Gem-difluorocycloheptane compound, preparation therefor, and use thereof

Abstract

The present invention relates to a gem-difluorocycloheptane compound, preparation therefor, and use thereof. Specifically, the compound of the present invention has a structure represented by formula (I), wherein the definitions of each group and substituent are as described in the specification. Also disclosed in the present invention are a preparation method for the compound and use thereof in the prevention and / or treatment of Erα-positive tumors.

Description

Gem-difluorocycloheptane compounds, their preparation and uses Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to gem-difluorocycloheptane compounds, their preparation, and uses. Background Technology

[0002] In 2022, there were 2.309 million new cases of breast cancer worldwide, accounting for 11.6% of all new cancer cases, ranking second and first among new cancers in women (CA Cancer J Clin. 2024 May-Jun; 74(3):229-263.). Estrogen receptor (ER) positive breast cancer is the most common subtype of breast cancer, accounting for about 80% of all breast cancer patients (CA Cancer J Clin. 2019 Nov; 69(6):438-451.). ERα is considered one of the most important driving factors in breast cancer. Estrogen-induced activation of the ERα nuclear receptor promotes the proliferation and survival of normal and cancerous breast tissues through the transcription of survival-promoting genes (genomic regulation) and the activation of cell signaling pathways (non-genomic regulation). After ERα binds to estrogen, ERα dimers and translocates to the cell nucleus, where the ERα dimer binds to the coactivator (CoA) to form the transcriptionally active ER complex (Cancer Cell. 2020 April 13; 37(4):496–513.).

[0003] Endocrine therapy is one of the most effective treatments for ERα-positive breast cancer. Endocrine therapy drugs include aromatase inhibitors (AIs), estrogen receptor modulators (SERMs), and estrogen receptor degraders (SERDs). Although endocrine therapy can significantly prolong patient survival, reduce mortality, and improve prognosis, a large number of patients still experience disease progression such as endocrine resistance, ERα mutations, recurrence, and metastasis. In addition, adjuvant endocrine therapy requires long-term medication for several years, and patients suffer from side effects such as hot flashes, sexual dysfunction, weight gain, musculoskeletal disorders, decreased bone density, depression, cognitive impairment, and fatigue (J Natl Cancer Inst. 2011 Sep 7; 103(17):1299-309.; J Natl Cancer Inst. 2012 Mar 7; 104(5):386-405.), which seriously impairs patients' quality of life and reduces treatment adherence (Ann Oncol. 2019 Nov 1; 30(11):1784-1795.). Therefore, there remains a significant unmet clinical need for the treatment of ERα-positive breast cancer. Besides breast cancer, other ERα-positive diseases such as ovarian cancer, uterine cancer, and endometrial cancer also face similar unmet clinical needs.

[0004] ErSO is an activator of endoplasmic reticulum stress and unfolded protein response in ERα-positive tumor cells (Sci Transl Med. 2021 Jul 21; 13(603): eabf1383.), inducing cell swelling and necrosis, and has the potential to treat ERα-positive cancers. In in vitro experiments, ErSO showed broad-spectrum and highly efficient killing activity against ERα-positive tumor cells; in in vivo experiments, ErSO could induce rapid regression of tumors in mice and had the same efficacy against ERα mutant strains. However, ErSO has poor selectivity for ERα-negative cells and also has a strong inhibitory effect on some ERα-negative cells, such as HT-29 IC50. 50 The concentration reached 0.25 μM, posing a significant safety risk (J Med Chem. 2022 Mar 10; 65(5):3894-3912.), limiting its further research and development. NC1 is a structural analogue with the same mechanism of action as ErSO, and it also has a strong killing effect on ERα tumor cells (J Med Chem. 2010 Oct 14; 53(19):7140-5.). Related studies have shown that NC1 may induce mitochondrial damage through cell osmotic pressure, thereby inducing swelling and necrosis of ERα tumor cells (Cell Death Dis. 2023 Apr 5; 14(4):238.). However, NC1 also has not solved the problem of high cytotoxicity and poor selectivity to ERα-negative cells, such as the IC50 of NC1 against HT-29. 50 The concentration reached 0.266 μM, posing a significant risk to drug safety. Summary of the Invention

[0005] The purpose of this invention is to provide a compound of Formula I, a method for its preparation, and its use in the prevention and / or treatment of ERα-positive tumors.

[0006] In a first aspect, the present invention provides a compound, said compound being a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof.

[0007] in:

[0008] X is selected from the following group: O, S, NR A ;

[0009] Y is selected from the following group: O, S, NR A ;

[0010] Each R A Each is independently selected from the following groups: H, C 1-6 alkyl,

[0011] R A-1 Selected from the following groups: H, C 1-6 alkyl;

[0012] R 1 R 2 R 3 R 4 Each is independently selected from the following groups: H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 Alkyl, OR B SR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B OS(=O)2R B NR B S(=O)2R B C(=O)R B C(=O)OR B C(=O)N(R) B 2. S(=O)R B S(=O)2R B ;

[0013] Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 alkyl;

[0014] Or, R 1 and R 2 Structures selected from the group consisting of carbon, nitrogen, or oxygen atoms are formed by the connection of carbon, nitrogen, or oxygen atoms: C 4-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0015] R 5 Selected from the following group: H, halogens;

[0016] Z is selected from the following group: OR C SR C B(OR) C )2;

[0017] Each R C Each is independently selected from the following groups: H, C 1-6 Alkyl, P(=O)(OR) C-1 (OR) C-2 ), CH2OP(=O)(OR C- 1 (OR) C-2 ), CH(CH3)OP(=O)(OR C-1 (OR) C-2 ), C(=O)R C-3 C(=O)OR C-3 C(=O)N(R) C-3 2. C 2-10 amino acids;

[0018] Each R C-1 R C-2 Each of the following elements is independently selected: H, Na, K, Ca, Mg, NH4, C 1-6 Alkyl, Halogenated C 1- 6-alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl;

[0019] Each R C-3 Each is independently selected from the following groups: H, C 1-6 alkyl and amino substituted C 1-6 Alkyl, Halogenated C 1-6 Alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl;

[0020] R m Selected from the following group: halogens, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0021] G is selected from the following group:

[0022] Each R D Each is independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6Alkoxy;

[0023] n is selected from the following group: 0, 1, 2, 3, 4, 5, 6.

[0024] In another preferred embodiment, X is NH; Y is O.

[0025] In another preferred embodiment, G is

[0026] Each R D Each is independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy;

[0027] n is selected from the following group: 0, 1, 2, 3, 4, 5, 6.

[0028] In another preferred embodiment, G is

[0029] In another preferred embodiment, G is

[0030] In another preferred embodiment, R 1 R 2 Each is independently selected from the following groups: H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 Alkyl, OR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B OS(=O)2R B NR B S(=O)2R B C(=O)R B C(=O)OR B C(=O)N(R) B 2. S(=O)R B S(=O)2R B ;

[0031] Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 alkyl;

[0032] Or, R 1 and R 2 Structures selected from the group consisting of carbon, nitrogen, or oxygen atoms are formed by the connection of carbon, nitrogen, or oxygen atoms: C 4-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0033] R 3 For H;

[0034] R 4 For H.

[0035] In another preferred embodiment, the compound is the compound shown in formula (II):

[0036] in:

[0037] R 1 R 2 Each is independently selected from the following groups: H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2- 6-Alkyne, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 Alkyl, OR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B OS(=O)2R B NR B S(=O)2R B C(=O)R B C(=O)OR B C(=O)N(R) B 2. S(=O)R B S(=O)2R B;

[0038] Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 alkyl;

[0039] Or, R 1 and R 2 Structures selected from the group consisting of carbon, nitrogen, or oxygen atoms are formed by the connection of carbon, nitrogen, or oxygen atoms: C 4-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0040] R 5 Selected from the following group: H, halogens;

[0041] Z is selected from the following group: OR C SR C B(OR) C )2;

[0042] Each R C Each is independently selected from the following groups: H, C 1-6 Alkyl, P(=O)(OR) C-1 (OR) C-2 ), CH2OP(=O)(OR C- 1 (OR) C-2 ), CH(CH3)OP(=O)(OR C-1 (OR) C-2 ), C(=O)R C-3 C(=O)OR C-3 C(=O)N(R) C-3 2. C 2-10 amino acids;

[0043] Each R C-1 R C-2 Each of the following elements is independently selected: H, Na, K, Ca, Mg, NH4, C 1-6 Alkyl, Halogenated C 1- 6-alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl;

[0044] Each R C-3 Each is independently selected from the following groups: H, C 1-6 alkyl and amino substituted C1-6 Alkyl, Halogenated C 1-6 Alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl;

[0045] R m Selected from the following group: halogens, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0046] Each R D Each is independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy;

[0047] n is selected from the following group: 0, 1, 2, 3, 4, 5, 6.

[0048] In another preferred embodiment, R 1 Selected from the following group: halogens, C 1-6 Alkyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, cyano.

[0049] In another preferred embodiment, R 1 Selected from the following groups: F, Cl, Br, Me, CF3, CF2H, CN, ethynyl group.

[0050] In another preferred embodiment, R 2 Selected from the following groups: H, halogens, C 1-6 Alkyl, cyano, OR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B C(=O)R B C(=O)OR B C(=O)N(R) B )2、S(=O)2R B ;

[0051] Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C1-6 Alkyl, halogenated and deuterated C 1-6 alkyl.

[0052] In another preferred embodiment, R 2 Selected from the following groups: H, F, Me, OMe, OCD3, OCHF2, OCDF2, CN, NH2, C(O)OMe, NHC(O)Me, C(O)Me, C(O)OH, C(O)NH2, S(O2)Me.

[0053] In another preferred embodiment, R 1 and R 2 Cyclopentane is formed by carbon atom bonding.

[0054] In another preferred embodiment, Z is selected from the group consisting of: OH, B(OH)2, OP(O)(OH)2, OP(O)(ONa)2, OC(O)CH3, OC(O)CH2CH3, OC(O)CH(CH3)2, OC(O)N(CH3)2, OCH2OP(O)(OH)2, OCH2OP(O)(ONa)2, OCH(CH3)OP(O)(OH)2, and OCH(CH3)OP(O)(ONa)2. and / or

[0055] R 5 Selected from the following groups: H, F, Cl.

[0056] In another preferred embodiment, the compound is a compound of formula (IIIa) or (IIIb):

[0057] G is selected from the following group:

[0058] Other groups are as defined above.

[0059] In another preferred embodiment, the compound is selected from the group consisting of the compound shown in formula (IV-a), the compound shown in formula (IV-b), the compound shown in formula (IV-c), and the compound shown in formula (IV-d).

[0060] Each group is as defined above.

[0061] In another preferred embodiment, the compound is selected from the group consisting of: the compound shown in formula (Va), the compound shown in formula (Vb), the compound shown in formula (Vc), and the compound shown in formula (Vd);

[0062] Each group is as defined above.

[0063] In another preferred embodiment, the compound is selected from the group consisting of compounds of formula (VI-a) and compounds of formula (VI-b);

[0064] Each group is as defined above.

[0065] In another preferred embodiment, the compound is selected from the group consisting of:

[0066] In another preferred embodiment, the compound is selected from the group consisting of:

[0067] In another preferred embodiment, the compound is selected from the group consisting of:

[0068] In another preferred embodiment, the compound is selected from the group consisting of:

[0069] In another preferred embodiment, the compound is selected from the group consisting of:

[0070] In another preferred embodiment, the compound is selected from the group consisting of:

[0071] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound described in the first aspect of the present invention.

[0072] A third aspect of the invention provides the use of the compound described in the first aspect of the invention for the preparation of a medicament for the prevention and / or treatment of ERα-positive tumors.

[0073] In another preferred embodiment, the ERα-positive tumor is selected from the group consisting of: ERα-positive breast cancer, ERα-positive ovarian cancer, ERα-positive uterine cancer, ERα-positive cervical cancer, and ERα-positive endometrial cancer.

[0074] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0075] Figure 1 is a single crystal structure diagram of compound 9-A.

[0076] Figure 2 is a comparison of the ERα-negative / ERα-positive cytotoxicity of compound 9-A and the comparative examples ErSO, NC1, and (S)-45.

[0077] Figure 3 shows the weight changes in mice using the MCF-7 human breast cancer BALB / c nude mouse orthotopic transplantation model.

[0078] Figure 4 shows the changes in tumor volume in mice using the MCF-7 human breast cancer BALB / c nude mouse orthotopic transplantation model. Detailed Implementation

[0079] Through long-term and in-depth research and structural optimization, the inventors obtained a compound of formula I with excellent selective inhibitory activity against ERα-positive cells, excellent pharmacokinetic properties, and excellent safety. Based on this, the inventors completed this invention.

[0080] the term

[0081] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0082] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0083] In this invention, "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0084] In this invention, the term "C" 2-6 "Alkenyl" refers to a straight-chain or branched alkenyl group with 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0085] In this invention, the term "C" 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group with 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0086] In this invention, the term "C" 3-6"Cyclic hydrocarbon group" includes groups selected from the following group: C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 3- 6-cyclic ynyl group.

[0087] In this invention, the term "C" 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3-6 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "C"... 4-8 "Cycloalkyl" has a similar meaning.

[0088] In this invention, the term "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is C16. 1-4 Alkyl group.

[0089] In this invention, the term "heterocyclic alkyl" refers to a 3-8 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0090] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C". 6-10 Aryl. The term "C" 6- 10 "Aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0091] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0092] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0093] In this invention, the term "deuteration" refers to being replaced by deuterium.

[0094] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0095] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0096] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0097] compound

[0098] This invention provides compounds of formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or prodrugs thereof.

[0099] The groups are defined above.

[0100] In another preferred embodiment, in the compound, R 1 R 2 R 3 R 4 R 5 Each of X, Y, Z, and G is an independent group corresponding to the specific compound described in this invention.

[0101] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0102] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0103] Furthermore, the compounds of this invention also include prodrugs of the compounds shown in formula (I). The term "prodrug" includes compounds that are biologically active or inactive on their own, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of formula (I), or salts or solutions of compounds of formula (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0104] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion (e.g., enantiomer mixtures, diastereomer mixtures), all of which are within the scope of the present invention.

[0105] In this invention, the term "stereoisomer" refers to molecules that have the same atomic composition and connection mode but different three-dimensional spatial arrangements. It includes, but is not limited to, cis-trans isomers, enantiomers and diastereomers, conformational isomers, etc.

[0106] In this invention, the term "enantiomer" refers to two stereoisomers that are chemically mirror-symmetric but cannot be completely superimposed by rotation, translation, or vibration. A mixture of two enantiomers in any proportion is called an enantiomer mixture, and the term "racemic mixture" refers to an enantiomer mixture of two enantiomers in a 50%:50% ratio. Enantiomer mixtures can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, including but not limited to chiral HPLC separation, chiral SFC separation, and chiral reagent resolution.

[0107] In this invention, the term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as optical rotation, melting point, boiling point, spectral properties, or biological activity. A mixture of two or more enantiomers in any proportion is called a diastereomer mixture. Diastereomer mixtures can be separated using conventional methods or high-resolution analytical methods, including but not limited to recrystallization, column chromatography, and high-performance liquid chromatography.

[0108] Many organic compounds exist in an optically active form, meaning they are capable of rotating the plane of polarized light. When describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L, or (+), (-) are used to name the symbol for the rotation of plane-polarized light in a compound; (-) or L indicates that the compound is levorotatory, and the prefix (+) or D indicates that the compound is dextrorotatory.

[0109] The compounds disclosed in this invention may have one, two, or more chiral centers, each chiral center independently having an R configuration or an S configuration. Some compounds disclosed in this invention have chiral centers labeled R* or S*, indicating that the absolute configuration of that chiral center has not been identified, but the compound has been chirally resolved and the chiral center is a mono-configured chiral center; the compound is a mono-configured enantiomer monomer or a mono-configured diastereomer monomer. Some compounds disclosed in this invention have chiral centers labeled R*R*, R*S*, S*R*, or S*S*, indicating that the compound has two chiral centers, the absolute configurations of which have not been identified, but the compound has been chirally resolved and both chiral centers are mono-configured chiral centers; the compound is a mono-configured enantiomer monomer or a mono-configured diastereomer monomer. The chiral centers of some compounds disclosed in this invention are labeled R*R*+S*S*, S*S*+R*R*, R*S*+S*R*, or S*R*+R*S*, indicating that the compound has two chiral centers whose absolute configurations have not been identified. However, the compound has been separated by high-performance liquid chromatography or chiral resolution, and is either an enantiomer mixture (in some compounds, this enantiomer mixture is a racemic compound) or a diastereomer mixture. When the absolute configuration of the chiral centers of the compounds disclosed in this invention has not been identified, such compounds can be identified based on their retention times (RT or Rt) under the corresponding chromatographic column conditions (e.g., column type, column packing material, column size, mobile phase, etc.).

[0110] In this invention, "hydrogen" includes all its isotopes, including protium, deuterium, and tritium. Deuterated drugs, formed by replacing hydrogen with deuterium, have higher bond energies between deuterium atoms and carbon atoms than between ordinary hydrogen atoms and carbon atoms. Compared to undeuterated drugs, deuterated drugs offer advantages such as improved drug stability, reduced drug toxicity, enhanced efficacy, and improved pharmacokinetics. All deuterated derivatives of the compounds of this invention should be included within the scope of this patent.

[0111] The embodiments of this invention specifically describe methods for preparing compounds of formula (I) of this invention, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0112] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0113] Pharmaceutical Compositions and Administration

[0114] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the present invention.

[0115] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0116] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0117] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0118] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0119] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0120] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound in such compositions may be delayed in a portion of the digestive tract. Examples of encapsulating components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0122] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0123] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0124] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0125] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0126] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0127] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0128] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0129] Compared with the prior art, the present invention has the following main advantages:

[0130] (1) The compound of the present invention overcomes the problems of high toxicity and poor selectivity of existing compounds to ERα-negative cells, and has a selectivity of up to thousands of times for ERα-negative cells (HT-29), and significantly reduces extra-target toxicity;

[0131] (2) The compounds of the present invention have stronger antitumor activity;

[0132] (3) The compounds of the present invention have excellent pharmacokinetic properties and excellent safety.

[0133] (4) The compounds of the present invention have excellent tumor tissue selectivity.

[0134] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0135] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0136] Example 1: Preparation of compounds 1-P1, 1-P2, 1-A, 1-B, 1-C, and 1-D

[0137] Preparation of compounds 1-2:

[0138] Compound 1-1 (1.16 g, 5.39 mmol) and 4,4-difluorocycloheptanone (1.20 g, 8.10 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Zinc powder (2.12 g, 32.4 mmol) was added to the reaction solution. The mixture was cooled to 0 °C under nitrogen protection. Titanium tetrachloride (1.18 mL, 10.8 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (20 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.31 g of a red oily substance was obtained, which was dissolved in toluene (30 mL). PPTS (132 mg, 0.525 mmol) was added, and the reaction solution was refluxed for 1.5 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-25%) was performed to give title compounds 1-2 (1.30 g, pink solid), in 73% yield.

[0139] LC-MS(ESI)m / z[M+H] + 332.47.

[0140] Preparation of compounds 1-3:

[0141] Compounds 1-2 (1.22 g, 3.68 mmol) were dissolved in a mixed solution of tetrahydrofuran (10 mL) and methanol (10 mL). After cooling to 0 °C, sodium borohydride (166 mg, 4.39 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give compound 1-3 (886 mg, white solid), in 72% yield.

[0142] LC-MS(ESI)m / z[M+H]+ 334.53.

[0143] Preparation of compounds 1-4:

[0144] Compounds 1-3 (800 mg, 2.40 mmol) were dissolved in a mixed solution of toluene (8 mL) and tetrahydrofuran (8 mL). After cooling to 0 °C, tert-butyl hydroperoxide (309 mg, 2.40 mmol, 70% aqueous solution) and potassium tert-butoxide (269 mg, 2.40 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compounds 1-4 (679 mg, yellow oil), in 81% yield.

[0145] LC-MS(ESI)m / z[M-(OH)] + 332.53.

[0146] Preparation of compound 1:

[0147] Phenol (188 mg, 2.00 mmol) was dissolved in anhydrous 1,2-dichloroethane (50 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.88 mL, 9.94 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compounds 1-4 (350 mg, 1.00 mmol) in 1,2-dichloroethane (40 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 2 hours. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give title compound 1 (295 mg, yellow oil), yield 69%.

[0148] LC-MS(ESI)m / z[M+H] + 426.55.

[0149] Preparation of compounds 1-P1 and 1-P2:

[0150] Compound 1 (85 mg, 0.20 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to give compound 1-P1 (4.3 mg, white powder, RT = 21.438 min), yield 5.1%, and compound 1-P2 (5.7 mg, white powder, RT = 22.370 min), yield 6.7%.

[0151] Compound 1-P1: 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.48(s,1H),7.65(d,J=7.5Hz,1H),7.5 3(d,J=8.1Hz,1H),7.21(t,J=7.8Hz,1H),7.14(d,J=8.3Hz,2H),6.72(d,J=8. 3Hz,2H),2.70(t,J=11.0Hz,1H),2.16–2.00(m,2H),1.98–1.83(m,2H),1.66– 1.50(m,2H),1.47–1.26(m,3H),1.13(q,J=11.9Hz,1H).LC-MS(ESI)m / z[M+H] + 426.55.

[0152] Compound 1-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.95 (s, ¹H), 9.46 (s, ¹H), 7.60 (d, J = 7.5Hz, ¹H), 7.56 (d, J = 8.1Hz, ¹H), 7.23 (t, J = 7.8Hz, ¹H), 7.11 (d, J = 8.4Hz, 2H), 6.72 (d, J = 8.3Hz, 2H), 2.70 (t, J = 10.8Hz, 1H), 2.19–1.98 (m, 2H), 1.98–1.77 (m, 2H), 1.60–1.50 (m, 3H), 1.48–1.30 (m, 2H), 0.89 (q, J = 10.2Hz, 1H). LC-MS (ESI) m / z [M+H] + 426.55.

[0153] Preparation of compounds 1-A, 1-B, 1-C, and 1-D: 950 mg of compound 1 was dissolved in 30 mL of ethanol and subjected to two separate chiral separations using SFC. First separation conditions: Instrument model: Waters SFC 150; Column model: [not specified] IG (250*50mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.2% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. Second separation conditions: Instrument model: Waters SFC 150, Column model; AD (250*50mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.2% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 120mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following compounds were obtained: 1-A 209mg, 1-B 211mg, 1-C 206mg, 1-D 238mg.

[0154] Compound 1-A: Chiral analysis method (Instrument model: Waters UPCC (CA-185); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 90:10; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.929min). 1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),9.49(s,1H),7.60(d,J=7.5Hz,1H),7 .56(d,J=8.2Hz,1H),7.23(t,J=7.9Hz,1H),7.11(d,J=8.4Hz,2H),6.72(d, J=8.3Hz,2H),2.76–2.65(m,1H),2.18–1.98(m,2H),1.97–1.78(m,2H),1.6 0–1.50(m,3H),1.47–1.35(m,2H),0.97–0.84(m,1H).LC-MS(ESI)m / z[M+H] + 426.55.

[0155] Compound 1-B: Chiral analysis method (Instrument model: Waters UPCC (CA-185); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 90:10; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.631min). 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 9.48 (s, 1H), 7.65 (d, J = 7.5Hz, 1H), 7.5 3(d,J=8.0Hz,1H),7.21(t,J=7.8Hz,1H),7.14(d,J=8.3Hz,2H),6.72(d,J=8. 3Hz,2H),2.74–2.67(m,1H),2.14–1.99(m,2H),1.99–1.84(m,2H),1.65–1.52 (m,2H),1.49–1.27(m,3H),1.13(q,J=12.4,11.9Hz,1H).LC-MS(ESI)m / z[M+H] + 426.55.

[0156] Compound 1-C: Chiral analysis method (Instrument model: Waters UPCC (CA-185); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 90:10; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.916min). 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.46(s,1H),7.60(d,J=7.5Hz,1H),7.5 6(d,J=8.1Hz,1H),7.23(t,J=7.8Hz,1H),7.11(d,J=8.4Hz,2H),6.72(d,J=8. 3Hz,2H),2.70(t,J=10.8Hz,1H),2.17–2.00(m,2H),1.97–1.77(m,2H),1.59– 1.49(m,3H),1.47–1.34(m,2H),0.89(q,J=10.2Hz,1H).LC-MS(ESI)m / z[M+H] + 426.55.

