Lot. No. 08CBS‐0112);

Peptide FAM‐P22 (GL Biochem, Cat. No. 112393, Lot. No. P080401‐XY112393);

ATP (Sigma, Cat. No. A7699‐1G, CAS No. 987‐65‐5);

DMSO (Sigma, Cat. No. D2650, Lot. No. 474382);

EDTA (Sigma, Cat. No. E5134, CAS No. 60‐00‐4);

96-well test tray (Corning, Cat. 3365, Lot. No. 22008026);

384-well test disk (Corning, Cat. 3573, Lot. No. 12608008);

Staurosporine (Sigma, Cat. No. S4400‐1 MG, Lot. No. 046K4080).

Test sample

Each sample was separately formulated into a solution having a concentration of 10 mM.

experimental method

1. Prepare 1.25x kinase basic buffer solution and quenching buffer solution for experimental kinase.

1. 1.25x kinase basic buffer solution containing no manganese chloride (MnCl ₂ )

HEPES solution at a concentration of 62.5 mM, pH = 7.5,

Brij‐35 with a concentration of 0.001875%,

a solution of magnesium dichloride (MgCl ₂ ) at a concentration of 12.5 mM,

a DTT solution at a concentration of 2.5 mM;

2. 1.25x kinase basic buffer solution containing manganese chloride (MnCl ₂ )

HEPES solution at a concentration of 62.5 mM, pH = 7.5,

Brij‐35 with a concentration of 0.001875%,

a solution of magnesium dichloride (MgCl ₂ ) at a concentration of 12.5 mM,

a solution of manganese dichloride (MnCl ₂ ) at a concentration of 12.5 mM,

a DTT solution at a concentration of 2.5 mM;

3, quenching buffer solution

HEPES solution at a concentration of 100 mM, pH = 7.5,

Brij-35 at a concentration of 0.015%,

No. 3 surface reagent with a concentration of 0.2%,

The concentration was 50 mM EDTA solution.

2. Preparing compounds for experimental kinases

Serial dilution of the compound series

1. Pipette 5 μl of the compound solution with a concentration of 10 mM into a test tube, add 95 μl of DMSO, and dilute to a compound concentration of 500 μM;

2. Transfer the compound in the test tube to one of the 96-well storage trays, transfer 30 μL of the compound to the next adjacent well, and add 60 μL of DMSO to dilute it. Continue to dilute by this method to obtain a concentration from 500 μM. 10 compound solutions of 0.025 μM;

3. In the same 96-well test tray, add 60 μL of DMSO to each row of wells for DMSO control;

4. Transfer 5 μL of solution from each well to another 96-well test tray and add 45 μL of H ₂ O;

5. Transfer 70 μL of 250 mM EDTA for low control;

6. Transfer 5 μL of each well to a 384-well assay plate; the 96-well plate contains a low-controlled A1 transfer to A1 and A2 in a 384-well plate, and the 96-well plate contains the highest compound concentration. The A2 is transferred to the A3 and A4 of the 384-well plate, and so on.

Thus, this assay plate contained a 10% DMSO solution in 5% of the compound at a starting concentration of 50 [mu]M.

Third, the kinase reaction

1. Prepare 2.5x enzyme solution

Adding the kinase to a 1.25x kinase base buffer solution;

2. Prepare 2.5x peptide solution

Adding FAM-labeled peptide and ATP to a 1.25x kinase base buffer solution;

3. Transfer the 2.5x kinase solution to the assay plate.

Now analyze 5 μL of compound in 10% DMSO solution in the plate;

Add 10 μL of 2.5x enzyme solution to each well of the 384-well assay plate;

Incubate for 10 minutes at room temperature;

4. Transfer the 2.5x peptide solution to the analysis plate.

Add 10 μL of 2.5x peptide solution to each well of the 384-well assay plate;

5, enzyme reaction and quenching

Incubate at 28 ° C for a certain period of time, in this experiment is 1 hour;

Add 25 μL of quenching buffer solution to stop the reaction;

6, Caliper read data

Caliper collects data

7, curve fitting

Copy data from Caliper;

Convert the conversion value to a suppression value:

Percent inhibition = (maximum - conversion value) / (maximum - minimum value) * 100,

Wherein the maximum value represents DMSO control; the minimum value represents low control;

Fitting data in Xlfit to get IC ₅₀ values

Use the following equation:

Y=Bottom+(Top‐Bottom)/(1+10^((LogIC ₅₀ ‐X)*HillSlope)).

