Nitrogen-containing heterocyclic compounds and their uses

Abstract

This invention discloses nitrogen-containing heterocyclic compounds and their uses, specifically, compounds represented by formula (II), their stereoisomers, and pharmaceutically acceptable salts thereof. [Case 1] TIFF2026517958000240.tif32168

Description

[Technical Field]

[0001] This application claims the following priority: Application number: CN202310537851.9, Application date: May 12, 2023 Application number: CN202311235509.X, Application date: September 22, 2023 Application number: CN202311542512.6, Application date: November 17, 2023 Application number: CN202410027233.4, Application date: January 8, 2024 Application number: CN202410149461.9, Application date: February 1, 2024.

[0002] (Technical field) The present invention relates to nitrogen-containing heterocyclic compounds and their uses, and more specifically discloses compounds represented by formula (II), their stereoisomers, and pharmaceutically acceptable salts thereof. [Background technology]

[0003] Hypertension is a clinical syndrome primarily characterized by elevated arterial blood pressure in the systemic circulation (systolic and / or diastolic blood pressure) (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg), accompanied by functional or organic damage to organs such as the heart, brain, and kidneys. Medications commonly used to treat hypertension include five categories: calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), diuretics, and beta-blockers, as well as fixed-ratio combination preparations of these drugs. Furthermore, some individuals with hypertension may also use alpha-blockers or other types of antihypertensive drugs (e.g., renin inhibitors, central nervous system agonists, etc.).

[0004] For adult hypertensive patients requiring drug therapy, one of three antihypertensive drugs (diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, or calcium channel blockers) is recommended as the first-line treatment. For hypertensive patients whose blood pressure cannot be controlled to the target level with a single drug, the combination of antihypertensive drugs is the basic method of antihypertensive treatment. Most hypertensive patients need to use two or more antihypertensive drugs to achieve the target blood pressure level. If a patient's blood pressure remains above 140 mmHg despite taking at least three different types of antihypertensive drugs (one of which is a diuretic), it is called refractory hypertension. In patients with refractory hypertension, a fourth drug such as a beta-blocker, aldosterone receptor blocker, triamterene, clonidine, or alpha-blocker is needed in addition to the three drugs.

[0005] Since 2007, no new antihypertensive drugs have been approved for sale, and many patients with refractory hypertension still do not receive appropriate treatment. Both refractory hypertension and hyperaldosteronism are characterized by sodium and water retention. Clinical trials have shown that baxdrostat dose-dependently lowers blood pressure and aldosterone secretion levels, indicating that aldosterone is a key factor in drug resistance in patients with refractory hypertension. The main pharmacological targets for treating refractory hypertension by lowering aldosterone levels include blockade of mineralocorticoid receptors and inhibition of aldosterone synthase.

[0006] Aldosterone is encoded by the CYP11B2 gene, which simultaneously possesses the functions of 11-β-hydroxylase, 18-hydroxylase, and 18-dehydrogenase. Its role is primarily in the final stage of aldosterone synthesis, producing aldosterone using 11-deoxycorticosterone (11-DOC) as a substrate. CYP11B1 and CYP11B2 have 93% similar amino acid sequences, and inhibiting CYP11B1 activity may cause adrenal insufficiency. Highly selective inhibition of aldosterone synthase is highly necessary but difficult to achieve. Baxdrostat, a small molecule, highly selective aldosterone synthase inhibitor, was confirmed in a phase 2 trial to have four main advantages: a significant blood pressure reduction effect, no effect on cortisol levels, a low incidence of increased serum potassium levels, and no accumulation of steroid precursors. Baxdrostat, at a dose of 2 mg, is effective in lowering systolic and diastolic blood pressure in the doctor's office for patients with refractory hypertension, and has good safety and tolerability. [Overview of the project] [Problems that the invention aims to solve]

[0007] In summary, the development of selective aldosterone synthase inhibitors represents a new drug with great potential for treating diseases associated with elevated aldosterone levels (including refractory hypertension and primary aldosteronism), providing more treatment options in clinical practice. [Means for solving the problem]