[0157] Compound 1-D: Chiral analysis method (Instrument model: Waters UPCC (CA-185); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 90:10; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 4.147min). 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.48(s,1H),7.65(d,J=7.5Hz,1H),7.5 3(d,J=8.1Hz,1H),7.21(t,J=7.8Hz,1H),7.14(d,J=8.3Hz,2H),6.72(d,J=8. 3Hz,2H),2.70(t,J=11.0Hz,1H),2.16–2.00(m,2H),1.99–1.83(m,2H),1.70– 1.52(m,2H),1.49–1.27(m,3H),1.13(q,J=11.9Hz,1H).LC-MS(ESI)m / z[M+H] + 426.55.

[0158] Example 2: Preparation of compounds 2-P1, 2-P2, 2-A, 2-B, 2-C, and 2-D

[0159] Preparation of compound 2-2:

[0160] Compound 2-1 (285 mg, 1.22 mmol) and 4,4-difluorocycloheptanone (217 mg, 1.46 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL). Zinc powder (318 mg, 4.86 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.27 mL, 2.46 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (30 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 525 mg of a yellow oil was obtained. This oil was dissolved in toluene (6 mL), and PPTS (23 mg, 0.0915 mmol) was added. The reaction solution was refluxed for 30 minutes and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-5%) yielded the title compound 2-2 (260 mg, yellow solid), in 61% yield.

[0161] LC-MS(ESI)m / z[M+H] +350.32.

[0162] Preparation of compounds 2-3:

[0163] Compound 2-2 (260 mg, 0.745 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and methanol (3 mL). After cooling to 0 °C, sodium borohydride (34 mg, 0.899 mmol) was added. The mixture was stirred at 0 °C for 20 minutes, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-5%) to give the title compound 2-3 (163 mg, yellow oil), in 62% yield.

[0164] LC-MS(ESI)m / z[M+H] + 352.39.

[0165] Preparation of compounds 2-4:

[0166] Compounds 2-3 (163 mg, 0.464 mmol) were dissolved in a mixed solution of toluene (2 mL) and tetrahydrofuran (2 mL). After cooling to 0 °C, tert-butyl hydroperoxide (60 mg, 0.466 mmol, 70% aqueous solution) and potassium tert-butoxide (52 mg, 0.464 mmol) were added. The mixture was stirred at 0 °C for 30 minutes, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 2-4 (50 mg, colorless oil), in 29% yield.

[0167] LC-MS(ESI)m / z[M-(OH)] + 350.32.

[0168] Preparation of compound 2:

[0169] Phenol (26 mg, 0.276 mmol) was dissolved in anhydrous 1,2-dichloroethane (20 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.12 mL, 1.36 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 2-4 (50 mg, 0.136 mmol) in 1,2-dichloroethane (2 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product of compound 2 (75 mg, yellow oil) was concentrated and used directly for further preparative liquid chromatography purification.

[0170] LC-MS(ESI)m / z[M+H] + 444.34.

[0171] Preparation of compounds 2-P1 and 2-P2:

[0172] The crude compound 2 (75 mg) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to obtain compound 2-P1 (6.2 mg, white powder, RT = 22.10 min), with a two-step yield of 10%, and compound 2-P2 (12.3 mg, white powder, RT = 23.20 min), with a two-step yield of 20%.

[0173] Compound 2-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, ¹H), 9.50 (s, ¹H), 7.65 (dd, J = 8.5, 5.1 Hz, ¹H), 7.13 (d, J = 8.6 Hz, 2H), 7.09–7.05 (m, ¹H), 6.72 (d, J = 8.3 Hz, 2H), 2.74–2.66 (m, ¹H), 2.14–2.00 (m, 2H), 1.98–1.83 (m, 2H), 1.65–1.49 (m, 2H), 1.48–1.33 (m, 2H), 1.31–1.21 (m, ¹H), 1.14 (q, J = 12.0 Hz, 1H). LC-MS (ESI) m / z [M+H] + 444.34.

[0174] Compound 2-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s, ¹H), 9.55 (s, ¹H), 7.61 (dd, J = 8.5, 5.1 Hz, ¹H), 7.16–7.06 (m, ³H), 6.72 (d, J = 8.3 Hz, 2H), 2.75–2.65 (m, ¹H), 2.20–2.01 (m, 2H), 1.99–1.78 (m, 2H), 1.62–1.49 (m, ³H), 1.48–1.32 (m, 2H), 1.01–0.85 (m, ¹H). LC-MS (ESI) m / z [M+H] + 444.34.

[0175] Preparation of compounds 2-A, 2-B, 2-C, and 2-D:

[0176] 487 mg of compound 2 was dissolved in 27.5 mL of methanol and separated by chiral separation using SFC. Instrument model: Waters SFC 150; Column model: [not specified]. AD (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: IPA (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following compounds were obtained: 2-A 96mg, 2-B 61mg, 2-C 68mg, and 2-D 106mg.

[0177] Compound 2-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.267min). 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.55(s,1H),7.61(dd,J=8.5,5.1Hz,1H),7.16–7.06(m,3H),6.72(d,J=8.3Hz,2H),2.76–2 .66(m,1H),2.20–2.01(m,2H),1.98–1.78(m,2H),1.62–1.47(m,3H),1.48–1.32(m,2H),1.01–0.85(m,1H).LC-MS(ESI)m / z[M+H] + 444.35.

[0178] Compound 2-B: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.645min). 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.50(s,1H),7.65(dd,J=8.5,5.1Hz, 1H),7.13(d,J=8.6Hz,2H),7.09–7.05(m,1H),6.72(d,J=8.3Hz,2H),2.74–2 .66(m,1H),2.14–2.00(m,2H),1.96–1.83(m,2H),1.65–1.49(m,2H),1.47–1 .31(m,2H),1.31–1.21(m,1H),1.14(q,J=12.0Hz,1H).LC-MS(ESI)m / z[M+H] + 444.34.

[0179] Compound 2-C: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.948min). 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.55(s,1H),7.61(dd,J=8.5,5.1Hz,1H),7.16–7.06(m,3H),6.72(d,J=8.3Hz,2H),2.76–2 .66(m,1H),2.20–2.01(m,2H),1.98–1.78(m,2H),1.62–1.47(m,3H),1.48–1.32(m,2H),1.01–0.85(m,1H).LC-MS(ESI)m / z[M+H] + 444.35.

[0180] Compound 2-D: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.397min). 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.50(s,1H),7.65(dd,J=8.5,5.1Hz, 1H),7.13(d,J=8.6Hz,2H),7.09–7.05(m,1H),6.72(d,J=8.3Hz,2H),2.74–2 .66(m,1H),2.14–2.00(m,2H),1.96–1.83(m,2H),1.65–1.49(m,2H),1.47–1 .31(m,2H),1.31–1.21(m,1H),1.14(q,J=12.0Hz,1H).LC-MS(ESI)m / z[M+H] + 444.34.

[0181] Example 3: Preparation of compounds 3-P1 and 3-P2

[0182] Preparation of compound 3-2:

[0183] Compound 3-1 (400 mg, 2.20 mmol) and 4,4-difluorocycloheptanone (489 mg, 3.30 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Zinc powder (573 mg, 8.76 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.48 mL, 4.38 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 2 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (40 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 911 mg of a white solid was obtained. This solid was dissolved in toluene (20 mL), and PPTS (44 mg, 0.175 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 3-2 (361 mg, white solid), in 55% yield.

[0184] LC-MS(ESI)m / z[M+H] +298.36.

[0185] Preparation of compound 3-3:

[0186] Compound 3-2 (361 mg, 1.21 mmol) was dissolved in a mixture of tetrahydrofuran (7.5 mL) and methanol (7.5 mL). After cooling to 0 °C, sodium borohydride (46 mg, 1.21 mmol) was added. The mixture was stirred at 0 °C for 2 hours, followed by the addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-25%) to give the title compound 3-3 (226 mg, colorless transparent liquid), in 62% yield.

[0187] LC-MS(ESI)m / z[M+H] + 300.36.

[0188] Preparation of compounds 3-4:

[0189] Compound 3-3 (226 mg, 0.756 mmol) was dissolved in a mixed solution of toluene (10 mL) and tetrahydrofuran (10 mL). After cooling to 0 °C, tert-butyl hydroperoxide (97 mg, 0.756 mmol, 70% aqueous solution) and potassium tert-butoxide (85 mg, 0.756 mmol) were added. The mixture was stirred at 0 °C for 10 minutes, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-45%) to give the title compound 3-4 (155 mg, colorless transparent oil), in 65% yield.

[0190] LC-MS(ESI)m / z[M-(OH)] + 298.36.

[0191] Preparation of compound 3:

[0192] Phenol (70 mg, 0.743 mmol) was dissolved in anhydrous 1,2-dichloroethane (55 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.66 mL, 7.43 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compounds 3-4 (117 mg, 0.371 mmol) in 1,2-dichloroethane (6 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 2 hours. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was Flash separated (ethyl acetate / dichloromethane = 0-40%) to give title compound 3 (120 mg, pale yellow oil), in 83% yield.

[0193] LC-MS(ESI)m / z[M+H] + 392.43.

[0194] Preparation of compounds 3-P1 and 3-P2:

[0195] Compound 3 (51 mg, 0.175 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 3-P1 (11 mg, white powder, RT = 19.93 min), yield 22%, and compound 3-P2 (14 mg, white powder, RT = 20.82 min), yield 28%.

[0196] Compound 3-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.93 (s, ¹H), 9.44 (s, ¹H), 7.32 (dd, J = 7.8, 6.2Hz, 2H), 7.13 (d, J = 8.7Hz, 2H), 7.05 (t, J = 7.8Hz, 1H), 6.70 (d, J = 8.4Hz, 2H), 2.72–2.61 (m, ¹H), 2.15–1.99 (m, 2H), 1.98–1.80 (m, 2H), 1.65–1.52 (m, 2H), 1.47–1.24 (m, 3H), 1.10 (q, J = 12.5, 12.0Hz, 1H). LC-MS (ESI) m / z [M+H] + 392.43.

[0197] Compound 3-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.90–10.83 (m, 1H), 9.44 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.14–7.03 (m, 3H), 6.70 (d, J = 8.4 Hz, 2H), 2.71–2.61 (m, 1H), 2.17–1.98 (m, 2H), 1.84 (dq, J = 23.8, 11.4 Hz, 2H), 1.59–1.48 (m, 3H), 1.39 (p, J = 12.3, 11.8 Hz, 2H), 0.90 (t, J = 11.1 Hz, 1H). LC-MS (ESI) m / z [M+H] + 392.43.

[0198] Example 4: Preparation of compounds 4-P1, 4-P2, 4-A, 4-B, 4-C, and 4-D

[0199] Preparation of compound 4-2:

[0200] Compound 4-1 (8.7 g, 43.6 mmol) and 4,4-difluorocycloheptanone (9.6 g, 65.4 mmol) were dissolved in anhydrous tetrahydrofuran (250 mL). Zinc powder (11.3 g, 174 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (9.58 mL, 87.2 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 2.5 hours. The reaction solution was cooled to 0 °C, and the reaction was quenched with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 21.6 g of a red viscous substance was obtained. This substance was dissolved in toluene (120 mL), and PPTS (1.63 g, 6.5 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-25%) was performed to give the title compound 4-2 (9.75 g, white solid), yield 71%.

[0201] LC-MS(ESI)m / z[M+H] + 316.34.

[0202] Preparation of compound 4-3:

[0203] Compound 4-2 (7.0 g, 22.2 mmol) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and methanol (50 mL). After cooling to 0 °C, sodium borohydride (840 mg, 22.2 mmol) was added in portions. The mixture was stirred at 0 °C for 30 minutes, and then the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-10%) to give compound 4-3 (7.0 g, red solid), in 99% yield.

[0204] LC-MS(ESI)m / z[M+H] + 318.29.

[0205] Preparation of compound 4-4:

[0206] Compound 4-3 (2.5 g, 7.87 mmol) was dissolved in a mixed solution of toluene (30 mL) and tetrahydrofuran (30 mL). After cooling to 0 °C, tert-butyl hydroperoxide (1.0 g, 7.8 mmol, 70% aqueous solution) and potassium tert-butoxide (873 mg, 7.8 mmol) were added. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give the title compound 4-4 (890 mg, yellow oil), in 34% yield.

[0207] LC-MS(ESI)m / z[M-(OH)] + 316.34.

[0208] Preparation of compound 4:

[0209] Phenol (1.07 g, 11.4 mmol) was dissolved in anhydrous 1,2-dichloroethane (780 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (5.0 mL, 57 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 4-4 (1.9 g, 5.69 mmol) in 1,2-dichloroethane (20 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 2 hours. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was Flash separated (ethyl acetate / dichloromethane = 0-20%) to give title compound 4 (1.75 g, white solid), yield 75%.

[0210] LC-MS(ESI)m / z[M+H] + 410.35.

[0211] Preparation of compounds 4-P1 and 4-P2:

[0212] Compound 4 (430 mg, 1.05 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 4-P1 (94 mg, white powder, RT = 19.535 min), yield 22%, and compound 4-P2 (84 mg, white powder, RT = 20.304 min), yield 20%.

[0213] Compound 4-P1: ¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s, ¹H), 9.43 (s, ¹H), 7.31–7.26 (m, ¹H), 7.14–7.01 (m, ³H), 6.70 (d, J = 7.8 Hz, ²H), 2.70–2.61 (m, ¹H), 2.16–1.99 (m, ²H), 1.98–1.77 (m, ²H), 1.60–1.48 (m, ³H), 1.46–1.31 (m, ²H), 0.98–0.84 (m, ¹H). LC-MS (ESI) m / z [M+H] + 410.35.

[0214] Compound 4-P2: 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.42(s,1H),7.34(dd,J=8.2,4.9Hz,1H),7.12(d,J=8.7Hz,2H),7.04(dd,J=10.0,8.3Hz,1H),6.71(d,J=8.8H z,2H),2.70–2.62(m,1H),2.14–1.99(m,2H),1.98–1.80(m,2H),1.65–1.5 3(m,2H),1.50–1.22(m,3H),1.10(q,J=11.9Hz,1H).LC-MS(ESI)m / z[M+H] + 410.35.

[0215] Preparation of compounds 4-A, 4-B, 4-C, and 4-D:

[0216] Compound 4 (980 mg) was subjected to two SFC chiral separations. First separation conditions: Instrument model: Waters SFC 150; Column model: [not specified] IG (250*50mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 75:25; Flow rate: 150mL / min; Column temperature: RT; Detection wavelength: 214nM. Second separation conditions: Instrument model: Waters SFC 150, Column model; AD (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following compounds were obtained: 4-A 216mg, 4-B 210mg, 4-C 180mg, and 4-D 198mg.

[0217] Compound 4-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.752min). 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.43(s,1H),7.31–7.25(m,1H),7.15–7.02(m,3H),6.70(d,J=7.8Hz,2H),2.71–2.62( m,1H),2.17–2.00(m,2H),2.00–1.73(m,2H),1.59–1.48(m,3H),1.46–1.32(m,2H),0.96–0.84(m,1H).LC-MS(ESI)m / z[M+H] + 410.35.

[0218] Compound 4-B: Chiral analysis method 1 (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.502min). Chiral analysis method two (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.425min). 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),9.44(s,1H),7.33(dd,J=8.4,4.8Hz,1H),7.12(d,J=8.4Hz,2H),7.03(t,J=9.1Hz,1H),6.71(d,J=8.2Hz ,2H),2.70–2.60(m,1H),2.13–2.00(m,2H),1.99–1.81(m,2H),1.67–1 .52(m,2H),1.48–1.20(m,3H),1.17–1.04(m,1H).LC-MS(ESI)m / z[M+H] + 410.35.

[0219] Compound 4-C: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.618min). Chiral analysis method two (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.275min). 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.43(s,1H),7.28(t,J=6.8Hz,1H),7.13–7.02(m,3H),6.70(d,J=7.1Hz,2H),2.71–2.60( m,1H),2.16–1.99(m,2H),1.95–1.78(m,2H),1.62–1.48(m,3H),1.45–1.31(m,2H),0.89(q,J=10.3Hz,1H).LC-MS(ESI)m / z[M+H] + 410.35.

[0220] Compound 4-D: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.700min). 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.42(s,1H),7.34(dd,J=8.2,4.9Hz,1H),7.12(d,J=8.7Hz,2H),7.04(dd,J=10.0,8.3Hz,1H),6.71(d,J=8. 8Hz,2H),2.71–2.62(m,1H),2.14–1.99(m,2H),1.99–1.81(m,2H),1.65– 1.52(m,2H),1.48–1.21(m,3H),1.18–1.04(m,1H).LC-MS(ESI)m / z[M+H] + 410.35.

[0221] Example 5: Preparation of compounds 5-P1 and 5-P2

[0222] Preparation of compound 5-2:

[0223] Compound 5-1 (300 mg, 1.42 mmol) and 4,4-difluorocycloheptanone (316 mg, 2.13 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Zinc powder (554 mg, 8.53 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.31 mL, 2.84 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (20 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 480 mg of a yellow oil was obtained. This oil was dissolved in toluene (6 mL), and PPTS (35 mg, 0.14 mmol) was added. The reaction solution was refluxed for 30 minutes and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-10%) yielded the title compound 5-2 (236 mg, yellow solid), in 51% yield.

[0224] LC-MS(ESI)m / z[M+H] + 328.40.

[0225] Preparation of compound 5-3:

[0226] Compound 5-2 (233 mg, 0.711 mmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and methanol (3 mL). After cooling to 0 °C, sodium borohydride (32 mg, 0.855 mmol) was added. The mixture was stirred at 0 °C for 2 hours, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-10%) to give the title compound 5-3 (176 mg, yellow solid), in 75% yield.

[0227] LC-MS(ESI)m / z[M+H] + 330.33.

[0228] Preparation of compound 5-4:

[0229] Compound 5-3 (146 mg, 0.443 mmol) was dissolved in a mixed solution of toluene (2.5 mL) and tetrahydrofuran (2.5 mL). After cooling to 0 °C, tert-butyl hydroperoxide (57 mg, 0.443 mmol, 70% aqueous solution) and potassium tert-butoxide (50 mg, 0.443 mmol) were added. The mixture was stirred at room temperature for 3 hours, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 5-4 (72 mg, colorless oil), in 47% yield.

[0230] LC-MS(ESI)m / z[M-(OH)] + 328.34.

[0231] Preparation of compound 5:

[0232] Phenol (33 mg, 0.348 mmol) was dissolved in anhydrous 1,2-dichloroethane (9 mL), and cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (313 mg, 2.09 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A solution of compound 5-4 (60 mg, 0.174 mmol) in 1,2-dichloroethane (9 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 15 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give title compound 5 (59 mg, yellow oil), in 80% yield.

[0233] LC-MS(ESI)m / z[M+H] + 422.28.

[0234] Preparation of compounds 5-P1 and 5-P2:

[0235] Compound 5 (73 mg, 0.173 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 5-P1 (9.8 mg, white powder, RT = 16.452 min), yield 13%, and compound 5-P2 (10.9 mg, white powder, RT = 17.079 min), yield 15%.

[0236] Compound 5-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.84 (s, ¹H), 9.40 (s, ¹H), 7.25 (d, J = 8.3 Hz, ¹H), 7.12 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 2.61 (s, 1H), 2.16–1.81 (m, 4H), 1.66–1.51 (m, 2H), 1.41–1.22 (m, 3H), 1.05 (q, J = 11.8 Hz, 1H). LC-MS (ESI) m / z [M+H] + 422.28.

[0237] Compound 5-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.43 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 2H), 3.87 (s, 3H), 2.72–2.57 (m, 1H), 2.20–1.74 (m, 4H), 1.63–1.33 (m, 5H), 0.97–0.81 (m, 1H). LC-MS (ESI) m / z [M+H] + 422.28.

[0238] Example 6: Preparation of compounds 6-P1, 6-P2, 6-A, 6-B, 6-C, and 6-D

[0239] Preparation of compound 6-2:

[0240] Compound 6-1 (1.5 g, 6.64 mmol) and 4,4-difluorocycloheptanone (1.46 g, 9.85 mmol) were dissolved in anhydrous tetrahydrofuran (60 mL). Zinc powder (2.57 g, 39.3 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (1.45 mL, 13.2 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 3.3 g of a yellow oily substance was obtained. This substance was dissolved in toluene (45 mL), and PPTS (230 mg, 0.916 mmol) was added. The reaction solution was refluxed for 1 hour and cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / petroleum ether = 0-25%) was performed to give the title compound 6-2 (1.31 g, reddish-brown solid), in 58% yield.

[0241] LC-MS(ESI)m / z[M+H] + :342.19,344.19.

[0242] Preparation of compound 6-3:

[0243] Compound 6-2 (1.28 g, 3.74 mmol) was dissolved in a mixed solution of tetrahydrofuran (8 mL) and methanol (8 mL). After cooling to 0 °C, sodium borohydride (159 mg, 4.20 mmol) was added. The mixture was stirred at 0 °C for 1 hour, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-30%) to give the title compound 6-3 (880 mg, yellow solid), in 68% yield.

[0244] LC-MS(ESI)m / z[M+H] + :344.26,346.26.

[0245] Preparation of compound 6-4:

[0246] Compound 6-3 (820 mg, 2.38 mmol) was dissolved in a mixed solution of toluene (10 mL) and tetrahydrofuran (10 mL). After cooling to 0 °C, tert-butyl hydroperoxide (295 mg, 2.28 mmol, 70% aqueous solution) and potassium tert-butoxide (268 mg, 2.39 mmol) were added. The mixture was stirred at room temperature for 1 hour, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-40%) to give the title compound 6-4 (510 mg, yellow oil), in 59% yield.

[0247] LC-MS(ESI)m / z[M-(OH)] + :342.19,344.26.

[0248] Preparation of compound 6:

[0249] Phenol (233 mg, 2.48 mmol) was dissolved in anhydrous 1,2-dichloroethane (60 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (1.09 mL, 12.4 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 6-4 (450 mg, 1.25 mmol) in 1,2-dichloroethane (60 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-57%) to give compound 6 (290 mg, white solid), yield 53%.

[0250] LC-MS(ESI)m / z[M+H] + :436.21,438.21.

[0251] Preparation of compounds 6-P1 and 6-P2:

[0252] Compound 6 (70 mg, 0.160 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 6-P1 (23 mg, white powder, RT = 22.042 min), yield 33%, and compound 6-P2 (20 mg, white powder, RT = 22.995 min), yield 29%.

[0253] Compound 6-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, ¹H), 9.42 (s, ¹H), 7.44 (d, J = 8.2 Hz, ¹H), 7.36 (d, J = 7.5 Hz, ¹H), 7.14 (d, J = 8.2 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.71 (d, J = 8.2 Hz, 2H), 2.70–2.62 (m, ¹H), 2.15–2.01 (m, 2H), 1.97–1.83 (m, 2H), 1.64–1.51 (m, 2H), 1.43–1.10 (m, 4H). LC-MS (ESI) m / z [M+H] + :436.21,438.21.

[0254] Compound 6-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.74 (s, ¹H), 9.45 (s, ¹H), 7.46 (d, J = 7.5Hz, ¹H), 7.31 (d, J = 7.4Hz, ¹H), 7.11 (d, J = 7.1Hz, 2H), 7.01 (t, J = 7.0Hz, 1H), 6.71 (d, J = 6.5Hz, 2H), 2.70–2.62 (m, ¹H), 2.15–2.02 (m, 2H), 1.97–1.74 (m, 2H), 1.58–1.37 (m, 5H), 0.91 (d, J = 9.9Hz, 1H). LC-MS (ESI) m / z [M+H] + :436.21,438.21.