The IC ₅₀ (nM) values of the inhibitory activity of the obtained test sample against anaplastic lymphoma kinase (ALK) are shown in the following table:

化合物Compound	最高浓度(uM)Highest concentration (uM)	ALK IC ₅₀(nM) ALK IC ₅₀ (nM)
StaurosporineStaurosporine	11	2.632.63
c‐1C‐1	1010	4.994.99
c‐2C‐2	1010	5.635.63
c‐3C‐3	1010	49.2349.23
c‐4C‐4	1010	0.960.96
c‐5C‐5	1010	11.0711.07
c‐6C‐6	1010	0.970.97
c‐7C‐7	1010	3.773.77
c‐8C‐8	1010	4.454.45
c‐9C‐9	1010	8.228.22
c‐14C‐14	1010	0.580.58
c‐15C‐15	1010	0.610.61
c‐16C‐16	1010	1.111.11
c‐17C‐17	1010	0.920.92
c‐18C‐18	1010	0.670.67
brigatinibBrigatinib	1010	20.3320.33

As can be seen from the above table, the compounds synthesized by Staurosporine (brassinin) and brigitinib (brutinib) as reference materials have good effects on anaplastic lymphoma kinase (ALK). Inhibition ability.

The above is only the embodiment of the present invention, and is not intended to limit the scope of the invention, and equivalent transformations made by the contents of the specification of the present invention, or directly or indirectly applied to other related technical fields, are included in the present invention. Within the scope of patent protection.

Claims

a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

among them:

n is 0 or 1;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, anthracene, halogen, cyano, nitro, ester, C 1-6 alkyl , C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1‐6 Alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 cycloalkylamino;

Y 1 and Y 2 are each independently selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from H, hydrazine, halogen, C. a 1 to 6 alkyl group, a C 3-6 cycloalkyl group or a C 1 to 6 haloalkyl group;

R a is H, 氘,
Methoxy,
Cyano group,
Halogen, acetyl,
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;

R b is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 Cycloalkylamino;

R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio;

R d is selected from any of the following structures:
A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in Formula II or Formula III:

In formula III, R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C a 1 to 6 haloalkoxy group, a C 3-6 cycloalkoxy group, a C 1 to 6 haloalkyl group, a C 1 to 6 alkylthio group, a C 1 to 6 acyl group, a C 1 to 6 alkylamino group or a C 3-6 cycloalkylamino group;

In formula II or formula III,

n is 0 or 1;

X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkyl sulfide a C 1 - 6 acyl group, a C 1 - 6 alkylamino group or a C 3-6 cycloalkylamino group;

Y 1 and Y 2 are each independently selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from H, hydrazine, halogen, C. a 1 to 6 alkyl group, a C 3-6 cycloalkyl group or a C 1 to 6 haloalkyl group;

R a is H, 氘,
Methoxy,
Cyano group,
Halogen, acetyl,
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;

R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio;

R d is selected from any of the following structures:
A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in Formula IV or Formula V:

In formula V, R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C a 1 to 6 haloalkoxy group, a C 3-6 cycloalkoxy group, a C 1 to 6 haloalkyl group, a C 1 to 6 alkylthio group, a C 1 to 6 acyl group, a C 1 to 6 alkylamino group or a C 3-6 cycloalkylamino group;

In Formula IV or Formula V,

n is 0 or 1;

X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkyl sulfide a C 1 - 6 acyl group, a C 1 - 6 alkylamino group or a C 3-6 cycloalkylamino group;

Y 2 is selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from the group consisting of H, hydrazine, halogen, C 1 - 6 alkyl a C 3-6 cycloalkyl or a C 1-6 haloalkyl group;

R a is H, 氘,
Methoxy,
Cyano group,
Halogen, acetyl,
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;

R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio;

R d is selected from any of the following structures:
A compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as shown in Formula VI or Formula VII:

Wherein: in Formula VII, R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy , C 1 - 6 haloalkoxy, C 3-6 cycloalkoxy, C 1 - 6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkane An amino group or a C 3-6 cycloalkylamino group;

In formula VI or formula VII,

R a is H, 氘,
Methoxy,
Cyano group,
Halogen, acetyl,
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;

R d is selected from any of the following structures:

R 4 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 Cycloalkylamino;

R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio group.
The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein R 1 is a halogen.
The compound according to claim 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein R a is H, hydrazine, methoxy, cyano, halogen, acetyl base,

R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from the group consisting of H, anthracene, halogen, and C 1-6 alkyl.
The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein R d is selected from any one of the following structures:
The compound according to claim 7, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein R c is selected from the group consisting of H, isopropoxy, difluoromethoxy, Deuterated monofluoromethoxy, deuterated difluoromethoxy.
The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein R 4 is selected from the group consisting of H, C 1 - 6 alkyl, C 3 - a cycloalkyl group of 6 , a C 1 - 6 alkoxy group.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is selected from the group consisting of the compounds represented by the following structural formula:
The compound according to any one of claims 1 to 10, wherein the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of hydrochloride, hydrobromide, and hydrogen. Iodate, sulphate, hydrogen sulphate, nitrate, phosphate, acid phosphate; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate , glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate , benzenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier;

as well as,

A compound according to any one of claims 1 to 10, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug or isotopic variation thereof.
Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for inhibiting cell proliferation.
Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of cancer.
Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for inhibiting anaplastic lymphoma kinase.
Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.