[0255] Preparation of compounds 6-A, 6-B, 6-C, and 6-D

[0256] Compound 6 (998 mg) was subjected to two SFC chiral separations. First separation conditions: Instrument model: Waters SFC 150; Column model: ... IG (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.2% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 120mL / min; Column temperature: RT; Detection wavelength: 214nM. Second separation conditions: Instrument model: Waters SFC 150; Column model: CHIRAL ART Collulose SC (250*25mm 10μm); Mobile phase: A: Supercritical CO2, B: MeOH (+0.2% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 120mL / min; Column temperature: RT; Detection wavelength: 214nM. After separation, the following were obtained: 6-A 211mg, 6-B 213mg, 6-C 225mg, and 6-D 219mg.

[0257] Compound 6-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.860min). 1H NMR (400MHz, DMSO-d6) δ10.74(s,1H),9.45(s,1H),7.46(d,J=7.5Hz,1H),7.31(d,J=7.4Hz,1H),7.11(d,J=7.1Hz,2H),7.01(t,J=7.0Hz,1H), 6.71(d,J=6.5Hz,2H),2.70–2.62(m,1H),2.15–2.02(m,2H),1.97–1.74(m,2H),1.58–1.37(m,5H),0.91(d,J=9.9Hz,1H).LC-MS(ESI)m / z[M+H] + :436.21,438.21.

[0258] Compound 6-B: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.514min). 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.42(s,1H),7.44(d,J=8.2Hz,1H),7.36(d,J=7.5Hz,1H),7.14(d,J=8.2Hz,2H),6.99(t,J=7.8Hz,1H) ,6.71(d,J=8.2Hz,2H),2.70–2.62(m,1H),2.15–2.01(m,2H),1.97–1.83(m,2H),1.64–1.51(m,2H),1.43–1.10(m,4H).LC-MS(ESI)m / z[M+H] + :372.37.LC-MS(ESI)m / z[M+H] + :436.21,438.21.

[0259] Compound 6-C: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 4.214min). 1H NMR (400MHz, DMSO-d6) δ10.74(s,1H),9.45(s,1H),7.46(d,J=7.5Hz,1H),7.31(d,J=7.4Hz,1H),7.11(d,J=7.1Hz,2H),7.01(t,J=7.0Hz,1H), 6.71(d,J=6.5Hz,2H),2.70–2.62(m,1H),2.15–2.02(m,2H),1.97–1.74(m,2H),1.58–1.37(m,5H),0.91(d,J=9.9Hz,1H).LC-MS(ESI)m / z[M+H] + :436.21,438.21.

[0260] Compound 6-D: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 8.142min). 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.42(s,1H),7.44(d,J=8.2Hz,1H),7.36(d,J=7.5Hz,1H),7.14(d,J=8.2Hz,2H),6.99(t,J=7.8Hz,1H) ,6.71(d,J=8.2Hz,2H),2.70–2.62(m,1H),2.15–2.01(m,2H),1.97–1.83(m,2H),1.64–1.51(m,2H),1.43–1.10(m,4H).LC-MS(ESI)m / z[M+H] + :436.21,438.21.

[0261] Example 7: Preparation of compounds 7-P1, 7-P2, 7-A, 7-B, 7-C, and 7-D

[0262] Preparation of compound 7-2:

[0263] Compound 7-1 (500 mg, 2.049 mmol) and 4,4-difluorocycloheptanone (455 mg, 3.074 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Zinc powder (533 mg, 8.196 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.45 mL, 4.098 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 911 mg of a red solid was obtained. This solid was dissolved in toluene (20 mL), and PPTS (43 mg, 0.172 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 7-2 (611 mg, red solid), in 83% yield.

[0264] LC-MS(ESI)m / z[M+H] + 360.25, 362.25.

[0265] Preparation of compound 7-3:

[0266] Compound 7-2 (611 mg, 1.696 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and methanol (6 mL). After cooling to 0 °C, sodium borohydride (95 mg, 2.513 mmol) was added. The mixture was stirred at 0 °C for 20 minutes, followed by the addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-35%) to give the title compound 7-3 (511 mg, pink liquid), in 83% yield.

[0267] LC-MS(ESI)m / z[MF] + :342.26,344.26.

[0268] Preparation of compound 7-4:

[0269] Compound 7-3 (499 mg, 1.378 mmol) was dissolved in a mixed solution of toluene (3 mL) and tetrahydrofuran (3 mL). After cooling to 0 °C, tert-butyl hydroperoxide (177 mg, 1.378 mmol, 70% aqueous solution) and potassium tert-butoxide (154 mg, 1.378 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-65%) to give the title compound 7-4 (165 mg, pale yellow oil), in 32% yield.

[0270] LC-MS(ESI)m / z[M-(OH)] + :360.31,362.31.

[0271] Preparation of compound 7:

[0272] Phenol (82 mg, 0.873 mmol) was dissolved in anhydrous 1,2-dichloroethane (50 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.39 mL, 4.37 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 7-4 (165 mg, 0.436 mmol) in 1,2-dichloroethane (8 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for another hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-60%) to give the title compound 7 (100 mg, white powder), in 50% yield.

[0273] LC-MS(ESI)m / z[M+H] + :454.17,456.27.

[0274] Preparation of compounds 7-P1 and 7-P2:

[0275] Compound 7 (30 mg, 0.0660 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 7-P1 (7.11 mg, white powder, RT = 22.80 min), yield 24%, and compound 7-P2 (6.72 mg, white powder, RT = 23.60 min), yield 22%.

[0276] Compound 7-P1: ¹H NMR (400MHz, DMSO-d6) δ 11.02 (s, ¹H), 9.47 (s, ¹H), 7.36 (dd, J = 8.4, 5.0 Hz, ¹H), 7.12 (d, J = 8.3 Hz, 2H), 7.00 (t, J = 8.9 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 2.73–2.60 (m, ¹H), 2.17–1.98 (m, 2H), 1.98–1.82 (m, 2H), 1.65–1.51 (m, 2H), 1.47–1.21 (m, 3H), 1.19–1.02 (m, ¹H). LC-MS (ESI) m / z [M+H] + :454.17,456.27.

[0277] Compound 7-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.97 (s, ¹H), 9.47 (s, ¹H), 7.31 (dd, J = 8.3, 5.0 Hz, ¹H), 7.10 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 8.9 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 2.70–2.61 (m, ¹H), 2.17–1.98 (m, 2H), 1.97–1.76 (m, 2H), 1.60–1.47 (m, 4H), 1.47–1.30 (m, 1H), 0.90 (q, J = 10.1 Hz, 1H). LC-MS (ESI) m / z [M+H] + :454.17,456.27.

[0278] Preparation of compounds 7-A, 7-B, 7-C, and 7-D

[0279] 1g of compound 7 was subjected to two SFC chiral separations. First separation conditions: Instrument model: Waters SFC 150, column model; IG (250*25mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. Second separation conditions: Instrument model: Waters SFC 150, Column model; AD (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: MeOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following compounds were obtained: 7-A 227mg, 7-B 204mg, 7-C 215mg, 7-D 205mg.

[0280] Compound 7-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.469min). 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.47(s,1H),7.31(dd,J=8.3,5.0Hz,1H),7.10(d,J=8.4Hz,2H),7.02(t,J=8.9Hz,1H),6.71(d,J=8.4Hz,2 H),2.70–2.61(m,1H),2.17–1.98(m,2H),1.97–1.76(m,2H),1.60–1.47 (m,4H),1.47–1.30(m,1H),0.90(q,J=10.1Hz,1H).LC-MS(ESI)m / z[M+H] + :454.17,456.27.

[0281] Compound 7-B: Chiral analysis method 1 (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.457min). Chiral analysis method two (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 1.869min). 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.47(s,1H),7.36(dd,J=8.4,5.0Hz,1H),7.12(d,J=8.3Hz,2H),7.00(t,J=8.9Hz,1H),6.71(d,J=8.4Hz ,2H),2.73–2.60(m,1H),2.17–1.98(m,2H),1.98–1.82(m,2H),1.65–1 .51(m,2H),1.47–1.21(m,3H),1.19–1.02(m,1H).LC-MS(ESI)m / z[M+H] + :454.17,456.27.

[0282] Compound 7-C: Chiral Analysis Method 1 (Instrument Model: Waters UPCC (CA-352); Column Model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.421min). Chiral analysis method two (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.309min). 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.47(s,1H),7.31(dd,J=8.3,5.0Hz,1H),7.10(d,J=8.4Hz,2H),7.02(t,J=8.9Hz,1H),6.71(d,J=8.4Hz,2 H),2.70–2.61(m,1H),2.17–1.98(m,2H),1.97–1.76(m,2H),1.60–1.47 (m,4H),1.47–1.30(m,1H),0.90(q,J=10.1Hz,1H).LC-MS(ESI)m / z[M+H] + :454.17,456.27.

[0283] Compound 7-D: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 5.042min). 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.47(s,1H),7.36(dd,J=8.4,5.0Hz,1H),7.12(d,J=8.3Hz,2H),7.00(t,J=8.9Hz,1H),6.71(d,J=8.4Hz ,2H),2.73–2.60(m,1H),2.17–1.98(m,2H),1.98–1.82(m,2H),1.65–1 .51(m,2H),1.47–1.21(m,3H),1.19–1.02(m,1H).LC-MS(ESI)m / z[M+H] + :454.17,456.27.

[0284] Example 8: Preparation of compounds 8-P1 and 8-P2

[0285] Preparation of compound 8-2:

[0286] Compound 8-1 (916 mg, 3.58 mmol) and 4,4-difluorocycloheptanone (798 mg, 5.39 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Zinc powder (1.4 g, 21.5 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.70 mL, 7.18 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (30 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 1.38 g of a red oily substance was obtained. This substance was dissolved in toluene (14 mL), and PPTS (90 mg, 0.359 mmol) was added. The reaction solution was refluxed for 30 minutes and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-5%) was performed to give the title compound 8-2 (340 mg, red solid), yield 26%.

[0287] LC-MS(ESI)m / z[M+H] + :372.31,374.24.

[0288] Preparation of compound 8-3:

[0289] Compound 8-2 (340 mg, 0.913 mmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and methanol (5 mL). After cooling to 0 °C, sodium borohydride (42 mg, 1.1 mmol) was added. The mixture was stirred at 0 °C for 1 hour, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-5%) to give the title compound 8-3 (323 mg, red oil), in 95% yield.

[0290] LC-MS(ESI)m / z[M+H] + :374.31,376.30.

[0291] Preparation of compound 8-4:

[0292] Compound 8-3 (290 mg, 0.775 mmol) was dissolved in a mixed solution of toluene (5 mL) and tetrahydrofuran (5 mL). After cooling to 0 °C, tert-butyl hydroperoxide (100 mg, 0.777 mmol, 70% aqueous solution) and potassium tert-butoxide (87 mg, 0.777 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give the title compound 8-4 (142 mg, colorless oil), in 47% yield.

[0293] LC-MS(ESI)m / z[M-(OH)] + :372.31,374.31.

[0294] Preparation of compound 8:

[0295] Phenol (69 mg, 0.73 mmol) was dissolved in anhydrous 1,2-dichloroethane (50 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (547 mg, 3.65 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 8-4 (142 mg, 0.364 mmol) in 1,2-dichloroethane (3 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 10 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-5%) to give the title compound 8 (170 mg, white solid), in 100% yield.

[0296] LC-MS(ESI)m / z[M+H] + :466.27,468.27.

[0297] Preparation of compounds 8-P1 and 8-P2:

[0298] Compound 8 (36 mg, 0.0772 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-75%; flow rate: 20 mL / min) to obtain compound 8-P1 (7.1 mg, white powder, RT = 20.230 min), yield 20%, and compound 8-P2 (5.5 mg, white powder, RT = 21.254 min), yield 15%.

[0299] Compound 8-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.66 (s, ¹H), 9.43 (s, ¹H), 7.28 (d, J = 8.2 Hz, ¹H), 7.13 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 3.85 (s, 3H), 2.68–2.53 (m, ¹H), 2.15–1.98 (m, 2H), 1.95–1.78 (m, 2H), 1.67–1.52 (m, 2H), 1.46–1.23 (m, 3H), 1.12–1.02 (m, ¹H). LC-MS (ESI) m / z [M+H] + :466.27,468.27.

[0300] Compound 8-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.63 (s, ¹H), 9.43 (s, ¹H), 7.22 (d, J = 8.2 Hz, ¹H), 7.11 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.86 (s, 3H), 2.62 (t, J = 10.9 Hz, 1H), 2.19–1.99 (m, 2H), 1.98–1.75 (m, 2H), 1.61–1.48 (m, 2H), 1.47–1.31 (m, 3H), 0.96–0.75 (m, 1H). LC-MS (ESI) m / z [M+H] + :466.27,468.27.

[0301] Example 9: Preparation of compounds 9-P1, 9-P2, 9-A, 9-B, 9-C, and 9-D

[0302] Preparation of compound 9-2:

[0303] Compound 9-1 (300 mg, 1.64 mmol) and 4,4-difluorocycloheptanone (364 mg, 2.46 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Zinc powder (640 mg, 9.84 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.36 mL, 3.28 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (20 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 510 mg of a red oily substance was obtained. This substance was dissolved in toluene (6 mL), and PPTS (40 mg, 0.161 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-5%) yielded the title compound 9-2 (185 mg, red solid), in 38% yield.

[0304] LC-MS(ESI)m / z[M+H] + 300.22.

[0305] Preparation of compound 9-3:

[0306] Compound 9-2 (185 mg, 0.618 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and methanol (2 mL). After cooling to 0 °C, sodium borohydride (28 mg, 0.742 mmol) was added. The mixture was stirred at 0 °C for 1 hour, then saturated ammonium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-10%) to give the title compound 9-3 (86 mg, white solid), in 46% yield.

[0307] LC-MS(ESI)m / z[MF] + 282.37.

[0308] Preparation of compound 9-4:

[0309] Compound 9-3 (145 mg, 0.482 mmol) was dissolved in a mixed solution of toluene (2.5 mL) and tetrahydrofuran (2.5 mL). After cooling to 0 °C, tert-butyl hydroperoxide (62 mg, 0.482 mmol, 70% aqueous solution) and potassium tert-butoxide (54 mg, 0.482 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 9-4 (67 mg, colorless oil), in 44% yield.

[0310] LC-MS(ESI)m / z[M-(OH)] + 300.36.

[0311] Preparation of compound 9:

[0312] Phenol (42 mg, 0.442 mmol) was dissolved in anhydrous dichloromethane (18 mL), and the mixture was cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (331 mg, 2.21 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A solution of compound 9-4 (70 mg, 0.221 mmol) in dichloromethane (7 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 20 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give title compound 9 (60 mg, white solid), yield 69%.

[0313] LC-MS(ESI)m / z[M+H] + 394.43.

[0314] Preparation of compounds 9-P1 and 9-P2:

[0315] Compound 9 (52 mg, 0.132 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to obtain compound 9-P1 (9.5 mg, white powder, RT = 20.519 min), yield 18%, and compound 9-P2 (8.2 mg, white powder, RT = 21.468 min), yield 16%.

[0316] Compound 9-P1: ¹H NMR (400MHz, DMSO-d6) δ 11.25 (s, ¹H), 9.44 (s, ¹H), 7.18 (dd, J = 8.5, 4.4 Hz, ¹H), 7.12 (d, J = 8.8 Hz, 2H), 7.08–6.99 (m, ¹H), 6.70 (d, J = 8.8 Hz, 2H), 2.71–2.58 (m, ¹H), 2.15–1.98 (m, 2H), 1.98–1.80 (m, 2H), 1.67–1.52 (m, 2H), 1.45–1.25 (m, 3H), 1.01–1.14 (m, ¹H). LC-MS (ESI) m / z [M+H] + 394.43.

[0317] Compound 9-P2: ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, ¹H), 9.44 (s, ¹H), 7.16–7.01 (m, 4H), 6.70 (d, J = 8.3 Hz, 2H), 2.71–2.59 (m, ¹H), 2.20–1.97 (m, 2H), 1.96–1.73 (m, 2H), 1.61–1.48 (m, 3H), 1.47–1.32 (m, 2H), 0.95–0.81 (m, ¹H). LC-MS (ESI) m / z [M+H] + 394.43.

[0318] Preparation of compounds 9-A, 9-B, 9-C, and 9-D:

[0319] 985 mg of compound 9 was dissolved in 49 mL of methanol and subjected to chiral separation by SFC. Instrument model: Waters SFC 150; Column model: [not specified]. IG (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: IPA (+0.1% DEA); Elution gradient: A:B = 80:20; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following compounds were obtained: 9-A 204mg, 9-B 210mg, 9-C 204mg, 9-D 211mg.

[0320] Compound 9-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.214min. 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),9.42(s,1H),7.16–7.01(m,4H),6.71(d,J=8.8Hz,2H),2.71–2.59(m,1H),2. 20–1.97(m,2H),1.96–1.73(m,2H),1.61–1.48(m,3H),1.47–1.32(m,2H),0.95–0.81(m,1H).LC-MS(ESI)m / z[M+H] + 394.43.

[0321] Compound 9-B: Chiral analysis method (instrument model: Waters UPCC (CA-352); column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.948min). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),9.44(s,1H),7.18(dd,J=8.5,4.3Hz,1H),7.12(d,J=8.8Hz,2H),7.08–6.99(m,1H),6.71(d,J=8.7Hz, 2H),2.71–2.58(m,1H),2.15–1.98(m,2H),1.98–1.80(m,2H),1.67–1.52(m,2H),1.45–1.25(m,3H),1.01–1.14(m,1H).LC-MS(ESI)m / z[M+H] + 394.43.

[0322] Compound 9-C: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 3.260min). 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),9.42(s,1H),7.16–7.01(m,4H),6.71(d,J=8.8Hz,2H),2.71–2.59(m,1H),2. 20–1.97(m,2H),1.96–1.73(m,2H),1.61–1.48(m,3H),1.47–1.32(m,2H),0.95–0.81(m,1H).LC-MS(ESI)m / z[M+H] + 394.43.

[0323] Compound 9-D: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: IPA (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 4.475min). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),9.44(s,1H),7.18(dd,J=8.5,4.3Hz,1H),7.12(d,J=8.8Hz,2H),7.08–6.99(m,1H),6.71(d,J=8.7Hz, 2H),2.71–2.58(m,1H),2.15–1.98(m,2H),1.98–1.80(m,2H),1.67–1.52(m,2H),1.45–1.25(m,3H),1.01–1.14(m,1H).LC-MS(ESI)m / z[M+H] + 394.43.

[0324] X-ray crystallographic data of compound 9-A:

[0325] Single crystal cultivation: Ethyl acetate / petroleum ether = 1:3 as solvent, naturally evaporated;

[0326] Testing instrument: D8 Venture;

[0327] Instrument parameters: Light source: Cu target; X-rays: Detector: CMOS surface detector; Resolution: Current and voltage: 50kV, 1.2mA; Exposure time: 10s; Distance from surface detector to sample: 40mm; Test temperature: 170(2)K;

[0328] Structural analysis and refinement process: After integrating and restoring the diffraction data using the SAINT program, the data were empirically absorbed and corrected using the SADABS program; the single crystal structure was analyzed using the SHELXT2014 direct method, and the structure was refined using the least squares method. The hydrogen atom refinement process was obtained by isotropic calculation, the hydrogen atoms on N and O were obtained by residual electron density, and the hydrogen atoms on CH were obtained by calculated hydrogen addition, and the riding model was used for refinement. The Flack constant is 0.04 (8). The molecular stereostructure diagram is shown in Figure 1, where C1 is the S configuration and C3 is the R configuration.

[0329] Crystal data

[0330] Data collection

[0331] Refinement

[0332] Special details

[0333] Example 10: Preparation of compounds 10-P1 and 10-P2

[0334] Preparation of compound 10-2:

[0335] Compound 10-1 (500 mg, 2.562 mmol) and 4,4-difluorocycloheptanone (572 mg, 3.866 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). Zinc powder (670 mg, 10.308 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.56 mL, 5.154 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 951 mg of a yellow solid was obtained. This solid was dissolved in toluene (20 mL), and PPTS (52 mg, 0.206 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-35%) to give the title compound 10⁻² (520 mg, orange-red solid), in 65% yield.

[0336] LC-MS(ESI)m / z[M+H] + 312.35.

[0337] Preparation of compound 10-3:

[0338] Compound 10⁻² (470 mg, 1.51 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and 10% Pd / C (47 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The solution was diluted with ethyl acetate (50 mL), filtered through diatomaceous earth, concentrated, and then separated using Flash chromatography (ethyl acetate / dichloromethane = 0-30%) to give the title compound 10⁻³ (355 mg, pale yellow solid), in 75% yield.

[0339] LC-MS(ESI)m / z[M+H] + 314.41.

[0340] Preparation of compound 10-4:

[0341] Compound 10⁻³ (397 mg, 1.268 mmol) was dissolved in a mixed solution of toluene (3 mL) and tetrahydrofuran (3 mL). After cooling to 0 °C, tert-butyl hydroperoxide (163 mg, 1.268 mmol, 70% aqueous solution) and potassium tert-butoxide (142 mg, 1.268 mmol) were added. The mixture was stirred at 0 °C for 3 hours, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-50%) to give the title compound 10⁻⁴ (134 mg, white solid), in 32% yield.

[0342] LC-MS(ESI)m / z[M+Na] + 352.39.

[0343] Preparation of compound 10:

[0344] Phenol (77 mg, 0.814 mmol) was dissolved in anhydrous 1,2-dichloroethane (50 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.36 mL, 4.07 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 10-4 (134 mg, 0.407 mmol) in 1,2-dichloroethane (8 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for another hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-60%) to give the title compound 10 (130 mg, white powder), in 79% yield.

[0345] LC-MS(ESI)m / z[M+H] + 406.36.

[0346] Preparation of compounds 10-P1 and 10-P2:

[0347] Compound 10 (130 mg, 0.321 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 10-P1 (25.9 mg, white powder, RT = 16.32 min), yield 20%, and compound 10-P2 (24.0 mg, white powder, RT = 17.10 min), yield 18%.

[0348] Compound 10-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.97 (s, ¹H), 9.40 (s, ¹H), 7.11 (t, J = 9.7 Hz, ³H), 6.79 (t, J = 7.9 Hz, ¹H), 6.69 (d, J = 8.2 Hz, 2H), 3.85 (s, ³H), 2.66–2.55 (m, ¹H), 2.16–1.98 (m, 2H), 1.98–1.81 (m, 2H), 1.67–1.53 (m, 2H), 1.47–1.22 (m, 3H), 1.11–0.98 (m, ¹H). LC-MS (ESI) m / z [M+H] + 406.36.

[0349] Compound 10-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.93 (s, ¹H), 9.41 (s, ¹H), 7.11 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H), 2.69–2.56 (s, ¹H), 2.17–1.98 (m, 2H), 1.98–1.74 (m, 2H), 1.53 (t, J = 10.0 Hz, 3H), 1.38 (dt, J = 25.2, 12.5 Hz, 2H), 0.93–0.81 (m, 1H). LC-MS (ESI) m / z [M+H] + 406.36.

[0350] Example 11: Preparation of compounds 11-P1, 11-P2, 11-A, 11-B, 11-C, and 11-D

[0351] Preparation of compound 11-1:

[0352] Compound 6 (430 mg, 0.986 mmol) and PTSA (4 mg, 0.02 mmol) were dissolved in 1.5 mL of 3,4-dihydro-2H-pyran. The mixture was stirred at room temperature for 10 minutes, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-67%) to give the title compound 11-1 (320 mg, white solid), in 62% yield.

[0353] LC-MS(ESI)m / z[M+H] + :520.32,522.32.

[0354] Preparation of compound 11-2:

[0355] Compound 11-1 (160 mg, 0.307 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), cooled to -78 °C, and a tetrahydrofuran solution of n-butyllithium (0.31 mL, 2.5 mol / L, 0.775 mmol) was slowly added. The mixture was stirred at -78 °C for 1 hour, then anhydrous DMF (71 μL, 0.917 mmol) was added, and the mixture was slowly heated to -50 °C and stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-45%) to give the title compound 11-2 (115 mg, clear oil), in 80% yield.

[0356] LC-MS(ESI)m / z[M+H] + 470.47.

[0357] Preparation of compound 11-3:

[0358] Compound 11-2 (90 mg, 0.192 mmol) was dissolved in 1,2-dichloroethane (3 mL), and DAST (306 mg, 1.9 mmol) was slowly added. The mixture was stirred at 50 °C for 1.5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product of the title compound 11-3 (200 mg, yellow oil) was obtained and proceeded directly to the next reaction without further separation.

[0359] LC-MS(ESI)m / z[M+H] + 492.46.

[0360] Preparation of compound 11:

[0361] The crude compound 11-3 (200 mg) was dissolved in tetrahydrofuran (5 mL), and 1 N hydrochloric acid (1 mL) was slowly added. The mixture was stirred at room temperature for 15 minutes, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-45%) to give the title compound 11 (74 mg, yellow oil), with a two-step yield of 95%.

[0362] LC-MS(ESI)m / z[M+H] + 408.42.

[0363] Preparation of compounds 11-P1 and 11-P2:

[0364] Compound 11 (95 mg, 0.233 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 11-P1 (14.5 mg, white powder, RT = 19.003 min), yield 15%, and compound 11-P2 (6.9 mg, white powder, RT = 19.974 min), yield 7.3%.

[0365] Compound 11-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.92 (s, ¹H), 9.41 (s, ¹H), 7.53 (d, J = 7.5 Hz, ¹H), 7.43 (d, J = 8.1 Hz, ¹H), 7.19–7.12 (m, 3H), 7.11 (t, J = 108 Hz, 1H), 6.70 (d, J = 6.7 Hz, 2H), 2.71–2.62 (m, ¹H), 2.13–2.01 (m, 2H), 1.97–1.80 (m, 2H), 1.63–1.52 (m, 2H), 1.41–1.07 (m, 4H). LC-MS (ESI) m / z [M+H] + 408.42.

[0366] Compound 11-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.88 (s, ¹H), 9.42 (s, ¹H), 7.47 (t, J = 6.9 Hz, 2H), 7.18 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 108 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 2.72–2.59 (m, ¹H), 2.21–2.02 (m, 2H), 2.01–1.75 (m, 2H), 1.60–1.48 (m, 3H), 1.48–1.33 (m, 2H), 0.98–0.83 (m, 1H). LC-MS (ESI) m / z [M+H] + 408.42.

[0367] Preparation of compounds 11-A, 11-B, 11-C, and 11-D:

[0368] Compound 11 (808 mg) was dissolved in 40 mL of methanol and separated by chiral separation using SFC. Separation conditions: Instrument: Waters SFC 150; Column: [not specified]. IG (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% DEA); Elution gradient: A:B = 80:20; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following components were obtained: 11-A 114mg, 11-B 158mg, 11-C 159mg, 11-D 168mg.

[0369] Compound 11-A: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 1.514 min. LC-MS (ESI) m / z [M+H] + 408.41.

[0370] Compound 11-B: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 2.062 min. LC-MS (ESI) m / z [M+H] + 408.41.

[0371] Compound 11-C: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 2.230 min. LC-MS (ESI) m / z [M+H] + 408.41.

[0372] Compound 11-D: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 85:15; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nm; Retention time: RT = 2.924 min. LC-MS (ESI) m / z [M+H] + 408.41.

[0373] Example 12: Preparation of compounds 12-P1 and 12-P2

[0374] Preparation of compound 12-2:

[0375] Compound 12-1 (1.0 g, 6.21 mmol) and 4,4-difluorocycloheptanone (1.15 g, 7.76 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (2.4 g, 37.2 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (1.36 mL, 12.4 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 2 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (40 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.6 g of a yellow viscous substance was obtained. This substance was dissolved in toluene (40 mL), and PPTS (221 mg, 0.88 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / petroleum ether = 0-25%) was performed to give the title compound 12-2 (1.16 g, white solid), yield 67%.

[0376] LC-MS(ESI)m / z[M+H] + 278.38.

[0377] Preparation of compound 12-3:

[0378] Compound 12-2 (1.14 g, 4.11 mmol) was dissolved in a mixed solution of tetrahydrofuran (8 mL) and methanol (8 mL). After cooling to 0 °C, sodium borohydride (168 mg, 4.92 mmol) was added. The mixture was stirred at 0 °C for 1 hour, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-25%) to give the title compound 12-3 (860 mg, yellow-brown solid), in 75% yield.

[0379] LC-MS(ESI)m / z[M+H] + 280.38.

[0380] Preparation of compound 12-4:

[0381] Compound 12-3 (800 mg, 2.86 mmol) was dissolved in a mixed solution of toluene (10 mL) and tetrahydrofuran (10 mL), cooled to 0 °C, and potassium tert-butoxide (320 mg, 2.86 mmol) was added. The mixture was stirred for 1 hour under an oxygen atmosphere (balloon). A saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-50%) to give the title compound 12-4 (520 mg, yellow oil), in 62% yield.

[0382] LC-MS(ESI)m / z[M-(OH)] + 278.38.

[0383] Preparation of compound 12:

[0384] Phenol (267 mg, 2.84 mmol) was dissolved in anhydrous 1,2-dichloroethane (55 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (1.2 mL, 14.2 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 12-4 (420 mg, 1.42 mmol) in 1,2-dichloroethane (5 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-35%) to give the title compound 12 (440 mg, white solid), in 83% yield. LC-MS (ESI) m / z [M+H] + 372.37.

[0385] Preparation of compounds 12-P1 and 12-P2:

[0386] Compound 12 (100 mg, 0.269 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 12-P1 (20 mg, white powder, RT = 19.086 min), yield 20%, and compound 12-P2 (29 mg, white powder, RT = 19.732 min), yield 29%.

[0387] Compound 12-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.50 (s, ¹H), 9.35 (s, ¹H), 7.15 (t, J = 7.2Hz, 3H), 7.04 (d, J = 7.6Hz, 1H), 6.94 (t, J = 7.5Hz, 1H), 6.68 (d, J = 8.4Hz, 2H), 2.65–2.57 (m, ¹H), 2.21 (s, 3H), 2.09–2.00 (m, 2H), 1.96–1.82 (m, 2H), 1.61–1.52 (m, 2H), 1.43–1.29 (m, 3H), 1.14–1.01 (m, 1H). LC-MS (ESI) m / z [M+H] + 372.37.

[0388] Compound 12-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.46 (s, ¹H), 9.36 (s, ¹H), 7.11 (t, J = 7.8 Hz, 3H), 7.06 (d, J = 7.7 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H), 2.64–2.58 (m, ¹H), 2.21 (s, 3H), 2.13–2.02 (m, 2H), 1.93–1.78 (m, 2H), 1.58–1.48 (m, 3H), 1.45–1.34 (m, 2H), 0.94–0.84 (m, 1H). LC-MS (ESI) m / z [M+H] + 372.37.

[0389] Example 13: Preparation of compounds 13-P1 and 13-P2

[0390] Preparation of compound 13-2:

[0391] Compound 13-1 (1.5 g, 8.37 mmol) and 4,4-difluorocycloheptanone (1.47 g, 9.96 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (2.15 g, 33.2 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (1.8 mL, 16.6 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and the reaction was quenched with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 4.1 g of a reddish-brown viscous substance was obtained. This substance was dissolved in toluene (40 mL), and PPTS (326 mg, 1.3 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / petroleum ether = 0-30%) yielded the title compound 13-2 (2.1 g, yellow-brown solid), in 85% yield.

[0392] LC-MS(ESI)m / z[M+H] + 296.49.

[0393] Preparation of compound 13-3:

[0394] Compound 13-2 (2.1 g, 7.11 mmol) was dissolved in a mixed solution of tetrahydrofuran (25 mL) and methanol (25 mL). After cooling to 0 °C, sodium borohydride (322 mg, 8.52 mmol) was added. The mixture was stirred at 0 °C for 20 minutes, and then the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-28%) to give compound 13-3 (1.12 g, pink solid), in 53% yield.

[0395] LC-MS(ESI)m / z[M+H] + 298.56.

[0396] Preparation of compound 13-4:

[0397] Compound 13-3 (1.12 g, 3.77 mmol) was dissolved in a mixed solution of toluene (15 mL) and tetrahydrofuran (15 mL), cooled to 0 °C, and peroxytert-butanol (489 mg, 3.8 mmol) and potassium tert-butoxide (426 mg, 3.8 mmol) were added. The mixture was stirred at room temperature for 1 hour, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-37%) to give the title compound 13-4 (350 mg, yellow solid), in 30% yield.

[0398] LC-MS(ESI)m / z[M-(OH)] + 296.49.

[0399] Preparation of compound 13:

[0400] Phenol (207 mg, 2.2 mmol) was dissolved in anhydrous 1,2-dichloroethane (150 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.97 mL, 11 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 13-4 (350 mg, 1.12 mmol) in 1,2-dichloroethane (10 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-26%) to give title compound 13 (215 mg, yellow oil), yield 67%. LC-MS (ESI) m / z [M+H] + 390.63.

[0401] Preparation of compounds 13-P1 and 13-P2:

[0402] Compound 13 (215 mg, 0.552 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 13-P1 (52 mg, white powder, RT = 21.385 min), yield 24%, and compound 13-P2 (45 mg, white powder, RT = 22.171 min), yield 21%).

[0403] Compound 13-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.72 (s, 1H), 9.37 (s, 1H), 7.17 (dd, J = 8.3, 5.2Hz, 1H), 7.13 (d, J = 8.7Hz, 2H), 6.80 (dd, J = 10.3, 8.3Hz, 1H), 6.69 (d, J = 8.6Hz, 2H), 2.66–2.56 (m, 1H), 2.14 (d, J = 1.5Hz, 3H), 2.09–1.78 (m, 4H), 1.63–1.52 (m, 2H), 1.46–1.21 (m, 3H), 1.07 (q, J = 11.8Hz, 1H). LC-MS (ESI) m / z [M+H] + 390.63.

[0404] Compound 13-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.68 (s, ¹H), 9.38 (s, ¹H), 7.15–7.08 (m, 3H), 6.82 (dd, J = 10.3, 8.2 Hz, ¹H), 6.69 (d, J = 8.5 Hz, 2H), 2.68–2.57 (m, ¹H), 2.14 (s, 3H), 2.11–1.99 (m, 2H), 1.94–1.74 (m, 2H), 1.60–1.48 (m, 3H), 1.47–1.28 (m, 2H), 0.94–0.82 (m, ¹H). LC-MS (ESI) m / z [M+H] + 390.63.

[0405] Example 14: Preparation of compounds 14-P1, 14-P2, 14-A, 14-B, 14-C, and 14-D

[0406] Preparation of compound 14-2:

[0407] Compound 14-1 (600 mg, 3.14 mmol) and 4,4-difluorocycloheptanone (697 mg, 4.71 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (1.23 g, 18.8 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.69 mL, 6.28 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (30 mL) was added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 1.69 g of a brown solid was obtained. This solid was dissolved in toluene (35 mL), and PPTS (131 mg, 0.52 mmol) was added. The mixture was refluxed for 1 hour and then cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-25%) yielded the title compound 14-2 (900 mg, yellow solid), in 93% yield.

[0408] LC-MS(ESI)m / z[M+H] + 308.42.

[0409] Preparation of compound 14-3:

[0410] Compound 14-2 (415 mg, 1.35 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (15 mL), and 10% Pd / C (42 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The solution was diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, concentrated, and then separated using Flash chromatography (ethyl acetate / dichloromethane = 0-25%) to give the title compound 14-3 (270 mg, white solid), in 65% yield.

[0411] LC-MS(ESI)m / z[M+H] + 310.42.

[0412] Preparation of compound 14-4:

[0413] Compound 14-3 (163 mg, 0.527 mmol) was dissolved in a mixed solution of toluene (2 mL) and tetrahydrofuran (2 mL). After cooling to 0 °C, tert-butyl hydroperoxide (60 mg, 0.464 mmol, 70% aqueous solution) and potassium tert-butoxide (52 mg, 0.464 mmol) were added. The mixture was stirred at 0 °C for 30 minutes, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 14-4 (50 mg, colorless oil), in 29% yield.

[0414] LC-MS(ESI)m / z[M-(OH)] + 308.35.

[0415] Preparation of compound 14:

[0416] Phenol (26 mg, 0.272 mmol) was dissolved in anhydrous 1,2-dichloroethane (20 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.12 mL, 1.36 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 14-4 (50 mg, 0.154 mmol) in 1,2-dichloroethane (2 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude compound 14 was concentrated to obtain crude compound 14 (75 mg, yellow oil). The crude compound was directly used for further preparative liquid chromatography purification.

[0417] LC-MS(ESI)m / z[M+H] + 402.42.

[0418] Preparation of compounds 14-P1 and 14-P2:

[0419] The crude compound 14 (75 mg) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 14-P1 (5.6 mg, white powder, RT = 20.020 min), with a two-step yield of 9.1%, and compound 14-P2 (5.1 mg, white powder, RT = 20.650 min), with a two-step yield of 8.2%.

[0420] Compound 14-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.46 (s, ¹H), 9.33 (s, ¹H), 7.15–7.09 (m, 3H), 6.67 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 2.64–2.53 (m, 1H), 2.04 (s, 3H), 2.09–1.98 (m, 1H), 1.94–1.80 (m, 2H), 1.64–1.54 (m, 2H), 1.42–1.19 (m, 4H), 1.10–0.97 (m, 1H). LC-MS (ESI) m / z [M+H] + 402.42.

[0421] Compound 14-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.46 (s, ¹H), 9.33 (s, ¹H), 7.15–7.09 (m, 3H), 6.67 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 2.64–2.53 (m, 1H), 2.04 (s, 3H), 2.11–1.97 (m, 1H), 1.94–1.80 (m, 2H), 1.64–1.54 (m, 2H), 1.42–1.19 (m, 4H), 1.10–0.97 (m, 1H). LC-MS (ESI) m / z [M+H] + 402.42.

[0422] Preparation of compounds 14-A, 14-B, 14-C, and 14-D

[0423] Compound 14 (600 mg) was subjected to two SFC chiral separations. First separation conditions: Instrument: Waters SFC 150; Column type: ... IG (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. Second separation conditions: Instrument model: Waters SFC 150, Column model; AD (250*30mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 85:15; Flow rate: 140mL / min; Column temperature: RT; Detection wavelength: 214nM. After resolution, the following components were obtained: 14-A 107mg, 14-B 118mg, 14-C 117mg, 14-D 125mg.

[0424] Compound 14-A: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (150*3mm 5μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 3.0 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 3.290 min. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.33(s,1H),7.15–7.09(m,3H),6.67(d,J=8.6Hz,2H),6.61(d,J=8.4Hz,1H),3.78(s,3H),2.64–2.5 3(m,1H),2.04(s,3H),2.11–1.97(m,1H),1.94–1.80(m,2H),1.64–1.54(m,2H),1.42–1.19(m,4H),1.10–0.97(m,1H).LC-MS(ESI)m / z[M+H] + 402.42.

[0425] Compound 14-B: Chiral analysis method 1 (Instrument model: Waters UPCC (CA-352); Column model: IG (150*3mm 5μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 3.0 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 3.943 min). Chiral analysis method 2 (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.105min). 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.33(s,1H),7.15–7.09(m,3H),6.67(d,J=8.6Hz,2H),6.61(d,J=8.4Hz,1H),3.78(s,3H),2.64–2.5 3(m,1H),2.04(s,3H),2.09–1.98(m,1H),1.94–1.80(m,2H),1.64–1.54(m,2H),1.42–1.19(m,4H),1.10–0.97(m,1H).LC-MS(ESI)m / z[M+H] + :402.42.LC-MS(ESI)m / z[M+H] + 402.42.

[0426] Compound 14-C: Chiral analysis method (Instrument model: Waters UPCC (CA-352); Column model: IG (150*3mm 5μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 3.0 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 3.839 min). Chiral analysis method 2 (Instrument model: Waters UPCC (CA-352); Column model: AD (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 1.5mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Retention time: RT = 2.468min). 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.33(s,1H),7.15–7.09(m,3H),6.67(d,J=8.6Hz,2H),6.61(d,J=8.4Hz,1H),3.78(s,3H),2.64–2.5 3(m,1H),2.04(s,3H),2.11–1.97(m,1H),1.94–1.80(m,2H),1.64–1.54(m,2H),1.42–1.19(m,4H),1.10–0.97(m,1H).LC-MS(ESI)m / z[M+H] + 402.42.

[0427] Compound 14-D: Chiral Analysis Method 1 (Instrument Model: Waters UPCC (CA-352); Column Model: IG (150*3mm 5μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 80:20; Flow rate: 3.0 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nm; Retention time: RT = 5.864 min. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.33(s,1H),7.15–7.09(m,3H),6.67(d,J=8.6Hz,2H),6.61(d,J=8.4Hz,1H),3.78(s,3H),2.64–2.5 3(m,1H),2.04(s,3H),2.09–1.98(m,1H),1.94–1.80(m,2H),1.64–1.54(m,2H),1.42–1.19(m,4H),1.10–0.97(m,1H).LC-MS(ESI)m / z[M+H] + :402.42.LC-MS(ESI)m / z[M+H] + 402.42.

[0428] Example 15: Preparation of compounds 15-P1, 15-P2, 15-A, a mixture of compounds 15-B and 15-C, and compound 15-D.

[0429] Preparation of compound 15-2:

[0430] Compound 15-1 (4.0 g, 26.1 mmol) was dissolved in DMSO (50 mL), and potassium hydroxide (5.86 g, 104 mmol) and deuterated iodomethane (7.57 g, 52.2 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 30 minutes. The reaction solution was poured into an ice-water mixture and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, crude compound 15-2 (3.88 g) was obtained. The crude product was used directly in the next reaction without further purification.

[0431] Preparation of compound 15-3:

[0432] The crude compound 15-2 (3.88 g) was dissolved in anhydrous ethanol (40 mL), 10% Pd / C (530 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere (balloon). After filtration through diatomaceous earth, the solution was concentrated to obtain the title compound 15-3 (3.20 g, brown liquid), with a two-step yield of 87%.

[0433] LC-MS(ESI)m / z[M+H] + 141.37.

[0434] Preparation of compound 15-4:

[0435] Compound 15-3 (3.20 g, 22.8 mmol) was dissolved in anhydrous tetrahydrofuran (45 mL). Triethylamine (3.46 g, 34.2 mmol) and monoethyl oxaloyl chloride (3.42 g, 25.1 mmol) were added at 0 °C, and the mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was quenched with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, crude product of the title compound 15-4 (5.6 g) was obtained and proceeded directly to the next reaction without further purification.

[0436] LC-MS(ESI)m / z[M+H] + 241.34.

[0437] Preparation of compound 15-5:

[0438] The crude compound 15-4 (5.6 g) was dissolved in anhydrous ethanol (60 mL). A 10% sodium hydroxide aqueous solution (11.2 g, 28 mmol) was added at 0 °C. After stirring at room temperature for 30 minutes, the mixture was filtered. The filter cake was washed with water, and the combined filtrates were adjusted to pH 2 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Concentration yielded the title compound 15-5 (3.6 g, white solid), with a two-step yield of 74%.

[0439] LC-MS(ESI)m / z[M+H] + 213.31.

[0440] Preparation of compound 15-6:

[0441] Compound 15-5 (3.5 g, 16.5 mmol) was dissolved in anhydrous dichloromethane (50 mL). Phosphorus pentachloride was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Then, aluminum trichloride was added, and the system temperature was maintained below 10 °C. Stirring was continued for 5 hours. The reaction mixture was then poured into a 1N hydrochloric acid aqueous solution (50 mL) pre-cooled to 0 °C, and stirring was continued for 30 minutes. The dichloromethane was evaporated to dryness, and the aqueous phase was directly slurried, filtered, and the filter cake was washed with water and dried to give the title compound 15-6 (2.7 g, white solid), with a yield of 84%.

[0442] LC-MS(ESI)m / z[M+H] + 195.34.

[0443] Preparation of compound 15-7:

[0444] Compound 15-6 (2.70 g, 13.9 mmol) was dissolved in anhydrous ethanol (40 mL), and hydrazine hydrate (1.0 g, 16.7 mmol) was added at room temperature. The mixture was refluxed and stirred for 1.5 hours. The reaction mixture was cooled to room temperature, and sodium ethoxide (2.30 g, 33.4 mmol) was added. The mixture was then refluxed and stirred for another 20 hours. After the reaction mixture was cooled to room temperature, it was slowly poured into an ice-water mixture (100 mL), concentrated to remove the ethanol, and the crude aqueous solution was slurried, filtered, and the filter cake was washed with water and dried to give the title compound 15-7 (1.50 g, yellow solid), with a yield of 60%.

[0445] LC-MS(ESI)m / z[M+H] + 181.36.

[0446] Preparation of compound 15-8:

[0447] Compound 15-7 (1.50 g, 8.32 mmol) and 4,4-difluorocycloheptanone (1.48 g, 10 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Under nitrogen protection, pyridine (0.98 g, 12.5 mmol) and tetraethoxytitanium (3.80 g, 16.6 mmol) were added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at 50 °C for 3 hours. After cooling the reaction solution to room temperature, saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-20%) to give the title compound 15-8 (1.50 g, yellow solid), in 58% yield.

[0448] LC-MS(ESI)m / z[M+H] + 311.48.

[0449] Preparation of compounds 15-9:

[0450] Compound 15-8 (1.50 g, 4.83 mmol) was dissolved in a mixture of tetrahydrofuran (15 mL) and methanol (15 mL), and 10% Pd / C (150 mg) was added. The mixture was stirred at 50 °C for 2 hours under a hydrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, concentrated, and then separated by Flash (ethyl acetate / dichloromethane = 0-20%) to give the title compound 15-9 (1.46 g, yellow solid), in 97% yield.

[0451] LC-MS(ESI)m / z[M+H] + 313.55.

[0452] Preparation of compounds 15-10:

[0453] 900 mg, 7.02 mmol, 70% aqueous solution of tert-butyl hydroperoxide was dissolved in toluene (6 mL), stirred at room temperature for 10 minutes, allowed to stand for separation, the aqueous phase was removed, and the organic phase was dried over anhydrous sodium sulfate. The solution of tert-butyl hydroperoxide in anhydrous toluene was obtained by filtration and reserved for use. 1.46 g, 4.67 mmol, of compound 15-9 was dissolved in tetrahydrofuran (30 mL), and the above anhydrous toluene solution of tert-butyl hydroperoxide was added. Under nitrogen protection, the mixture was heated to 65 °C, and potassium tert-butoxide (570 mg, 5.14 mmol) was added to the reaction solution. The mixture was stirred at 65 °C for 40 minutes. The reaction solution was cooled to room temperature and poured into 15 mL of 5% citric acid aqueous solution pre-cooled in an ice-water bath. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-30%) yielded the title compound 15-10 (1.30 g, yellow oil), with a yield of 85%.

[0454] LC-MS(ESI)m / z[M-(OH)] + 311.48.

[0455] Preparation of compound 15:

[0456] Phenol (370 mg, 4.0 mmol) was dissolved in anhydrous dichloromethane (24 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.16 mL, 1.8 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A dichloromethane (24 mL) solution of compound 15-10 (1.20 g, 3.65 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was slurried with dichloromethane, filtered, and concentrated to give the title compound 15 (1.20 g, white solid), in 81% yield.

[0457] LC-MS(ESI)m / z[M+H] + 405.56.

[0458] Preparation of compounds 15-P1 and 15-P2:

[0459] Compound 15 (604 mg, 1.49 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-82%; flow rate: 20 mL / min) to obtain compound 15-P1 (194 mg, white powder, RT = 19.51 min), yield 32%, and compound 15-P2 (232 mg, white powder, RT = 20.52 min), yield 38%.

[0460] Compound 15-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.47 (s, ¹H), 9.34 (s, ¹H), 7.16 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.2 Hz, 1H), 2.65–2.55 (m, ¹H), 2.07 (s, 3H), 2.06–2.00 (m, 2H), 1.99–1.82 (m, 2H), 1.61 (d, J = 10.7 Hz, 2H), 1.47–1.29 (m, 3H), 1.14–1.00 (m, 1H). LC-MS (ESI) m / z [M+H] + 405.56.

[0461] Compound 15-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.44 (s, ¹H), 9.35 (s, ¹H), 7.15 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.2 Hz, 1H), 2.66–2.55 (m, ¹H), 2.20–2.07 (m, 2H), 2.07 (s, 3H), 1.86 (m, 2H), 1.63–1.50 (m, 3H), 1.48–1.31 (m, 2H), 0.96–0.86 (m, 1H). LC-MS (ESI) m / z [M+H] + 405.56.

[0462] Preparation of a mixture of compounds 15-A, 15-B, and 15-C, and 15-D:

[0463] 3.86 g of compound 15 was chirally separated by SFC. Separation conditions: Instrument: Waters SFC 150; Column: CHIRAL ART Collulose SC (250*25 mm 10 μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0 mol / L Ammonia in MeOH); Elution gradient: A:B = 70:30; Flow rate: 120 mL / min; Column temperature: RT; Detection wavelength: 214 nm. The separated compounds yielded: 1.07 g of compound 15-A, 1.57 g of a mixture of compounds 15-B and 15-C, and 893 mg of compound 15-D.

[0464] Compound 15-A: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 3.0mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Elution time: RT = 3.175min). 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),9.35(s,1H),7.15(d,J=8.5Hz,2H),7.07(d,J=8.3Hz,1H),6.70(d,J=8.7Hz,2H),6.64(d,J=8.2Hz,1H), 2.66-2.55(m,1H),2.20-2.07(m,2H),2.07(s,3H),1.86(m,2H),1.63-1 .50(m,3H),1.48-1.31(m,2H),0.96-0.86(m,1H).LC-MS(ESI)m / z[M+H] + 405.57.

[0465] Mixture of compounds 15-B and 15-C: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 3.0mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Elution time: RT = 3.723min). LC-MS (ESI) m / z [M+H] + 405.57.

[0466] Compound 15-D: Chiral analysis conditions (Instrument model: Waters UPCC (CA-352); Column model: IG (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 80:20; Flow rate: 3.0mL / min; Column temperature: 35℃; Column pressure: 1800psi; Detection wavelength: 214nM; Elution time: RT = 5.730min). 1H NMR (400MHz, DMSO-d6) δ10.47(s,1H),9.34(s,1H),7.16(d,J=8.7Hz,2H),7.13(d,J=8.3Hz,1H),6.70(d,J=8.7Hz,2H),6.62(d,J=8.2Hz,1H),2.65- 2.55(m,1H),2.07(s,3H),2.06-2.00(m,2H),1.99-1.82(m,2H),1.61(d,J =10.7Hz,2H),1.47-1.29(m,3H),1.14-1.00(m,1H).LC-MS(ESI)m / z[M+H] + 405.57.

[0467] Example 16: Preparation of compounds 16-P1 and 16-P2

[0468] Preparation of compound 16-2:

[0469] Potassium hydroxide (13.0 g, 232 mmol) was added to a mixed solution of acetonitrile (30 mL) and water (3 mL). The mixture was cooled to -20 °C, and compound 16-1 (2.0 g, 13.1 mmol) was added. After stirring for 10 minutes, diethyl phosphonate (7.0 g, 26.2 mmol) was slowly added, maintaining the reaction solution temperature below -10 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. The reaction solution was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate yielded crude compound 16-2 (2.20 g, yellow oil), which was directly used in the next reaction without further purification.

[0470] Preparation of compound 16-3:

[0471] The crude compound 16-2 (2.20 g) was dissolved in anhydrous ethanol (40 mL), 10% Pd / C (530 mg) was added, and the mixture was stirred for 18 hours under a hydrogen atmosphere (balloon). After filtration through diatomaceous earth and concentration, the title compound 16-3 (1.97 g, brown liquid) was obtained, with a two-step yield of 87%.

[0472] LC-MS(ESI)m / z[M+H] + 174.32.

[0473] Preparation of compound 16-4:

[0474] Anhydrous sodium sulfate (10.3 g, 72.8 mmol) was dissolved in water (60 mL), and chloral hydrate (2.6 g, 15.6 mmol) was added under vigorous stirring to obtain reaction solution 1. Hydroxylamine hydrochloride (4.0 g, 57.2 mmol), compound 16-3 (1.80 g, 10.4 mmol), and concentrated hydrochloric acid (3.0 mL) were added to water (30 mL) to obtain reaction solution 2. Reaction solution 2 was added to reaction solution 1, and the mixture was slowly heated to 45 °C and stirred for 1 hour, then heated to 82 °C and stirred for another 1 hour. The reaction solution was slowly cooled to 0 °C, filtered, and the filter cake was washed with water and dried to obtain crude product of the title compound 16-4 (2.94 g), which was directly used in the next reaction without further purification.

[0475] LC-MS(ESI)m / z[M+H] + 245.35.

[0476] Preparation of compound 16-5:

[0477] The crude compound 16-4 (2.94 g) was added to methanesulfonic acid (12 g, 121 mmol), and the mixture was heated to 50 °C and stirred for 30 minutes. The reaction mixture was cooled to room temperature and poured into an ice-water mixture. Extraction was performed with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-35%) was performed to give the title compound 16-5 (1.65 g, orange-yellow solid), with a two-step yield of 70%.

[0478] LC-MS(ESI)m / z[M+H] + 228.37.

[0479] Preparation of compound 16-6:

[0480] Compound 16-5 (1.36 g, 5.99 mmol) and 4,4-difluorocycloheptanone (1.06 g, 7.19 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (1.56 g, 23.96 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (2.28 g, 12.0 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and saturated sodium bicarbonate (20 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.57 g of a yellow solid was obtained. This solid was dissolved in toluene (50 mL), and PPTS (111 mg, 0.479 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-32%) to give the title compound 16-6 (150 mg, pink solid), in 7.3% yield.

[0481] LC-MS(ESI)m / z[M+H] + 344.46.

[0482] Preparation of compound 16-7:

[0483] Compound 16-6 (150 mg, 0.437 mmol) was dissolved in a mixed solution of tetrahydrofuran (6 mL) and methanol (6 mL), and 10% Pd / C (15 mg) was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, concentrated, and then separated by flash (ethyl acetate / dichloromethane = 0-30%) to give the title compound 16-7 (112 mg, pink solid), in 74% yield.

[0484] LC-MS(ESI)m / z[M+H] + 346.41.

[0485] Preparation of compound 16-8:

[0486] 90 mg of tert-butyl hydroperoxide (70% aqueous solution, 0.702 mmol) was dissolved in 2 mL of toluene. The mixture was stirred at room temperature for 10 minutes, allowed to stand to separate into layers, and the aqueous phase was removed. The organic phase was dried over anhydrous sodium sulfate and filtered to obtain an anhydrous toluene solution of tert-butyl hydroperoxide for later use. Compound 16-7 (161 mg, 0.466 mmol) was dissolved in 3 mL of tetrahydrofuran. The above anhydrous toluene solution of tert-butyl hydroperoxide was added, and the mixture was heated to 65 °C under nitrogen protection. Potassium tert-butoxide (52 mg, 0.467 mmol) was added to the reaction mixture, and the mixture was stirred at 65 °C for another 30 minutes. The reaction mixture was cooled to room temperature and poured into 15 mL of 5% citric acid aqueous solution pre-cooled in an ice-water bath. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-50%) yielded the title compound 16-8 (169 mg, colorless oil), 100% yield.

[0487] LC-MS(ESI)m / z[M-(OH)] + 344.39.

[0488] Preparation of compound 16:

[0489] Phenol (66 mg, 0.702 mmol) was dissolved in dichloromethane (5 mL), and the mixture was cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (35 mg, 0.234 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A solution of compound 16-8 (169 mg, 0.468 mmol) in dichloromethane (3 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 5 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 1 hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-50%) to give the title compound 16 (68 mg, yellow oil), in 33% yield.

[0490] LC-MS(ESI)m / z[M+H] + 438.48.

[0491] Preparation of compounds 16-P1 and 16-P2:

[0492] Compound 16 (174 mg, 0.398 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-82%; flow rate: 20 mL / min) to obtain compound 16-P1 (20.3 mg, white powder, RT = 16.14 min), yield 12%, and compound 16-P2 (23.2 mg, white powder, RT = 20.17 min), yield 13%.

[0493] Compound 16-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.72 (s, ¹H), 9.42 (s, ¹H), 7.24 (d, J = 8.2 Hz, ¹H), 7.20 (t, J = 72 Hz, ¹H), 7.16 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 2.74–2.58 (m, ¹H), 2.15 (s, 3H), 2.13–2.00 (m, 2H), 2.00–1.80 (m, 2H), 1.71–1.54 (m, 2H), 1.50–1.23 (m, 3H), 1.18–1.03 (m, 1H). LC-MS (ESI) m / z [M+H] + 438.48.

[0494] Compound 16-P2: 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),9.41(s,1H),7.19(d,J=12.5Hz,1H),7.21 (t,J=74Hz,1H),7.14(d,J=8.7Hz,2H),6.85(d,J=8.1Hz,1H),6.77-6.68(d,J=8 .7Hz,2H),2.71-2.59(m,1H),2.15(s,3H),2.15-2.03(m,2H),2.02-1.75(m,2H) ,1.62-1.50(m,3H),1.49-1.33(m,2H),0.99-0.85(m,1H).LC-MS(ESI)m / z[M+H] + 438.48.

[0495] Example 17: Preparation of compounds 17-P1, 17-P2, 17-A, and 17-C

[0496] Preparation of compound 17-2:

[0497] Compound 17-1 (2.5 g, 16.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to -20 °C, and sodium hydride (6.52 g, 163 mmol, 60%) was added in portions. After stirring for 10 minutes, heavy water (16.3 g, 815 mmol) was added, followed by the slow addition of diethyl (bromodifluoromethyl)phosphonate (8.70 g, 32.6 mmol). The reaction mixture was kept at <-10 °C, and the mixture was brought to room temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, crude compound 17-2 (2.24 g, yellow oil) was obtained and proceeded directly to the next step without further purification.

[0498] Preparation of compound 17-3:

[0499] The crude compound 17-2 (2.24 g) was dissolved in anhydrous ethanol (40 mL), 10% Pd / C (224 mg) was added, and the mixture was stirred for 18 hours under a hydrogen atmosphere (balloon). After filtration through diatomaceous earth and concentration, the title compound 17-3 (2.14 g, brown liquid) was obtained, with a two-step yield of 75%.

[0500] LC-MS(ESI)m / z[M+H] + 175.34.

[0501] Preparation of compound 17-4:

[0502] Anhydrous sodium sulfate (11.4 g, 82.4 mmol) was dissolved in water (60 mL), and chloral hydrate (2.9 g, 17.2 mmol) was added under vigorous stirring to obtain reaction solution 1. Hydroxylamine hydrochloride (4.4 g, 63.2 mmol), compound 17-3 (2.0 g, 11.5 mmol), and concentrated hydrochloric acid (3.0 mL) were added to water (30 mL) to obtain reaction solution 2. Reaction solution 2 was added to reaction solution 1, and the mixture was slowly heated to 45 °C and stirred for 1 hour, then heated to 82 °C and stirred for another 1 hour. The reaction solution was slowly cooled to 0 °C, filtered, and the filter cake was washed with water and dried to obtain crude product of the title compound 17-4 (2.93 g), which was directly used in the next reaction without further purification.

[0503] LC-MS(ESI)m / z[M+H] + 246.34.

[0504] Preparation of compound 17-5:

[0505] The crude compound 17-4 (2.93 g) was added to methanesulfonic acid (11.47 g, 119.5 mmol), and the mixture was heated to 50 °C and stirred for 30 minutes. The reaction mixture was cooled to room temperature and poured into an ice-water mixture. Extraction was performed with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-35%) was performed to give the title compound 17-5 (1.67 g, yellow solid), with a two-step yield of 64%.

[0506] LC-MS(ESI)m / z[M+H] + 229.39.

[0507] Preparation of compound 17-6:

[0508] Compound 17-5 (1.26 g, 5.53 mmol) and 4,4-difluorocycloheptanone (981 mg, 6.63 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (1.4 g, 22.1 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (2.1 g, 11.1 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and saturated sodium bicarbonate (20 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.38 g of an orange oil was obtained. This oil was dissolved in toluene (50 mL), and PPTS (102 mg, 0.44 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-35%) to give the title compound 17-6 (380 mg, pink solid), in 20% yield.

[0509] LC-MS(ESI)m / z[M+H] + 345.49.

[0510] Preparation of compound 17-7:

[0511] Compound 17-6 (530 mg, 1.54 mmol) was dissolved in a mixture of tetrahydrofuran (15 mL) and methanol (15 mL), and 10% Pd / C (53 mg) was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, concentrated, and then separated by flash (ethyl acetate / dichloromethane = 0-35%) to give the title compound 17-7 (530 mg, white solid), in 99% yield.

[0512] LC-MS(ESI)m / z[M+H] + 347.39.

[0513] Preparation of compound 17-8:

[0514] 295 mg, 2.30 mmol, 70% aqueous solution of tert-butyl hydroperoxide was dissolved in toluene (3 mL), stirred at room temperature for 10 minutes, allowed to stand for separation, the aqueous phase was removed, and the organic phase was dried over anhydrous sodium sulfate. The solution of tert-butyl hydroperoxide in anhydrous toluene was obtained by filtration and reserved for use. 530 mg, 1.53 mmol, of compound 17-7 was dissolved in tetrahydrofuran (10 mL), and the above anhydrous toluene solution of tert-butyl hydroperoxide was added. Under nitrogen protection, the mixture was heated to 65 °C, and potassium tert-butoxide (171 mg, 1.53 mmol) was added to the reaction solution. The mixture was stirred at 65 °C for another 30 minutes. The reaction solution was cooled to room temperature and poured into 10 mL of 5% citric acid aqueous solution pre-cooled in an ice-water bath. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / dichloromethane = 0-48%) yielded the title compound 17-8 (357 mg, pale yellow oil), with a yield of 64%.

[0515] LC-MS(ESI)m / z[M-(OH)] + 345.46.

[0516] Preparation of compound 17:

[0517] Phenol (155 mg, 1.65 mmol) was dissolved in dichloromethane (40 mL), and the mixture was cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (330 mg, 2.20 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A solution of compound 17-8 (398 mg, 1.10 mmol) in dichloromethane (10 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 5 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 1 hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by Flash (ethyl acetate / dichloromethane = 0-51%) to give the title compound 17 (366 mg, white oil), in 76% yield.

[0518] LC-MS(ESI)m / z[M+H] + 439.50.

[0519] Preparation of compounds 17-P1 and 17-P2:

[0520] Compound 17 (534 mg, 1.22 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-82%; flow rate: 20 mL / min) to obtain compound 17-P1 (118 mg, white powder, RT = 20.14 min), yield 22%, and compound 17-P2 (122 mg, white powder, RT = 20.82 min), yield 23%.

[0521] Compound 17-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.72 (s, ¹H), 9.39 (s, ¹H), 7.24 (d, J = 8.2 Hz, ¹H), 7.16 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 2.71–2.59 (m, ¹H), 2.15 (s, 3H), 2.12–2.02 (m, 2H), 2.01–1.82 (m, 2H), 1.69–1.54 (m, 2H), 1.48–1.24 (m, 3H), 1.19–1.05 (m, ¹H). LC-MS (ESI) m / z [M+H] + 439.50.

[0522] Compound 17-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.68 (s, ¹H), 9.40 (s, ¹H), 7.19 (d, J = 8.3Hz, ¹H), 7.14 (d, J = 8.8Hz, 2H), 6.85 (d, J = 8.1Hz, 1H), 6.71 (d, J = 8.8Hz, 2H), 2.64 (t, J = 10.5Hz, 1H), 2.16 (s, 3H), 2.13–2.04 (m, 2H), 2.04–1.77 (m, 2H), 1.63–1.49 (m, 3H), 1.49–1.32 (m, 2H), 0.98–0.85 (m, 1H). LC-MS (ESI) m / z [M+H] + 439.50.

[0523] Preparation of compounds 17-A and 17-C:

[0524] 100 mg of compound 17-P2 was separated by chiral separation using SFC. Separation conditions: Instrument: Waters SFC 150; Column: CHIRAL ART Collulose SC (250*25mm 10μm); Mobile phase: A: Supercritical CO2, B: EtOH (+0.1% 7.0mol / L Ammonia in MeOH); Elution gradient: A:B = 70:30; Flow rate: 120 mL / min; Column temperature: RT; Detection wavelength: 214 nm. The separated compounds yielded: 17-A 35 mg and 17-C 29 mg.

[0525] Compound 17-A: Chiral analysis method (Instrument: Waters UPCC (CA-352); Column: CHIRAL ART Collulose SC (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 70:30; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 1.271 min). LC-MS (ESI) m / z [M+H] + 439.50.

[0526] Compound 17-C: Chiral analysis method (Instrument: Waters UPCC (CA-352); Column: CHIRAL ART Collulose SC (100*3mm 3μm); Mobile phase: A: Supercritical CO2, B: EtOH (0.1% EDA); Elution gradient: A:B = 70:30; Flow rate: 1.5 mL / min; Column temperature: 35℃; Column pressure: 1800 psi; Detection wavelength: 214 nM; Retention time: RT = 1.769 min). LC-MS (ESI) m / z [M+H] + 439.50.

[0527] Example 18: Preparation of compounds 18-P1 and 18-P2

[0528] Preparation of compound 18-2:

[0529] Compound 18-1 (1.0 g, 4.17 mmol) and 4,4-difluorocycloheptanone (740 mg, 5.00 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Zinc powder (1.08 g, 16.7 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.91 mL, 8.33 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 1.76 g of a yellow solid was obtained. This solid was dissolved in toluene (25 mL), and PPTS (84 mg, 0.333 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-35%) to give the title compound 18-2 (1.05 g, yellow solid), in 71% yield.

[0530] LC-MS(ESI)m / z[M+H] + :356.58,358.58.

[0531] Preparation of compound 18-3:

[0532] Compound 18-2 (1.05 g, 2.95 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and methanol (10 mL). After cooling to 0 °C, sodium borohydride (112 mg, 2.95 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-40%) to give the title compound 18-3 (474 ​​mg, colorless transparent liquid), in 45% yield.

[0533] LC-MS(ESI)m / z[M+H] + :358.51,360.51.

[0534] Preparation of compound 18-4:

[0535] Compound 18-3 (428 mg, 1.20 mmol) was dissolved in a mixed solution of toluene (5 mL) and tetrahydrofuran (5 mL). After cooling to 0 °C, tert-butyl hydroperoxide (154 mg, 1.20 mmol, 70% aqueous solution) and potassium tert-butoxide (134 mg, 1.20 mmol) were added. The mixture was stirred at 0 °C for 30 minutes, and a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 18-4 (193 mg, white solid), in 43% yield.

[0536] LC-MS(ESI)m / z[M-(OH)] + :356.47,358.47.

[0537] Preparation of compound 18-5:

[0538] Phenol (109 mg, 1.16 mmol) was dissolved in anhydrous dichloromethane (80 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.5 mL, 5.78 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A dichloromethane solution of compound 18-4 (216 mg, 0.577 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1.5 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 1 hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was Flash separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 18-5 (232 mg, white solid), in 89% yield.

[0539] LC-MS(ESI)m / z[M+H] + :450.51,452.53.

[0540] Preparation of compound 18:

[0541] Compound 18-5 (100 mg, 0.222 mmol), methylboric acid (40 mg, 0.666 mmol), Pd(dppf)Cl2 (8 mg, 0.0111 mmol), and potassium carbonate (61 mg, 0.444 mmol) were dissolved in anhydrous 1,4-dioxane (1 mL) and reacted under a nitrogen atmosphere in a microwave environment (80 W, 110 °C) for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-66%) to give compound 18 (63 mg, yellow powder), yield 74%.

[0542] LC-MS(ESI)m / z[M+H] + 386.63.

[0543] Preparation of compounds 18-P1 and 18-P2:

[0544] Compound 18 (80 mg, 0.208 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 18-P1 (15.7 mg, white powder, RT = 23.639 min), yield 20%, and compound 18-P2 (16.2 mg, white powder, RT = 24.362 min), yield 20%.

[0545] Compound 18-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.41 (s, ¹H), 9.32 (s, ¹H), 7.13 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 2.65–2.55 (m, ¹H), 2.22 (s, 3H), 2.12 (s, 3H), 2.10–1.96 (m, 3H), 1.96–1.78 (m, 1H), 1.66–1.53 (m, 2H), 1.46–1.26 (m, 3H), 1.13–0.98 (m, 1H). LC-MS (ESI) m / z [M+H] + 386.63.

[0546] Compound 18-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.38 (s, ¹H), 9.34 (s, ¹H), 7.12 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 2.66–2.55 (m, ¹H), 2.23 (s, 3H), 2.12 (s, 3H), 2.09–1.99 (m, 2H), 1.96–1.73 (m, 2H), 1.58–1.49 (m, 3H), 1.45–1.32 (m, 2H), 0.95–0.84 (m, 1H). LC-MS (ESI) m / z [M+H] + 386.63.

[0547] Example 19: Preparation of compounds 19-P1 and 19-P2

[0548] Preparation of compound 19:

[0549] Compound 6 (700 mg, 1.60 mmol) was dissolved in anhydrous DMA (9 mL), and Zn(CN)₂ (281 mg, 2.4 mmol), Pd₂(dba)₃ (146 mg, 0.16 mmol), and dppf (177 mg, 0.32 mmol) were added. The mixture was bubbled under nitrogen for 10 minutes. The reaction solution was microwaved (90 W, 140 °C) for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) and water (50 mL) were added. The mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-50%) to give the title compound 19 (590 mg, yellow oil), with a yield of 96%.

[0550] LC-MS(ESI)m / z[M+H] + 383.46.

[0551] Preparation of compounds 19-P1 and 19-P2:

[0552] Compound 19 (590 mg, 1.54 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 65-75%; flow rate: 20 mL / min) to obtain compound 19-P1 (126 mg, white powder, RT = 13.200 min), yield 21%, and compound 19-P2 (165 mg, white powder, RT = 13.926 min), yield 28%.

[0553] Compound 19-P1: ¹H NMR (400 MHz, DMSO-d6) δ 11.48 (s, ¹H), 9.49 (s, ¹H), 7.64 (dd, J = 16.6, 7.7 Hz, 2H), 7.23–7.08 (m, 3H), 6.71 (d, J = 8.3 Hz, 2H), 2.74–2.62 (m, ¹H), 2.14–1.98 (m, 2H), 1.98–1.80 (m, 2H), 1.66–1.51 (m, 2H), 1.48–1.32 (m, 2H), 1.31–1.22 (m, ¹H), 1.17–1.04 (m, 1H). LC-MS (ESI) m / z [M+H] +383.46.

[0554] Compound 19-P2: 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),9.49(s,1H),7.63(dd,J=13.4,7.7Hz,2H ),7.19(t,J=7.8Hz,1H),7.09(d,J=8.4Hz,2H),6.71(d,J=8.3Hz,2H),2.75–2.6 0(d,J=11.4Hz,1H),2.20–1.99(m,2H),1.77–1.79(m,2H),1.61–1.47(s,3H),1 .40(dd,J=26.3,12.3Hz,2H),0.89(q,J=10.1,9.5Hz,1H).LC-MS(ESI)m / z[M+H] + 383.46.

[0555] Example 20: Preparation of compounds 20-P1 and 20-P2

[0556] Preparation of compound 20:

[0557] Compound 7 (100 mg, 0.220 mmol) was dissolved in anhydrous DMA (1.0 mL), and Zn(CN)₂ (39 mg, 0.33 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol), and dppf (24 mg, 0.044 mmol) were added. The mixture was bubbled under nitrogen for 10 minutes. The reaction solution was then microwaved (100 W, 140 °C) for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) and water (50 mL) were added. The mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-60%) to give title compound 20 (83 mg, white powder), yield 94%.

[0558] LC-MS(ESI)m / z[M+H] + 401.42.

[0559] Preparation of compounds 20-P1 and 20-P2:

[0560] Compound 20 (83 mg, 0.207 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to give compound 20-P1 (16.5 mg, white powder, RT = 16.07 min), yield 20%, and compound 20-P2 (14.0 mg, white powder, RT = 16.59 min), yield 17%.

[0561] Compound 20-P1: ¹H NMR (400MHz, DMSO-d6) δ 11.75 (s, ¹H), 9.46 (s, ¹H), 7.68 (dd, J = 8.4, 5.4 Hz, ¹H), 7.15–7.03 (m, 3H), 6.75–6.68 (m, 2H), 2.73–2.63 (m, ¹H), 2.15–2.00 (m, 2H), 1.98–1.80 (m, 2H), 1.66–1.51 (m, 2H), 1.48–1.32 (m, 2H), 1.32–1.21 (m, 1H), 1.18–1.04 (m, 1H). LC-MS (ESI) m / z [M+H] + 401.42.

[0562] Compound 20-P2: ¹H NMR (400 MHz, DMSO-d6) δ 11.71 (s, ¹H), 9.47 (s, ¹H), 7.62 (dd, J = 8.4, 5.4 Hz, ¹H), 7.14–7.05 (m, 3H), 6.75–6.68 (m, 2H), 2.74–2.62 (m, 1H), 2.20–1.98 (m, 2H), 1.96–1.74 (m, 2H), 1.62–1.48 (m, 3H), 1.48–1.25 (m, 2H), 1.00–0.81 (m, 1H). LC-MS (ESI) m / z [M+H] + 401.42.

[0563] Example 21: Preparation of compounds 21-P1 and 21-P2

[0564] Preparation of compound 21:

[0565] Compound 8 (74 mg, 0.159 mmol) was dissolved in anhydrous DMA (1.0 mL), and Zn(CN)₂ (28 mg, 0.239 mmol), Pd₂(dba)₃ (15 mg, 0.0159 mmol), and dppf (18 mg, 0.0318 mmol) were added. The mixture was bubbled under nitrogen for 10 minutes. The reaction solution was then microwaved (100 W, 150 °C) for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and water (10 mL) were added. The mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-60%) to give compound 21 (25 mg, white powder), in 38% yield.

[0566] LC-MS(ESI)m / z[M+H] + 413.47.

[0567] Preparation of compounds 21-P1 and 21-P2:

[0568] Compound 21 (34 mg, 0.082 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-78%; flow rate: 20 mL / min) to obtain compound 21-P1 (9.6 mg, white powder, RT = 15.26 min), yield 28%, and compound 21-P2 (8.2 mg, white powder, RT = 16.10 min), yield 24%.

[0569] Compound 21-P1: ¹H NMR (400 MHz, DMSO-d6) δ 11.44–11.25 (m, 1H), 9.46 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 2.73–2.56 (m, 1H), 2.14–2.00 (m, 2H), 1.97–1.81 (m, 2H), 1.70–1.51 (m, 2H), 1.47–1.18 (m, 3H), 1.14–0.96 (m, 1H). LC-MS (ESI) m / z [M+H] + 413.47.

[0570] Compound 21-P2: ¹H NMR (400MHz, DMSO-d6) δ 11.32 (s, ¹H), 9.45 (s, ¹H), 7.51 (d, J = 8.5 Hz, ¹H), 7.09 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H), 2.73–2.59 (m, ¹H), 2.17–1.97 (m, 2H), 1.95–1.78 (m, 2H), 1.64–1.47 (m, 3H), 1.46–1.22 (m, 2H), 0.86 (q, J = 10.1 Hz, 1H). LC-MS (ESI) m / z [M+H] + 413.47.

[0571] Example 22: Preparation of compounds 22-P1 and 22-P2

[0572] Preparation of compound 22-1:

[0573] Compound 6 (200 mg, 0.458 mmol), trimethylsilylacetylene (0.129 mL, 0.916 mmol), Pd(PPh3)2Cl2 (65 mg, 0.092 mmol), cuprous iodide (18 mg, 0.092 mmol), and triethylamine (0.317 mL, 0.229 mmol) were dissolved in anhydrous DMF (5.0 mL) and bubbled with nitrogen for 10 minutes. The reaction mixture was then microwaved (100 W, 120 °C) for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate (25 mL) and water (25 mL) were added. The mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-40%) to give the title compound 22-1 (45 mg, yellow oil), yield 22%.

[0574] LC-MS(ESI)m / z[M+H] + 454.40.

[0575] Preparation of compound 22:

[0576] Compound 22-1 (45 mg, 0.099 mmol) was dissolved in anhydrous methanol (3 mL), potassium carbonate was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-40%) to obtain crude compound 22 (30 mg, yellow oil). The crude product was used directly in the next step of the preparation and separation.

[0577] LC-MS(ESI)m / z[M+H] + 382.37.

[0578] Preparation of compounds 22-P1 and 22-P2:

[0579] The crude compound 22 (30 mg) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 22-P1 (4.2 mg, white powder, RT = 20.492 min), with a two-step yield of 11%, and compound 22-P2 (4.3 mg, white powder, RT = 21.425 min), with a two-step yield of 11%.

[0580] Compound 22-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.81 (s, ¹H), 9.42 (s, ¹H), 7.38 (d, J = 7.5Hz, ¹H), 7.30 (d, J = 7.3Hz, ¹H), 7.12 (d, J = 8.7Hz, 2H), 7.02 (t, J = 7.7Hz, ¹H), 6.70 (d, J = 8.7Hz, 2H), 4.39 (s, ¹H), 2.68–2.62 (m, ¹H), 2.12–2.01 (m, 2H), 1.97–1.83 (m, 2H), 1.62–1.52 (m, 2H), 1.40–1.08 (m, 4H). LC-MS (ESI) m / z [M+H] + 382.37.

[0581] Compound 22-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.77 (s, ¹H), 9.43 (s, ¹H), 7.33 (d, J = 7.7 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.04 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 8.3 Hz, 2H), 4.39 (s, ¹H), 2.69–2.61 (m, ¹H), 2.13–2.00 (m, 2H), 1.94–1.75 (m, 2H), 1.55–1.50 (m, 3H), 1.47–1.30 (m, 2H), 0.97–0.81 (m, ¹H). LC-MS (ESI) m / z [M+H] + 382.37.

[0582] Example 23: Preparation of compound 23

[0583] Preparation of compound 23-2:

[0584] Compounds 23-1 (400 mg, 2.14 mmol) and ZG-18-63 (475 mg, 3.209 mmol) were dissolved in anhydrous THF (10 mL). Zinc powder (556 mg, 8.556 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.47 mL, 4.278 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 2 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (40 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 903 mg of a yellow solid was obtained. This solid was dissolved in toluene (20 mL), and PPTS (44 mg, 0.176 mmol) was added. The reaction solution was refluxed for 2 hours and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-35%) to give compound 23-2 (404 mg, yellow solid), yield 62%.

[0585] LC-MS(ESI)m / z[M+H] + 304.49.

[0586] Preparation of compound 23-3:

[0587] Compound 23-2 (404 mg, 1.33 mmol) was dissolved in a mixture of tetrahydrofuran (7.5 mL) and methanol (7.5 mL). After cooling to 0 °C, sodium borohydride (51 mg, 1.333 mmol) was added. The mixture was stirred at 0 °C for 2 hours, followed by the addition of saturated ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-35%) to give compound 23-3 (322 mg, white solid), with a yield of 79%.

[0588] LC-MS(ESI)m / z[M+H] + 306.42.

[0589] Preparation of compound 23-4:

[0590] Compound 23-3 (322 mg, 1.056 mmol) was dissolved in a mixed solution of toluene (15 mL) and tetrahydrofuran (15 mL). After cooling to 0 °C, tert-butyl hydroperoxide (136 mg, 1.056 mmol, 70% aqueous solution) and potassium tert-butoxide (118 mg, 1.056 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0 °C, and a saturated ammonium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-65%) to give compound 23-4 (54 mg, pale yellow oil), with a yield of 16%. 99 mg of compound 23-4 was recovered.

[0591] LC-MS(ESI)m / z[M+Na] + 344.32.

[0592] Preparation of compound 23:

[0593] Phenol (32 mg, 0.336 mmol) was dissolved in anhydrous 1,2-dichloroethane (24 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.3 mL, 3.36 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 10 minutes. A solution of compound 23-4 (54 mg, 0.168 mmol) in 1,2-dichloroethane (3 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 40 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-45%) to give compound 23 (49 mg, colorless transparent oil). Further separation was performed using a C18 column in reverse polarity (2.5‰ formic acid / acetonitrile = 0-66%) to give the title compound 23 (9.1 mg, white powder), in 14% yield.

[0594] 1H NMR(400MHz,DMSO-d6)δ10.48(d,J=14.0Hz,1H),9.33(d,J=3.5Hz,1H),7.16– 6.99(m,3H),6.91(t,J=6.9Hz,1H),6.67(d,J=8.4Hz,2H),2.89–2.81(m,2H), 2.81–2.73(m,2H),2.64–2.55(m,1H),2.14–1.98(m,5H),1.97–1.79(m,2H),1 .64–1.47(m,2H),1.46–1.28(m,2H),1.13–0.81(m,1H).LC-MS(ESI)m / z[M+H] + 398.36.

[0595] Example 24: Preparation of compound 24

[0596] Compound 18-5 (170 mg, 0.378 mmol), tributyl(1-ethoxyethylene)tin (0.15 mL, 0.453 mmol), Pd(PPh3)2Cl2 (13 mg, 0.0189 mmol), and triethylamine (95 mg, 0.945 mmol) were dissolved in 1,4-dioxane (4 mL) and bubbled under nitrogen for 10 minutes. The reaction mixture was then microwaved (100 W, 120 °C) for 2 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate (20 mL) and saturated ammonium chloride solution (20 mL) were added and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 36 mg of a yellow oily substance was obtained, which was separated and purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to give compound 24 (7.8 mg, white powder, RT = 15.03 min), yield 5%).

[0597] 1H NMR (400MHz, DMSO-d6) δ10.65(d,J=16.1Hz,1H),9.41(d,J=2.2Hz,1H),7.49(dd,J=9 .2,7.9Hz,1H),7.28(dd,J=19.4,7.8Hz,1H),7.18–7.09(m,2H),6.73–6.67(m,2H),2 .72–2.62(m,1H),2.55(d,J=5.1Hz,3H),2.29(s,3H),2.16–2.00(m,2H),1.97–1.76( m,2H),1.64–1.49(m,3H),1.48–1.27(m,2H),1.24–0.90(m,1H).LC-MS(ESI)m / z[M+H] + 414.46.

[0598] Example 25: Preparation of Compound 25

[0599] Preparation of compound 25-2:

[0600] Compound 25-1 (1.55 g, 7.52 mmol) was dissolved in toluene (30 mL), and ethylene glycol (1.7 mL, 30.1 mmol) and PTSA (286 mg, 1.504 mmol) were added. The reaction mixture was refluxed using a water separator for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the title compound 25-2 (1.88 g, yellow solid) was given in 100% yield.

[0601] Preparation of compound 25-3:

[0602] Compound 25-2 (1.88 g, 7.51 mmol) was dissolved in a mixture of tetrahydrofuran (40 mL) and methanol (40 mL), and 10% Pd / C (188 mg) was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The solution was diluted with ethyl acetate (40 mL), filtered through diatomaceous earth, and concentrated to give the title compound 25-3 (1.65 g, brown solid), in 99% yield.

[0603] LC-MS(ESI)m / z[M+H] + 221.51.

[0604] Preparation of compound 25-4:

[0605] Compound 25-3 (500 mg, 2.27 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and then pyridine (0.73 mL, 9.09 mmol) and trifluoroacetic anhydride (0.95 mL, 6.82 mmol) were added sequentially. The mixture was heated to room temperature and stirred for 10 minutes. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, crude compound 25-4 (830 mg, reddish-brown solid) was obtained. Crude 25-4 was used directly in the next reaction without further purification.

[0606] LC-MS(ESI)m / z[M+H] + 317.54.

[0607] Preparation of compound 25-5:

[0608] The crude compound 25-4 (830 mg) was added to acetic acid (15 mL), followed by 3 mL of concentrated hydrochloric acid aqueous solution. The mixture was stirred at room temperature for 30 minutes, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the title compound 25-5 (604 mg, reddish-brown solid) was obtained, with a two-step yield of 98%.

[0609] LC-MS(ESI)m / z[M+H] + 273.52.

[0610] Preparation of compound 25-6:

[0611] Compound 25-5 (400 mg, 1.47 mmol) and 4,4-difluorocycloheptanone (261 mg, 1.77 mmol) were dissolved in anhydrous tetrahydrofuran (12 mL). Zinc powder (382 mg, 5.88 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (0.32 mL, 2.94 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 877 mg of a yellow solid was obtained. This solid was dissolved in toluene (25 mL), and PPTS (43 mg, 0.173 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 25-6 (395 mg, yellow solid), in 69% yield.

[0612] LC-MS(ESI)m / z[M+H] + 389.70.

[0613] Preparation of compound 25-7:

[0614] Compound 25-6 (244 mg, 0.618 mmol) was dissolved in a mixture of tetrahydrofuran (2.5 mL) and methanol (2.5 mL). After cooling to 0 °C, sodium borohydride (24 mg, 0.629 mmol) was added. The mixture was stirred at 0 °C for 2 hours, followed by the addition of a saturated ammonium chloride solution (mL). The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-40%) to give the title compound 25-7 (239 mg, white solid), in 99% yield.

[0615] LC-MS(ESI)m / z[M+H] + 391.63.

[0616] Preparation of compound 25-8:

[0617] Compound 25-7 (239 mg, 0.612 mmol) was dissolved in a mixed solution of toluene (2.5 mL) and tetrahydrofuran (2.5 mL). After cooling to 0 °C, tert-butyl hydroperoxide (79 mg, 0.613 mmol, 70% aqueous solution) and potassium tert-butoxide (69 mg, 0.613 mmol) were added. The mixture was heated to room temperature and stirred for 2 hours. A saturated ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-50%) to give the title compound 25-8 (56 mg, yellow oil), in 23% yield.

[0618] LC-MS(ESI)m / z[M-(OH)] + 389.57.

[0619] Preparation of compound 25-9:

[0620] Phenol (80 mg, 0.850 mmol) was dissolved in anhydrous dichloromethane (50 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.38 mL, 4.29 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A dichloromethane solution of compound 25-8 (172 mg, 0.423 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 3 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 1 hour. The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated using a Flash separator (ethyl acetate / dichloromethane = 0-51%) to give the title compound 25-9 (64 mg, yellow oil), in 31% yield.

[0621] LC-MS(ESI)m / z[M+H] + 483.80.

[0622] Preparation of compound 25:

[0623] Compound 25-9 (42 mg, 0.087 mmol) was dissolved in a mixed solution of THF / MeOH / H2O (0.4 mL / 0.2 mL / 0.1 mL), and lithium hydroxide monohydrate (37 mg, 0.870 mmol) was added. The mixture was stirred at 50 °C for 4 hours, and then saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30 × 150 mm, 10 μM; column temperature: 25 °C; gradient: 50-70%; flow rate: 20 mL / min) to give compound 25 (2.1 mg, white powder, RT = 12.51 min), yield 6.2%.

[0624] 1H NMR (400MHz, DMSO-d6) δ10.17(d,J=11.3Hz,1H),9.32(s,1H),7.13(d,J=8.3Hz,2 H),6.80(dd,J=25.0,8.0Hz,1H),6.66(d,J=8.3Hz,2H),6.31(dd,J=8.0,4.1Hz,1H ),4.88(s,2H),2.55–2.52(m,1H),2.15–1.99(m,2H),1.95(s,3H),1.92–1.79(m,2 H),1.67–1.48(m,3H),1.41–1.25(m,2H),1.13–0.82(m,1H).LC-MS(ESI)m / z[M+H] + 387.76.

[0625] Example 26: Preparation of Compound 26

[0626] Preparation of compound 26-1:

[0627] Compound 25-9 (45 mg, 0.0934 mmol) and PTSA (0.4 mg, 0.00187 mmol) were dissolved in 3,4-dihydro-2H-pyran (0.5 mL), stirred at room temperature for 10 minutes, and then extracted with ethyl acetate after adding saturated sodium bicarbonate (10 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 26-1 (50 mg, yellow oil) in 94% yield.

[0628] LC-MS(ESI)m / z[M+H] + 567.98.

[0629] Preparation of compound 26-2:

[0630] Compound 26-1 (50 mg, 0.0883 mmol) was dissolved in a mixed solution of THF / MeOH / H₂O (4 mL / 2 mL / 1 mL), and lithium hydroxide monohydrate (37 mg, 0.881 mmol) was added. The mixture was stirred at 50 °C for 4.5 hours. After cooling to room temperature, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, compound 26-2 (40 mg, yellow oil) was obtained in 96% yield.

[0631] LC-MS(ESI)m / z[M+H] + 471.87.

[0632] Preparation of compound 26-3:

[0633] Compound 26-2 (40 mg, 0.0850 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and pyridine (0.02 mL, 0.255 mmol) and acetic anhydride (0.024 mL, 0.255 mmol) were added. The mixture was stirred at room temperature for 4 hours, and then stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, and saturated citric acid aqueous solution (5 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, crude compound 26-3 (20 mg, yellow oil) was obtained, which was directly proceeded to the next step without further purification.

[0634] Preparation of compound 26:

[0635] The crude compound 26-3 (20 mg) was dissolved in acetone (3 mL), and 1 N hydrochloric acid aqueous solution (3 mL) was added. The mixture was stirred at room temperature for 10 minutes, then saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 50-70%; flow rate: 20 mL / min) to obtain compound 26 (1.38 mg, white powder, RT = 15.05 min), 3.8% yield.

[0636] 1H NMR(400MHz,DMSO-d6)δ10.58–10.44(m,1H),9.45(s,1H),9.36(s,1H),8.4 5(s,1H),7.22–7.11(m,2H),7.12–6.98(m,1H),6.71(d,J=8.3Hz,2H),2.68 –2.59(m,1H),2.13–2.05(s,8H),1.96–1.81(m,2H),1.67–1.49(m,2H),1.4 6–1.32(m,2H),1.14–1.04(m,1H),0.99–0.81(m,1H).LC-MS(ESI)m / z[M+H] + 429.81.

[0637] Example 27: Preparation of compounds 27-P1 and 27-P2

[0638] Preparation of compound 27:

[0639] Compound 18-5 (100 mg, 0.222 mmol) was dissolved in anhydrous DMA (1.0 mL), and Zn(CN)₂ (39 mg, 0.333 mmol), Pd₂(dba)₃ (20 mg, 0.0222 mmol), and dppf (25 mg, 0.0444 mmol) were added. The mixture was bubbled under nitrogen for 10 minutes. The reaction solution was then microwaved (100 W, 130 °C) for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) and water (50 mL) were added. The mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-63%) to give title compound 27 (45 mg, white powder), in 51% yield.

[0640] LC-MS(ESI)m / z[M+H] + 397.69.

[0641] Preparation of compounds 27-P1 and 27-P2:

[0642] Compound 27 (60 mg, 0.151 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to obtain compound 27-P1 (15.4 mg, white powder, RT = 15.90 min), yield 26%, and compound 27-P2 (16.6 mg, white powder, RT = 16.73 min), yield 28%.

[0643] Compound 27-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.96 (s, ¹H), 9.44 (s, ¹H), 7.46 (d, J = 7.8 Hz, ¹H), 7.38 (d, J = 7.8 Hz, ¹H), 7.13 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 2.74–2.65 (m, ¹H), 2.38 (s, 3H), 2.13–1.99 (m, 2H), 1.98–1.82 (m, 2H), 1.65–1.48 (m, 2H), 1.47–1.33 (m, 2H), 1.33–1.22 (m, ¹H), 1.21–1.09 (m, 1H). LC-MS (ESI) m / z [M+H] + 397.69.

[0644] Compound 27-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.93 (s, ¹H), 9.46 (s, ¹H), 7.50 (d, J = 7.8 Hz, ¹H), 7.36 (d, J = 7.8 Hz, ¹H), 7.12 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 2.79–2.65 (m, ¹H), 2.41 (s, 3H), 2.25–1.97 (m, 2H), 1.97–1.78 (m, 2H), 1.69–1.46 (m, 3H), 1.45–1.31 (m, 2H), 1.03–0.89 (m, ¹H). LC-MS (ESI) m / z [M+H] + 397.69.

[0645] Example 28: Preparation of compounds 28-P1 and 28-P2

[0646] Preparation of compound 28:

[0647] Compound 18-5 (130 mg, 0.289 mmol), sodium methanesulfonate (112 mg, 1.10 mmol), and cuprous iodide (209 mg, 1.01 mmol) were dissolved in anhydrous DMP (1.3 mL) and bubbled under nitrogen for 10 minutes. The reaction mixture was then microwaved (100 W, 140 °C) for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) and saturated ammonium chloride solution (50 mL) were added. The mixture was stirred for 5 minutes, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2‰ formic acid / acetonitrile = 0-57%) to give compound 28 (33 mg, white powder), yield 25%.

[0648] LC-MS(ESI)m / z[M+H] + 450.74.

[0649] Preparation of compounds 28-P1 and 28-P2:

[0650] Compound 28 (18 mg, 0.040 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 50-70%; flow rate: 20 mL / min) to obtain compound 28-P1 (3.76 mg, white powder, RT = 17.50 min), yield 21%, and compound 28-P2 (2.88 mg, white powder, RT = 18.10 min), yield 16%.

[0651] Compound 28-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.90 (s, ¹H), 9.48 (s, ¹H), 7.63 (d, J = 8.0 Hz, ¹H), 7.46 (d, J = 8.0 Hz, ¹H), 7.15 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 3.23 (s, 3H), 2.75–2.65 (m, ¹H), 2.52 (s, 3H), 2.15–2.03 (m, 2H), 1.98–1.83 (m, 2H), 1.72–1.49 (m, 2H), 1.48–1.35 (m, 2H), 1.33–1.09 (m, 2H). LC-MS (ESI) m / z [M+H] + 450.74.

[0652] Compound 28-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.86 (s, ¹H), 9.47 (s, ¹H), 7.65 (d, J = 8.0 Hz, ¹H), 7.42 (d, J = 8.0 Hz, ¹H), 7.11 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 3.24 (s, 3H), 2.74–2.65 (m, ¹H), 2.52 (s, 3H), 2.16–2.03 (m, 2H), 1.95–1.79 (m, 2H), 1.62–1.48 (m, 3H), 1.47–1.34 (m, 2H), 1.03–0.86 (m, ¹H). LC-MS (ESI) m / z [M+H] + 450.74.

[0653] Example 29: Preparation of compound 29

[0654] Preparation of compound 29-2:

[0655] Compound 29-1 (1.1 g, 5.018 mmol) and 4,4-difluorocycloheptanone (892 mg, 6.027 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Zinc powder (1.31 g, 20.1 mmol) was added to the reaction solution. Under nitrogen protection, the mixture was cooled to 0 °C. Titanium tetrachloride (1.1 mL, 10.046 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.08 mg of a red solid was obtained. This solid was dissolved in toluene (40 mL), and PPTS (118 mg, 0.469 mmol) was added. The reaction solution was refluxed for 1 hour and then cooled to room temperature. After dilution with ethyl acetate, saturated sodium bicarbonate solution was added and stirred for 5 minutes. The reaction mixture was allowed to stand and separate into layers. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 29-2 (422 mg, red solid), in 25% yield.

[0656] LC-MS(ESI)m / z[M+H] + 336.60.

[0657] Preparation of compound 29-3:

[0658] Compound 29-2 (322 mg, 0.960 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (3 mL), and 10% Pd / C (32 mg) was added. The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After dilution with ethyl acetate (20 mL), the mixture was filtered through diatomaceous earth, concentrated, and then separated using Flash chromatography (ethyl acetate / dichloromethane = 0-40%) to give the title compound 29-3 (291 mg, a pale yellow syrup), in 90% yield.

[0659] LC-MS(ESI)m / z[M+H] + 338.59.

[0660] Preparation of compound 29-4:

[0661] Compound 29-3 (276 mg, 0.819 mmol) was dissolved in toluene (11 mL), cooled to 0 °C, and then tert-butyl hydroperoxide (105 mg, 0.819 mmol, 70% aqueous solution) and potassium tert-butoxide (83 mg, 0.737 mmol) were added. The mixture was stirred at 0 °C for 1 hour, and then saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-65%) to give the title compound 29-4 (202 mg, pale yellow oil), in 70% yield.

[0662] LC-MS(ESI)m / z[M-(OH)] + 336.61.

[0663] Preparation of compound 29:

[0664] Phenol (85 mg, 0.901 mmol) was dissolved in anhydrous dichloromethane (36 mL) and anhydrous ethyl acetate (4 mL). The mixture was cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (0.40 mL, 4.5 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A solution of compound 29-4 (159 mg, 0.450 mmol) in dichloroethane (4 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 5 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 1 hour. The reaction solution was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the compound was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150mm, 10μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20mL / min) to obtain compound 29 (3.01mg, white powder, RT=18.14min), yield 1.6%.

[0665] LC-MS(ESI)m / z[M+H] + 430.75.

[0666] Example 30: Preparation of compound 30

[0667] Preparation of compound 30-1:

[0668] Compound 27 (627 mg, 1.58 mmol) and PTSA (6 mg, 0.032 mmol) were dissolved in 3,4-dihydro-2H-pyran (3 mL), stirred at room temperature for 10 minutes, and then a saturated sodium bicarbonate solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-30%) to give the title compound 30-1 (551 mg, yellow liquid), in 73% yield.

[0669] LC-MS(ESI)m / z[M+H] + 481.93.

[0670] Preparation of compound 30-2:

[0671] Compound 30-1 (100 mg, 0.208 mmol) was dissolved in anhydrous THF (2 mL), cooled to -78 °C under a nitrogen atmosphere, and a tetrahydrofuran solution of DIBAL-H (0.83 mL, 1 M / mL, 0.83 mmol) was slowly added. The mixture was stirred at -78 °C for 1 hour, then at room temperature for 1 hour. The reaction solution was cooled to 0 °C, sodium sulfate decahydrate (300 mg) was added, and the mixture was heated to room temperature and stirred for 30 minutes. After filtration and concentration, crude compound 30-2 (82 mg, colorless transparent oil) was obtained and proceeded directly to the next step of the reaction without further separation.

[0672] LC-MS(ESI)m / z[M+H] + 484.80.

[0673] Preparation of compound 30-3:

[0674] The crude compound 30-2 (82 mg) was dissolved in a mixed solvent of acetonitrile / ethyl acetate / water (2 mL / 2 mL / 2 mL), and ruthenium trichloride monohydrate (4 mg, 0.0166 mmol) and sodium periodate (146 mg, 0.681 mmol) were added. The mixture was stirred at room temperature for 1.5 hours, then saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the crude compound 30-3 (82 mg, yellow oil) was obtained, which was directly proceeded to the next reaction without further separation.

[0675] LC-MS(ESI)m / z[M+H] + 500.86.

[0676] Preparation of compound 30:

[0677] The crude compound 30-3 (82 mg) was dissolved in acetone (1 mL), and 1 M hydrochloric acid aqueous solution (1 mL) was added. The mixture was stirred at room temperature for 10 minutes, then saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated crude product was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 50-70%; flow rate: 20 mL / min) to obtain compound 30 (5.36 mg, white powder, RT = 20.02 min), with a three-step yield of 6.2%.

[0678] 1H NMR(400MHz,DMSO-d6)δ10.61(d,J=16.8Hz,1H),9.41(s,1H),7.48(t,J=7.5 Hz,1H),7.22(dd,J=20.6,7.9Hz,1H),7.17–7.08(m,2H),6.70(d,J=8.5Hz,2 H),2.67–2.63(m,1H),2.39(s,3H),2.13–2.01(m,2H),1.94–1.79(m,2H),1. 63–1.50(m,3H),1.48–1.27(m,2H),1.19–0.85(m,1H).LC-MS(ESI)m / z[M+H] + 416.68.

[0679] Example 31: Preparation of compound 31

[0680] Preparation of compound 31-1:

[0681] Compound 30-1 (116 mg, 0.241 mmol) was dissolved in DMSO (0.5 mL), and potassium carbonate (66 mg, 0.478 mmol) and hydrogen peroxide (268 mg, 2.36 mmol) were added at room temperature. The mixture was heated to 80 °C and stirred for 4 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (methanol / dichloromethane = 0-10%) to give the title compound 31-1 (62 mg, white solid), in 52% yield.

[0682] LC-MS(ESI)m / z[M+H] + 499.86.

[0683] Preparation of compound 31:

[0684] Compound 31-1 (62 mg, 0.124 mmol) was dissolved in acetone (1 mL), and 1 M hydrochloric acid aqueous solution (1 mL) was added. The mixture was stirred at room temperature for 1 hour, then saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 50-70%; flow rate: 20 mL / min) to obtain compound 31 (6.4 mg, white powder, RT = 13.176 min), yield 12%.

[0685] 1H NMR(400MHz,DMSO-d6)δ10.57(d,J=14.6Hz,1H),9.41(s,1H),7.74–7.69(m,1H) ,7.36(t,J=3.0Hz,1H),7.24–7.10(m,3H),7.06(dd,J=9.0,7.7Hz,1H),6.69(d,J =8.8Hz,2H),2.70–2.60(m,1H),2.24(s,3H),2.14–2.00(m,2H),1.98–1.80(m,2H ),1.65–1.50(m,2H),1.46–1.32(m,3H),1.19–0.88(m,1H).LC-MS(ESI)m / z[M+H] + 415.75.

[0686] Example 32: Preparation of compounds 32-P1 and 32-P2

[0687] Preparation of compound 32:

[0688] 2-Fluorophenol (269 mg, 2.40 mmol) was dissolved in anhydrous 1,2-dichloroethane (176 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (1.1 mL, 12.0 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 4-4 (400 mg, 1.20 mmol) in 1,2-dichloroethane (6 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 1.5 hours. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 30 minutes. The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was Flash separated (ethyl acetate / dichloromethane = 0-40%) to give the title compound 32 (426 mg, white viscous substance), yield 83%.

[0689] LC-MS(ESI)m / z[M+H] + 428.30.

[0690] Preparation of compounds 32-P1 and 32-P2:

[0691] Compound 32 (426 mg, 1.0 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 32-P1 (118 mg, white powder, RT = 21.31 min), yield 28%, and compound 32-P2 (99.2 mg, white powder, RT = 22.26 min), yield 23%.

[0692] Compound 32-P1: ¹H NMR (400 MHz, DMSO-d6) δ 11.27 (s, ¹H), 9.93 (s, ¹H), 7.46–7.38 (m, ¹H), 7.20 (d, J = 13.1 Hz, ¹H), 7.08 (t, J = 9.2 Hz, ¹H), 6.90 (s, 2H), 2.74–2.62 (m, ¹H), 2.16–2.02 (m, 2H), 2.01–1.82 (m, 2H), 1.69–1.52 (m, 2H), 1.51–1.25 (m, 3H), 1.19–1.06 (m, 1H). LC-MS (ESI) m / z [M+H] + 428.30.

[0693] Compound 32-P2: ¹H NMR (400 MHz, DMSO-d6) δ 11.22 (s, ¹H), 9.93 (s, ¹H), 7.41–7.32 (m, ¹H), 7.18 (d, J = 13.1 Hz, ¹H), 7.09 (t, J = 9.1 Hz, ¹H), 6.95–6.83 (m, 2H), 2.73–2.62 (m, 1H), 2.18–1.99 (m, 2H), 1.97–1.77 (m, 2H), 1.61–1.47 (m, 3H), 1.47–1.30 (m, 2H), 0.99–0.85 (m, 1H). LC-MS (ESI) m / z [M+H] + 428.30.

[0694] Example 33: Preparation of compounds 33-P1 and 33-P2

[0695] Preparation of compound 33:

[0696] 2-Chlorophenol (77 mg, 0.6 mmol) was dissolved in anhydrous 1,2-dichloroethane (40 mL), cooled to 0 °C under nitrogen protection, and trifluoromethanesulfonic acid (0.27 mL, 3.0 mmol) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 5 minutes. A solution of compound 4-4 (100 mg, 0.3 mmol) in 1,2-dichloroethane (2 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 10 minutes. The reaction solution was then poured into an ice-water mixture of saturated sodium bicarbonate and stirred for 30 minutes. The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-15%) to give the title compound 33 (109 mg, yellow oil), in 82% yield.

[0697] LC-MS(ESI)m / z[M+H] + 444.27.

[0698] Preparation of compounds 33-P1 and 33-P2:

[0699] Compound 33 (109 mg, 0.245 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20 mL / min) to obtain compound 33-P1 (25.3 mg, white powder, RT = 21.312 min), yield 23%, and compound 33-P2 (26.9 mg, white powder, RT = 21.974 min), yield 25%.

[0700] Compound 33-P1: ¹H NMR (400 MHz, DMSO-d6) δ 11.25 (s, ¹H), 10.32 (s, ¹H), 7.42 (dd, J = 8.4, 4.8 Hz, ¹H), 7.30 (d, J = 2.3 Hz, ¹H), 7.19–7.04 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 2.79–2.63 (m, ¹H), 2.16–2.03 (m, 2H), 2.03–1.83 (m, 2H), 1.68–1.53 (m, 2H), 1.52–1.24 (m, 3H), 1.20–1.03 (m, 1H). LC-MS (ESI) m / z [M+H] + 444.27.

[0701] Compound 33-P2: ¹H NMR (400 MHz, DMSO-d6) δ 11.24 (s, ¹H), 10.28 (s, ¹H), 7.36 (dd, J = 8.4, 4.9 Hz, ¹H), 7.27 (s, ¹H), 7.16–7.07 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 2.73–2.64 (m, 1H), 2.20–2.01 (m, 2H), 2.01–1.77 (m, 2H), 1.61–1.47 (m, 3H), 1.46–1.31 (m, 2H), 0.91 (q, J = 10.4 Hz, 1H). LC-MS (ESI) m / z [M+H] + 444.27.

[0702] Example 34: Preparation of compound 34-A

[0703] Compound 6-A (100 mg, 0.23 mmol) was dissolved in anhydrous dichloromethane (2.0 mL). Pyridine (73 mg, 0.92 mmol) and acetic anhydride (70 mg, 0.69 mmol) were added sequentially at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-40%) to give the title compound 34-A (110 mg, white solid), in 100% yield.

[0704] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),7.51–7.47(d,J=8.0Hz,1H),7.39–7.34(m,3H),7.10(d,J=8.8Hz,2H),7.04(t,J=7.8Hz,1H),2.81–2. 72(m,1H),2.25(s,3H),2.17–2.00(m,2H),1.97–1.76(m,2H),1.63–1.50(m,2H),1.49–1.37(m,3H),1.01–0.91(m,1H).LC-MS(ESI)m / z[M+H] + :478.60,480.60.

[0705] Example 35: Preparation of compound 35-A

[0706] Preparation of compound 35-A-2:

[0707] Preparation of fresh 35-A-1 (Reference: J Med Chem. 2006 Aug 24; 49(17): 5273-81).

[0708] Compound 14-A (400 mg, 0.996 mmol) was dissolved in anhydrous dichloromethane (8 mL). Under a nitrogen atmosphere, DIPEA (208 μM, 1.20 mmol) and DMAP (6 mg, 0.0449 mmol) were added. After stirring at room temperature for 5 minutes, a freshly prepared dichloromethane solution of compound 35-A-1 (355 mg, 1.20 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into an ice-water mixture and extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-66%) to give the title compound 35-A-2 (476 mg, white solid), yield 72%.

[0709] LC-MS(ESI)m / z[M+H] + 662.98.

[0710] Preparation of compound 35-A:

[0711] Compound 35-A-2 (476 mg, 0.719 mmol) was dissolved in anhydrous acetonitrile (10 mL). Under a nitrogen atmosphere, potassium iodide (324 mg, 2.160 mmol) and TMSCl (235 mg, 2.160 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. Ammonia (1 mL) and saturated sodium sulfite solution (5 mL) were added to the reaction mixture in one step, and the pH was adjusted to 4 with saturated citric acid solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-48%) to give the title compound 35-A (326 mg, white solid), in 94% yield.

[0712] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.32(d,J=8.8Hz,2H),7.17–7.07(m,3H),6.66(d,J=8.4Hz,1H),3.82(s,3H),2.77–2 .63(m,1H),2.08(s,3H),2.21–2.02(m,2H),2.00–1.71(m,2H),1.63–1.35(m,5H),1.08–0.87(m,1H).LC-MS(ESI)m / z[M+H] + 482.53.

[0713] Example 36: Preparation of compound 36-A

[0714] Compound 35-A (92 mg, 0.191 mmol) was suspended in water (15 mL), and sodium hydroxide aqueous solution (383 μM, 1 mol / L, 0.383 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 1 hour, and the reaction solution was directly freeze-dried to obtain the title compound 36-A (99 mg, white powder) with a yield of 99%.

[0715] 1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.38–6.96(m,5H),6.60(s,1H),3.79(s,3H),2.59(brs,1H),2.0 6(s,5H),1.94–1.75(m,2H),1.57(brs,3H),1.42(brs,2H),0.92(brs,1H).LC-MS(ESI)m / z[M-2Na+3H] + 482.66.

[0716] Example 37: Preparation of compounds 37-P1 and 37-P2

[0717] Preparation of compound 37-1:

[0718] Compound 4 (850 mg, 2.07 mmol) was dissolved in dichloromethane (32 mL) and cooled to 0 °C under a nitrogen atmosphere. Pyridine (1.03 mL, 10.4 mmol) and trifluoromethanesulfonic anhydride (1.17 g, 4.16 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-10%) to give the title compound 37-1 (964 mg, white solid), in 86% yield.

[0719] LC-MS(ESI)m / z[M+H] + 542.52.

[0720] Preparation of compound 37-2:

[0721] Compound 37-1 (100 mg, 0.185 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL), and (BPin)₂ (113 mg, 0.444 mmol), Pd(dppf)Cl₂ (14 mg, 0.0185 mmol), and potassium acetate (109 mg, 1.11 mmol) were added. The mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-25%) to give the title compound 37-2 (88 mg, colorless liquid), with a yield of 92%.

[0722] LC-MS(ESI)m / z[M+H] + 520.59.

[0723] Preparation of compound 37:

[0724] Compound 37-2 (84 mg, 0.162 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and water (0.25 mL), and NaIO4 (104 mg, 0.486 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then 3 M hydrochloric acid was added, followed by stirring for another 40 minutes. The reaction mixture was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-25%) to give the title compound 37 (61 mg, white solid), in 86% yield.

[0725] LC-MS(ESI)m / z[M+H] + 438.65.

[0726] Preparation of compounds 37-P1 and 37-P2:

[0727] Compound 37 (250 mg, 0.571 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 70-90%; flow rate: 20 mL / min) to obtain compound 37-P1 (61.5 mg, white powder, RT = 13.53 min), yield 25%, and compound 37-P2 (54.6 mg, white powder, RT = 14.21 min), yield 22%.

[0728] Compound 37-P1: 1H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.00(s,2H),7.70(d,J=7.9Hz,2H),7.35(dd,J=8.4,4.8Hz,1H),7.29(d,J=7.9Hz,2H),7.02(t,J=9.1Hz ,1H),2.84–2.70(m,1H),2.13–1.97(m,2H),1.96–1.78(m,2H),1.64–1 .46(m,2H),1.45–1.30(m,2H),1.31–1.06(m,2H).LC-MS(ESI)m / z[M+H] + 438.65.

[0729] Compound 37-P2: 1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.00(s,2H),7.70(d,J=8.0Hz,2H),7.3 0(dd,J=8.4,4.9Hz,1H),7.26(d,J=8.3Hz,2H),7.04(dd,J=10.0,8.3Hz,1H), 2.83–2.72(m,1H),2.15–1.98(m,2H),1.96–1.75(m,2H),1.60–1.49(m,2H),1 .49–1.39(m,2H),1.39–1.29(m,1H),1.02–0.88(m,1H).LC-MS(ESI)m / z[M+H] + 438.65.

[0730] Example 38: Preparation of compounds 38-P1 and 38-P2

[0731] Preparation of compound 38-1:

[0732] Compound 14 (129 mg, 0.321 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C under a nitrogen atmosphere, and pyridine (0.14 mL, 1.61 mmol) and trifluoromethanesulfonic anhydride (0.11 mL, 0.643 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash (ethyl acetate / dichloromethane = 0-15%) to give the title compound 38-1 (85 mg, yellow oil), in 50% yield.

[0733] LC-MS(ESI)m / z[M+H] + 534.65.

[0734] Preparation of compound 38-2:

[0735] Compound 38-1 (85 mg, 0.159 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL), and (BPin)₂ (97 mg, 0.383 mmol), Pd(dppf)Cl₂ (12 mg, 0.0159 mmol), and potassium acetate (93 mg, 0.954 mmol) were added. The mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-30%) to give the title compound 38-2 (59 mg, yellow oil), in 73% yield.

[0736] LC-MS(ESI)m / z[M+H] + 512.43.

[0737] Preparation of compound 38:

[0738] Compound 38-2 (59 mg, 0.115 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and water (0.25 mL), and NaIO4 (72 mg, 0.333 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then 3M hydrochloric acid (0.1 mL) was added, followed by stirring for another 50 minutes. The reaction mixture was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, crude compound 38 (59 mg, white oil) was obtained and used directly in the next step.

[0739] LC-MS(ESI)m / z[M+H] + 430.61.

[0740] Preparation of compounds 38-P1 and 38-P2:

[0741] The crude compound 38 (59 mg) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 70-90%; flow rate: 20 mL / min) to obtain compound 38-P1 (6.87 mg, white powder, RT = 13.74 min), with a two-step yield of 14%, and compound 38-P2 (4.60 mg, white powder, RT = 14.44 min), with a two-step yield of 9.3%.

[0742] Compound 38-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.56 (s, 1H), 8.03 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 3.81 (s, 3H), 2.76–2.67 (m, 1H), 2.08 (s, 3H), 2.14–2.00 (m, 2H), 1.98–1.81 (m, 2H), 1.67–1.53 (m, 2H), 1.49–1.28 (m, 3H), 1.14 (d, J = 12.6 Hz, 1H). LC-MS (ESI) m / z [M+H] + 430.61.

[0743] Compound 38-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.53 (s, 1H), 8.01 (s, 2H), 7.72 (d, J = 7.8Hz, 2H), 7.33 (d, J = 7.8Hz, 2H), 7.11 (d, J = 8.2Hz, 1H), 6.66 (d, J = 8.2Hz, 1H), 3.82 (s, 3H), 2.73 (s, 1H), 2.08 (s, 3H), 2.19–1.98 (m, 2H), 1.96–1.78 (m, 2H), 1.67–1.36 (m, 5H), 1.09–0.91 (m, 1H). LC-MS (ESI) m / z [M+H] + 430.61.

[0744] Example 39: Preparation of compounds 39-P1 and 39-P2

[0745] Preparation of compound 39-1:

[0746] Compound 5 (60 mg, 0.142 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 °C under a nitrogen atmosphere, and pyridine (0.057 mL, 0.715 mmol) and trifluoromethanesulfonic anhydride (0.048 mL, 0.286 mmol) were added sequentially. The mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding saturated ammonium chloride, extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0.28%) to give the title compound 39-1 (45 mg, yellow oil), in 57% yield.

[0747] LC-MS(ESI)m / z[M+H] + 554.59.

[0748] Preparation of compound 39-2:

[0749] Compound 39-1 (90 mg, 0.162 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL), and (BPin)₂ (98 mg, 0.384 mmol), Pd(dppf)Cl₂ (11 mg, 0.016 mmol), and potassium acetate (94 mg, 0.96 mmol) were added. The mixture was stirred at 100 °C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-25%) to give the title compound 39-2 (84 mg, yellow oil), in 98% yield.

[0750] LC-MS(ESI)m / z[M+H] + 532.65.

[0751] Preparation of compound 39:

[0752] Compound 39-2 (90 mg, 0.169 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.5 mL), and NaIO4 (110 mg, 0.507 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then 3M hydrochloric acid (0.12 mL) was added, with stirring continuing for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, crude product of the title compound 39 (90 mg, yellow oil) was obtained and used directly in the next step.

[0753] LC-MS(ESI)m / z[M+H] +450.54.

[0754] Preparation of compounds 39-P1 and 39-P2:

[0755] 90 mg of crude compound 39 was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-80%; flow rate: 20 mL / min) to obtain compound 39-P1 (4.81 mg, white powder, RT = 18.581 min), with a two-step yield of 6.3%, and compound 39-P2 (5.45 mg, white powder, RT = 19.321 min), with a two-step yield of 7.2%.

[0756] Compound 39-P1: ¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, ¹H), 8.04 (d, J = 1.7 Hz, 2H), 7.73 (d, J = 1.7 Hz, 2H), 7.38–7.27 (m, 3H), 6.80 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H), 2.84–2.72 (m, 1H), 2.15–2.00 (m, 2H), 1.99–1.83 (m, 2H), 1.66–1.54 (m, 2H), 1.48–1.29 (m, 3H), 1.15 (q, J = 12.5, 11.7 Hz, 1H). LC-MS (ESI) m / z [M+H] + 450.54.

[0757] Compound 39-P2: ¹H NMR (400MHz, DMSO-d6) δ 10.90 (s, 1H), 8.04 (s, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.86–2.71 (m, 1H), 2.16–2.01 (m, 2H), 2.00–1.78 (m, 2H), 1.65–1.34 (m, 5H), 1.04–0.93 (m, 1H). LC-MS (ESI) m / z [M+H] + 450.54.

[0758] Example 40: Preparation of Compound 40

[0759] Preparation of compound 40-1:

[0760] Compound 14-1 (1.0 g, 5.24 mmol) and 4,4,5,5-tetrafluorocycloheptanone (1.16 g, 6.28 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL). Zinc powder (1.37 g, 21.1 mmol) was added to the reaction solution, and the mixture was cooled to 0 °C under nitrogen protection. Titanium tetrachloride (1.15 mL, 10.5 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for 2 hours. The reaction solution was cooled to 0 °C, and 1 M hydrochloric acid (40 mL) was added. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration, 2.36 g of a yellow viscous substance was obtained, which was dissolved in toluene (40 mL). PPTS (131 mg, 0.52 mmol) was added, and the reaction solution was refluxed for 1 hour. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, Flash separation (ethyl acetate / petroleum ether = 0-25%) was performed to give the title compound 40-1 (1.07 g, yellow solid), in 60% yield.

[0761] LC-MS(ESI)m / z[M+H]+:344.32.

[0762] Preparation of compound 40-2:

[0763] Compound 40-1 (1.07 g, 3.12 mmol) was dissolved in a mixed solution of tetrahydrofuran (8 mL) and methanol (8 mL). After cooling to 0 °C, sodium borohydride (118 mg, 3.12 mmol) was added. The mixture was stirred at 0 °C for 1 hour, then saturated ammonium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-25%) to give the title compound 40-2 (845 mg, yellow solid), in 78% yield.

[0764] LC-MS(ESI)m / z[M+H]+:346.43.

[0765] Preparation of compound 40-3:

[0766] Compound 40-2 (800 mg, 2.32 mmol) was dissolved in a mixed solution of toluene (10 mL) and tetrahydrofuran (10 mL). After cooling to 0 °C, tert-butyl hydroperoxide (299 mg, 2.32 mmol, 70% aqueous solution) and potassium tert-butoxide (260 mg, 2.32 mmol) were added. The mixture was stirred at room temperature for 3 hours, and then a saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-25%) to give the title compound 40-3 (214 mg, yellow oil), in 26% yield.

[0767] LC-MS(ESI)m / z[M-(OH)]+:344.45.

[0768] Preparation of compound 40:

[0769] Phenol (54 mg, 0.574 mmol) was dissolved in anhydrous dichloromethane (30 mL), and the mixture was cooled to 0 °C under nitrogen protection. Trifluoromethanesulfonic acid (65 μL, 0.577 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0 °C for 5 minutes. A dichloromethane solution of compound 40-3 (201 mg, 0.557 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 30 minutes. The reaction solution was poured into an ice-water mixture of saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the compound was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150mm, 10μM; column temperature: 25℃; gradient: 60-85%; flow rate: 20mL / min) to obtain compound 40 (3.7mg, white powder, RT=21.073min), yield 1.5%.

[0770] Compound 40: ¹H NMR (400 MHz, DMSO-d6) δ 10.47 (s, ¹H), 9.38 (s, ¹H), 7.22–7.16 (m, ³H), 6.94 (d, J = 8.6 Hz, ²H), 6.68 (d, J = 8.4 Hz, ¹H), 3.74 (s, ³H), 2.62–2.51 (m, ¹H), 2.01 (s, ³H), 2.13–1.95 (m, ⁴H), 1.71–1.53 (m, ²H), 1.10–0.97 (m, ²H). LC-MS (ESI) m / z [M+H]+: 438.43.

[0771] Example 41: Preparation of compound 41-A

[0772] Compound 9-A (20 mg, 0.0508 mmol) was dissolved in anhydrous dichloromethane (1 mL). Pyridine (16 mg, 0.202 mmol) and acetic anhydride (16 mg, 0.157 mmol) were added sequentially at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-40%) to give the title compound 41-A (12.1 mg, white solid), yield 55%.

[0773] 1H NMR (400MHz, DMSO-d6) δ11.38(s,1H),7.38(d,J=8.3Hz,2H),7.25–7.19(m,1H),7.15–7.05(m,3H),2.84–2. 71(m,1H),2.27(s,3H),2.16–1.79(m,4H),1.64–1.35(m,5H),0.96(d,J=10.0Hz,1H).LC-MS(ESI)m / z[M+H] + 436.81.

[0774] Example 42: Preparation of compound 42-A

[0775] Preparation of compound 42-A-2:

[0776] Compound 9-A (50 mg, 0.127 mmol) was dissolved in anhydrous dichloromethane (2 mL). Under a nitrogen atmosphere, 42-A-1 (41 mg, 0.189 mmol), DMAP (1.5 mg, 0.0123 mmol), and DCC (39 mg, 0.189 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with 10% citric acid. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / petroleum ether = 0-38%) to give compound 42-A-2 (51 mg, white solid), yield 68%.

[0777] LC-MS(ESI)m / z[M+H] + 593.32.

[0778] Preparation of compound 42-A:

[0779] Compound 42-A-2 (51 mg, 0.0861 mmol) was dissolved in anhydrous dichloromethane (2 mL). Under a nitrogen atmosphere at 0 °C, trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2‰ formic acid / acetonitrile = 0.69%) to give the title compound 42-A (26 mg, white solid), in 61% yield.

[0780] 1H NMR (400MHz, DMSO-d6) δ11.36(brs,1H),7.38(d,J=8.8Hz,2H),7.20(dd,J=8.5,4.4Hz,1H),7.15–7.03(m,3H),3.37–3.30(m,1H),2.92– 2.71(m,1H),2.16–1.76(m,5H),1.60–1.33(m,5H),0.99–0.89(m,1H),0.97(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H).LC-MS(ESI)m / z[M+H] + 493.28.

[0781] Example 43: Preparation of compounds 43-A-2 and 43-A

[0782] Preparation of compound 43-A-1:

[0783] Compound 9-A (40 mg, 0.102 mmol) was dissolved in anhydrous dichloromethane (2 mL). DIPEA (22 μM, 0.122 mmol) and DMAP (0.6 mg, 0.0051 mmol) were added under a nitrogen atmosphere. After stirring at room temperature for 5 minutes, a freshly prepared solution of compound 35-A-1 (36 mg, 0.122 mmol) in dichloromethane (2 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into an ice-water mixture and extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-66%) to give the title compound 43-A-1 (45 mg, white solid), in 68% yield.

[0784] LC-MS(ESI)m / z[M+H] + 655.18.

[0785] Preparation of compound 43-A-2:

[0786] Compound 43-A-1 (45 mg, 0.0688 mmol) was dissolved in anhydrous acetonitrile (2 mL). Under a nitrogen atmosphere, potassium iodide (34 mg, 0.207 mmol) and TMSCl (22 mg, 0.207 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. Ammonia (1 mL) and saturated sodium sulfite solution (2 mL) were added to the reaction solution in one step, and the pH was adjusted to 4 with saturated citric acid solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by reverse-phase C18 column chromatography (2.5‰ formic acid / acetonitrile = 0-48%) to give the title compound 43-A-2 (18.7 mg, white solid), in 57% yield.

[0787] 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.28(d,J=8.5Hz,2H),7.17(dd,J=8.6,4.4Hz,1H),7.12(d,J=8.3Hz,2H),7. 10–7.02(m,1H),2.79–2.69(m,1H),2.19–1.75(m,4H),1.62–1.31(m,5H),1.00–0.86(m,1H).LC-MS(ESI)m / z[M+H] + 474.46.

[0788] Preparation of compound 43-A

[0789] Compound 43-A-2 (23 mg, 0.0486 mmol) was suspended in water (10 mL), and sodium hydroxide aqueous solution (0.972 mL, 0.10 mol / L, 0.0972 mmol) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 1 hour, and the reaction solution was directly freeze-dried to obtain the title compound 43-A (26 mg, white powder) in 100% yield.

[0790] 1H NMR(400MHz,DMSO-d6)δ7.21–6.75(m,6H),2.70–2.56(m,1H),2.15–1.95(m,2H),1.94–1.72 (m,2H),1.63–1.47(m,3H),1.46–1.29(m,2H),1.03–0.78(m,1H).LC-MS(ESI)m / z[M-2Na+3H] + 474.58.

[0791] Example 44: Preparation of compounds 44-P1 and 44-P2

[0792] Preparation of compounds 44-1 and 44-2:

[0793] Compound 7 (753 mg, 1.66 mmol), pinacol diboronate (1.26 g, 4.96 mmol), Pd2(dba)3 (76 mg, 0.0830 mmol), and potassium acetate (488 mg, 4.97 mmol) were dissolved in anhydrous 1,4-dioxane (15 mL) and reacted under a nitrogen atmosphere in a microwave environment (80 W, 120 °C) for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 950 mg of a crude mixture of 44-1 and 44-2 was obtained, which was directly used for the next reaction without further separation.

[0794] Preparation of compound 44:

[0795] A crude mixture of compounds 44-1 and 44-2 (950 mg), Pd(PPh3)4 (192 mg, 0.166 mmol), and potassium carbonate (686 mg, 4.97 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (9:1) (3.8 mL). The mixture was reacted in a nitrogen atmosphere using microwaves (80 W, 80 °C) for 1 hour. The reaction solution was cooled to room temperature, and ethyl acetate and water were added. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash-separated (ethyl acetate / dichloromethane = 0-40%) to give compound 44 (541 mg, yellow viscous liquid), with a two-step yield of 83%.

[0796] LC-MS(ESI)m / z[M+H] + 393.76.

[0797] Preparation of compounds 44-P1 and 44-P2:

[0798] Compound 44 (150 mg, 0.382 mmol) was purified by preparative liquid chromatography (preparation method: mobile phase: A: 1‰ formic acid / water; B: methanol; column: Welch Ultimate XB-C18, 30×150 mm, 10 μM; column temperature: 25℃; gradient: 60-79%; flow rate: 20 mL / min) to obtain compound 44-P1 (39.5 mg, white powder, RT = 22.021 min), with a two-step yield of 26%, and compound 44-P2 (41.5 mg, white powder, RT = 23.151 min), with a yield of 28%.

[0799] Compound 44-P1: ¹H NMR (400MHz, DMSO-d6) δ 10.72 (s, ¹H), 9.37 (s, ¹H), 7.17 (dd, J = 8.3, 5.2Hz, ¹H), 7.13 (d, J = 8.7Hz, 2H), 6.80 (dd, J = 10.3, 8.3Hz, 1H), 6.69 (d, J = 8.6Hz, 2H), 2.66–2.56 (m, ¹H), 2.09–1.78 (m, 4H), 1.63–1.52 (m, 2H), 1.46–1.21 (m, 3H), 1.07 (q, J = 11.8Hz, 1H). LC-MS (ESI) m / z [M+H] + 393.76.

[0800] Compound 44-P2: ¹H NMR (400 MHz, DMSO-d6) δ 10.68 (s, ¹H), 9.38 (s, ¹H), 7.15–7.08 (m, 3H), 6.82 (dd, J = 10.3, 8.2 Hz, ¹H), 6.69 (d, J = 8.5 Hz, 2H), 2.68–2.57 (m, ¹H), 2.11–1.99 (m, 2H), 1.94–1.74 (m, 2H), 1.60–1.48 (m, 3H), 1.47–1.28 (m, 2H), 0.94–0.82 (m, ¹H). LC-MS (ESI) m / z [M+H] + 393.76.

[0801] Test Example 1: Evaluation of Compound In Vitro Cell Activity

[0802] 1. Cell lines: Human breast cancer MCF-7 cell line was purchased from CAS. Human ovarian cancer cell line CaOV-3, human breast cancer cell line MDA-MB-231, human colon cancer cell line HCT116, human neuroblastoma cell line SH-SY5Y, human breast cancer cell line BT-20, and human colon cancer cell line HT-29 were purchased from ATCC. Human endometrial cancer cell line AN3-CA was purchased from Kebai. MCF-7, AN3-CA, and BT-20 cells were cultured in EMEM + 10% FBS. CaOV-3 and MDA-MB-231 cells were cultured in DMEM + 10% FBS. HT-29 and HCT116 cells were cultured in McCoy's 5A + 10% FBS. SH-SY5Y cells were cultured in EMEM / F12 + 10% FBS.

[0803] 2. Resuspend the cells and seed 100 μL of cells into 96-well plates. Cell densities for MCF-7, HT-29, SH-SY5Y, CaOV-3, MDA-MB-231, HCT116, AN3-CA, and BT-20 were 3000, 2000, 5000, 2500, 2000, 1500, 3500, and 5000 cells / well, respectively. Incubate overnight at 37°C and 5% CO2. The next day, add different concentrations of the test substance and incubate at 37°C and 5% CO2 for 72 hours. Equilibrate the cell plate to room temperature and add 40 μL of the test substance to each well. Add reagents and shake on a shaker for 2 minutes. Incubate at room temperature for 60 minutes and then detect the luminescence signal.

[0804] 3. Data Analysis:

[0805] (1) Calculate IC using GraphPad Prism 5 50 .

[0806] (2)%Inh=(Max signal-Compound signal) / (Max signal-Min signal)x100.

[0807] (3) The maximum signal is only DMSO.

[0808] (4) Min signal indicates only the culture medium.

[0809] 4. Partial test results: see Table 1 and Table 2.

[0810] Table 1: Cellular activity of some compounds against ERα-positive MCF-7 and ERα-negative HT-29. Note: ErSO is a compound that can induce the death of ERα-positive MCF-7 cells in vivo and in vitro (Sci Transl Med. 2021 Jul 21; 13(603):eabf1383.), with the following structural formula:

[0811] Table 1 shows that, compared with existing technologies, the compounds of the present invention exhibit superior activity against ERα-positive MCF-7 cells and lower toxicity against ERα-negative HT-29 cells, with a significantly increased cell selectivity. For example, the anti-MCF-7 activity (IC50) of compounds 4-A, 7-A, 9-A, 14-A, and 15-A are shown. 50 The toxicity (IC50) to HT-29 was 10.3 times, 10.7 times, 4.23 times, 9.5 times, and 9.9 times that to ErSO, respectively. 50The cell selectivity (IC50) was 160-fold, 132-fold, 257-fold, 124-fold, and 111-fold lower than that of ErSO, respectively, and the cell selectivity (IC50) was significantly lower. 50,HT-29 / IC 50,MCF-7 These figures are 1649 times, 1414 times, 1089 times, 1173 times, and 1100 times that of ErSO, respectively.

[0812] Table 2: Activity results of compounds on ERα-positive and ERα-negative cells Note: NC1 (J Med Chem. 2010 Oct 14; 53(19):7140-5.) and (S)-45 (WO2024 / 175114A1) are compounds that can induce the death of ERα-positive breast cancer cells MCF-7 in vivo and in vitro, with the following structural formula:

[0813] Table 2 shows that, compared with existing technologies, the compounds of this invention exhibit broad-spectrum high activity against a variety of ERα-positive tumor cells, while showing low toxicity to a variety of ERα-negative cells, demonstrating high ERα-negative / ERα-positive cell selectivity (see Figure 2). For example, in ERα-positive tumor cells, 9-A showed 4.2-fold and 5.8-fold higher MCF-7 activity than ErSO and (S)-45, respectively; BT-20 showed 2.6-fold and 6.6-fold higher activity, respectively; CaOV-3 showed 2.5-fold and 7.2-fold higher activity, respectively; and AN3-CA showed 2.6-fold and 19.2-fold higher activity, respectively. In ERα-negative cells, 9-A showed 1.9-fold, 2.4-fold, and 2.6-fold lower toxicity than ErSO, NC1, and (S)-45 MDA-MB-231, respectively; SH-SY5Y showed 1.4-fold, 1.9-fold, and 5.4-fold lower toxicity; HT-29 showed 257-fold, 262-fold, and 3.4-fold lower toxicity; and HCT116 showed 757-fold, 3470-fold, and 13-fold lower toxicity. Cell selectivity, such as the selectivity ratio (IC50) of HCT116 to CaOV-3, was also observed. 50,HCT116 / IC 50,CaOV-3 ), 9-A was 1879 times, 2279 times, and 95 times higher than ErSO, NC1, and (S)-45, respectively; the selectivity ratio of HCT116 and AN3-CA (IC) 50,HCT116 / IC 50, AN3-CA ), 9-A is 1950 times, 3061 times, and 251 times higher than ErSO, NC1, and (S)-45, respectively.

[0814] Conclusion: Compared with the prior art, the compound of the present invention significantly improves the activity of ERα-positive tumor cells, significantly reduces the toxicity of ERα-negative cells, and significantly improves cell selectivity.

[0815] Test Example 2: Mouse Pharmacokinetic Test

[0816] The compound was prepared and used immediately using 5% DMSO + 10% Tween-20 + 85% PBS as the solvent. Healthy female CD-1 mice were administered the compound intravenously (5 mL / kg) orally and orally (10 mL / kg). At designated time points (IV: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24 h after administration; PO: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24 h after administration), 30 μL of blood was collected via the jugular or mandibular vein and placed in EDTA-K2 tubes. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11000 rpm for 5 minutes within 30 minutes. The plasma was separated and frozen at -70°C for analysis. The concentration of the parent drug in the plasma was determined using LC-MS / MS.

[0817] Table 3: Pharmacokinetics in mice Note: " / " indicates that it is not applicable.

[0818] Conclusion: The compounds of this invention exhibit excellent pharmacokinetic properties in mice.

[0819] Test Example 3: Bacterial Reverse Mutation Experiment

[0820] The ability of the compounds to induce bacterial reversion mutations in histidine auxotrophic Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537) and tryptophan auxotrophic Escherichia coli WP2 uvrA (pKM101) was tested under conditions with and without the addition of an exogenous metabolic activation system (β-naphthylflavonoid and phenobarbital-induced rat liver S9). After pouring the mixture into plates, the plates were incubated at 37±2℃ for 48 to 72 hours. Counting was performed immediately after incubation.

[0821] Partial test results:

[0822] Compound 9-A is negative.

[0823] Test Example 4: In Vitro Micronucleus Experiment of Compounds

[0824] The ability of the compound to induce micronucleus formation in Chinese hamster ovary cells (CHO-WBL) under conditions with and without an exogenous metabolic activation system (β-naphthylflavonoid and phenobarbital-induced rat liver S9). In both the dose-exploration and micronucleus master assays, the following treatment series were established for CHO-WBL cells: a 3-hour series with S9 metabolic activation, a 3-hour series without metabolic activation, and a 24-hour series without metabolic activation. Cells were analyzed 24 hours after administration.

[0825] Partial test results:

[0826] Compound 9-A is negative.

[0827] Test Example 5: Caco-2 Cell Permeability Experiment

[0828] After 24 days of continuous culture, bidirectional transport of compounds was tested in a Caco-2 monolayer cell model. The drug concentrations were 1 μM and 20 μM, the transport time was 120 min, and the experimental system was pH 7.4 HBSS buffer (containing 0.1% BSA). The concentrations at the donor and receiver ends were detected using liquid chromatography-tandem mass spectrometry (LC-MS-MS), and the apparent permeability coefficient (Papp) and efflux ratio (ER) were calculated to assess drug permeability.

[0829] Some of the test results are shown in Table 4.

[0830] Table 4: Cell permeability test results of some compounds Caco-2

[0831] Conclusion: The compounds of this invention have good membrane permeability.

[0832] Test Example 6: MCF-7 Human Breast Cancer BALB / c Nude Mouse Orthotopic Transplantation Model Testing

[0833] 1. In vivo efficacy study: Human breast cancer MCF-7 cells in the exponential growth phase (1×10⁻⁶) were used in this study. 7 One mouse per tumor was inoculated into the fourth mammary fat pad of 66 female BALB / c nude mice (Shanghai Jihui, 6-8 weeks old) in 0.1 mL of DMEM containing 50% Matrigel, followed by subcutaneous injection of estradiol benzoate twice a week. The mean tumor volume reached 243-245 mm. 3 Subsequently, mice were randomly assigned to groups based on tumor volume using Excel randomization software, with 6 tumor-bearing mice in each group. The experiment included a solvent control group, an ErSO-30 mg / kg group, a 9-A-20 mg / kg group, and a 9-A-30 mg / kg group. All groups used 5% DMSO + 10% Tween-20 + 85% PBS as the solvent, administered orally once daily for 21 consecutive days. Body weight and tumor volume were measured twice weekly. The long and short diameters of the tumor were measured using calipers, and the formula V = 0.5a × b was used. 2 Calculate two-dimensional volume, unit mm 3 Statistical analysis was performed on data from all treatment groups on day 21 after administration. Two-way ANOVA was used to compare body weight and tumor volume. All data were analyzed using GraphPad Prism 5, and P < 0.05 was considered statistically significant. The antitumor efficacy of the test substance was assessed using the relative tumor proliferation rate (T / C%).

[0834] 2. Tissue distribution study: After the in vivo efficacy study, mice in the solvent control group were orally administered 9-A at 40 mg / kg once daily for 7 consecutive days. Plasma, brain, tumor, mammary gland, ovary, uterus and other tissues (n=2) were collected at 0.25 h, 0.5 h and 4.0 h after the last administration for drug concentration detection.

[0835] 3. Test Results: The efficacy results of MCF-7 in the BALB / c nude mouse orthotopic transplantation model of human breast cancer are shown in Table 5. The tissue distribution of compound 9-A in tumor-bearing mice is shown in Table 6. Figure 3 shows the trend of mouse body weight change over time. Figure 4 shows the trend of mouse tumor volume change over time.

[0836] Table 5: Antitumor efficacy of compounds against MCF-7 human breast cancer BALB / c nude mouse orthotopic transplantation model Note: a: Data on day 21 compared with the solvent control group for all treatment groups; b: T / C% = (RTV of treatment group / RTV of solvent control group) * 100%, RTV (relative tumor volume) = Vt / V0, V0 is the tumor volume at the time of administration (i.e., d0), and Vt is the tumor volume at the end of the experiment (i.e., d21); c: *** indicates P < 0.001.

[0837] Table 6: Tissue distribution results of compound 9-A in tumor-bearing mice Note: a: Tissue collection time point after the last administration of medication.

[0838] in conclusion:

[0839] In the MCF-7 human breast cancer BALB / c nude mouse orthotopic transplantation model, no significant decrease in body weight, serious adverse reactions, or deaths were observed in the treated mice, indicating good safety. Compared with the solvent control group, the ErSO-30mg / kg, 9-A-20mg / kg, and 9-A-30mg / kg groups all showed extremely significant rapid tumor shrinkage, with T / C values ​​of 0.21%, 4.39%, and 0, respectively. On day 21, five mice in the ErSO-30mg / kg group had tumor volumes of 0, and all mice in the 9-A 30mg / kg group had tumor volumes of 0. Compared with ErSO, 9-A, at the same dose, exhibited superior in vivo antitumor efficacy.

[0840] Tissue distribution results showed that 9-A exhibits excellent tumor tissue selectivity, with high and prolonged exposure concentrations in tumor tissues and low and short exposure concentrations in normal tissues, thus reducing the risk of toxicity to normal tissues. After administration, 9-A rapidly distributed to tumors, brain, breast, ovary, uterus, and other tissues, but the drug elimination rate in normal tissues was significantly faster than in tumor tissues. From 0.5 h to 4.0 h, the drug concentrations in the brain, breast, ovary, and uterus decreased by 71%, 84%, 80%, and 83%, respectively, while the drug concentration in tumor tissues decreased by only 6%. Combining the tissue distribution and cell activity (test example 1) test results, 9-A also shows great potential for treating ERα-positive breast cancer, ERα-positive ovarian cancer, ERα-positive endometrial cancer, and brain metastases of ERα-positive tumors.

[0841] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound, characterized in that, The compound is a compound of formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof. in: X is selected from the following group: O, S, NR A ; Y is selected from the following group: O, S, NR A ; Each R A Each is independently selected from the following groups: H, C 1-6 alkyl, R A-1 Selected from the following groups: H, C 1-6 alkyl; R 1 R 2 R 3 R 4 Each is independently selected from the following groups: H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 Alkyl, OR B SR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B OS(=O)2R B NR B S(=O)2R B C(=O)R B C(=O)OR B C(=O)N(R) B 2. S(=O)R B S(=O)2R B ; Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 alkyl; Or, R 1 and R 2 Structures selected from the group consisting of carbon, nitrogen, or oxygen atoms are formed by the connection of carbon, nitrogen, or oxygen atoms: C 4-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R 5 Selected from the following group: H, halogens; Z is selected from the following group: OR C SR C B(OR) C )2; Each R C Each is independently selected from the following groups: H, C 1-6 Alkyl, P(=O)(OR) C-1 (OR) C-2 ), CH2OP(=O)(OR C- 1 (OR) C-2 ), CH(CH3)OP(=O)(OR C-1 (OR) C-2 ), C(=O)R C-3 C(=O)OR C-3 C(=O)N(R) C-3 2. C 2-10 amino acids; Each R C-1 R C-2 Each of the following elements is independently selected: H, Na, K, Ca, Mg, NH4, C 1-6 Alkyl, Halogenated C 1- 6-alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl; Each R C-3 Each is independently selected from the following groups: H, C 1-6 alkyl and amino substituted C 1-6 Alkyl, Halogenated C 1-6 Alkyl, phenyl, R m Substituted phenyl, benzyl, R m Substituted benzyl; R m Selected from the following group: halogens, C 1-6 Alkyl, Halogenated C 1-6 alkyl; G is selected from the following group: Each R D Each is independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy; n is selected from the following group: 0, 1, 2, 3, 4, 5, 6.

2. The compound according to claim 1, characterized in that, G is Each R D Each is independently selected from the following groups: H, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy; n is selected from the following group: 0, 1, 2, 3, 4, 5, 6.

3. The compound according to claim 1, characterized in that, R 1 R 2 Each is independently selected from the following groups: H, halogen, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2- 6-Alkyne, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 Alkyl, OR B 、N(R B 2. OC (=O)R B NR B C(=O)R B OS(=O)R B NR B S(=O)R B OS(=O)2R B NR B S(=O)2R B C(=O)R B C(=O)OR B C(=O)N(R) B 2. S(=O)R B S(=O)2R B ; Each R B Each is independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated and deuterated C 1-6 alkyl; Or, R 1 and R 2 Structures selected from the group consisting of carbon, nitrogen, or oxygen atoms are formed by the connection of carbon, nitrogen, or oxygen atoms: C 4-8 Cycloalkyl groups, 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R 3 For H; R 4 For H.

4. The compound according to claim 1, characterized in that, Z is selected from the following group: OH, B(OH)2, OP(O)(OH)2, OP(O)(ONa)2, OC(O)CH3, OC(O)CH2CH3, OC(O)CH(CH3)2, OC(O )N(CH3)2, OCH2OP(O)(OH)2, OCH2OP(O)(ONa)2, OCH(CH3)OP(O)(OH)2, OCH(CH3)OP(O)(ONa)2, and / or R 5 Selected from the following groups: H, F, Cl.

5. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: compounds of formula (IV-a), compounds of formula (IV-b), compounds of formula (IV-c), and compounds of formula (IV-d); Each group is as defined in claim 1.

6. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

7. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

8. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The compound comprising a pharmaceutically acceptable carrier and a safe and effective amount as claimed in claim 1.

10. Use of the compound according to claim 1, characterized in that, Used to prepare a drug for the prevention and / or treatment of ERα-positive tumors.

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