[0008] The present invention provides a compound represented by formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] however, Ring A is Ring A1 and Ring A Selected from 2, Ring A1 is [ka] Selected from, Ring A2 is, [ka] Selected from the above, [ka] Each of these can be independently and optionally replaced by one, two, or three R1s. Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl, pyridyl, and pyridazinyl, and each of these is independently and optionally substituted with 1, 2, or 3 R6 rings. Ring B2 is selected from a 5-membered heteroaryl, and the 5-membered heteroaryl is optionally substituted with 1, 2, or 3 R6s. T is selected from single bonds, CH2, NH, and O. T1 is selected from O and CR4R5. R1 is H, =NR, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each of R2, R3, R4, and R5 is independently H, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Selected from haloalkoxys, where R2, R3, R4, and R5 cannot be H at the same time. Alternatively, R2 and R3, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R4 and R5, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R3 and R4, together with the carbon atoms linked to them, form a double bond or a cyclopropyl bond. Each R6 independently contains H, F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, Structural unit [Chemical formula] is selected from [Chemical formula] and is selected from R 71 is selected from 4- to 6-membered heterocycloalkyl, where the 4- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R a ; R 81 is selected from H, F, Cl, Br, I and C 1-3 alkyl; Ring C is selected from Ring C1 and Ring C2, Ring C1 is selected from C 5-6 cycloalkyl substituted by one R9, where R9 is -NHC(=O)-C 1-3 alkyl, -NH-C(=O)-5- to 6-membered heteroaryl, -NH-4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and [Chemical formula] and is selected from, where the -NHC(=O)-C 1-3 alkyl, -NH-C(=O)-5- to 6-membered heteroaryl, -NH-4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R b ; Ring C2 is [Chemical formula] and is selected from, where the [Chemical formula] are each independently optionally substituted by 1, 2 or 3 R e ; Each R aThese are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl and -S(=O)2-C 1-3 Selected from alkyl groups, Each R b These are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl and -NH-C(=O)-C 1-3 Selected from alkyl groups, R c and R d C 3-5 Forms a cycloalkyl or 5-6 member heterocycloalkyl, Each R e These are F, Cl, Br, I, =O, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHC(=O)-C 1-3 Alkyl, -NHC(=O)-C 1-3 Alkoxy, -NHC(=O)-C 1-3 Selected from alkylamino and =NR, R is C 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy is independently and optionally substituted with one, two, or three halogens. n is either 0 or 1. [ka] It is either a single bond or a double bond. In the aforementioned 5-membered heteroaryl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O, S, and N. The conditions are, 1) When ring A is selected from A1 and ring B is selected from B1, ring C is selected from C2, or 2) Ring A is selected from A1, ring B is selected from B1, and ring C is a C substituted with one R9. 5-6 When selected from cycloalkyl, R9 is [ka] Selected from.

[0009] The present invention provides a compound represented by formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] however, Ring A is selected from rings A1 and A2. Ring A1 is [ka] Selected from, Ring A2 is [ka] Selected from the above, [ka] Each of these can be independently and optionally replaced by one, two, or three R1s. Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl, pyridyl, and pyridazinyl, and each of these is independently and optionally substituted with 1, 2, or 3 R6 rings. Ring B2 is selected from a 5-membered heteroaryl, and the 5-membered heteroaryl is optionally substituted with 1, 2, or 3 R6s. T is selected from single bonds, CH2, NH, and O. T1 is selected from O and CR4R5. R1 is H, =NR, C 1-3 Alkyl and C1-3 Selected from haloalkyls, Each of R2, R3, R4, and R5 is independently H, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Selected from haloalkoxys, where R2, R3, R4, and R5 cannot be H at the same time. Alternatively, R2 and R3, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R4 and R5, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R3 and R4, together with the carbon atoms linked to them, form a double bond or a cyclopropyl bond. Each R6 independently contains H, F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, Structural unit [ka] teeth, [ka] Selected from, R 71 The R is selected from 4-6 member heterocycloalkyl groups, where the 4-6 member heterocycloalkyl group has 1, 2, or 3 R groups. a It is optionally replaced by, R 81 H, F, Cl, Br, I and C 1-3 Selected from alkyl groups, Ring C is selected from rings C1 and C2. Ring C1 is selected from a cyclohexyl substituted with one R9, where R9 is -NHC(=O)-C 1-3 Alkyl, -NH-C(=O)-5~6 member heteroaryl, -NH-4~6 member heterocycloalkyl, 4~6 member heterocycloalkyl and [ka] Selected from, the -NHC(=O)-C 1-3 Alkyl, -NH-C(=O)-5~6 member heteroaryl, -NH-4~6 member heterocycloalkyl, and 4~6 member heterocycloalkyl each independently have 1, 2, or 3 R b It is optionally replaced by, Ring C2 is, [ka] Selected from the above, [ka] Each of these is independently one, two, or three R's e It is optionally replaced by, Each R a These are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl and -S(=O)2-C 1-3 Selected from alkyl groups, Each R b These are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl and -NH-C(=O)-C 1-3 Selected from alkyl groups, R c and R d C 3-5 Forms a cycloalkyl or 5-6 member heterocycloalkyl, Each R e These are F, Cl, Br, I, =O, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHC(=O)-C 1-3 Alkyl, -NHC(=O)-C 1-3 Alkoxy, -NHC(=O)-C 1-3 Selected from alkylamino and =NR, R is C 1-3 Alkyl and C 1-3Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy is independently and optionally substituted with one, two, or three halogens. n is either 0 or 1. [ka] It is either a single bond or a double bond. In the aforementioned 5-membered heteroaryl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O, S, and N. The conditions are, 1) When ring A is selected from A1 and ring B is selected from B1, ring C is selected from C2, or, 2) When ring A is selected from A1, ring B is selected from B1, and ring C is selected from a cyclohexyl substituted with one R9, the R9 is [ka] Selected from.

[0010] The present invention provides a compound represented by formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] however, Ring A is selected from rings A1 and A2. Ring A1 is, [ka] Selected from, Ring A2 is, [ka] Selected from the above, [ka] Each of these can be independently and optionally replaced by one, two, or three R1s. Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl and pyridyl, and each of the phenyl and pyridyl is independently and optionally substituted with 1, 2, or 3 R6 rings. Ring B2 is selected from a 5-membered heteroaryl, and the 5-membered heteroaryl is optionally substituted with 1, 2, or 3 R6s. T is selected from CH2, NH, and O. T1 is selected from O and CR4R5. R1 is H, =NR, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each of R2, R3, R4, and R5 is independently H, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Selected from haloalkoxys, where R2, R3, R4, and R5 cannot be H at the same time. Alternatively, R2 and R3, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R4 and R5, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R3 and R4, together with the carbon atoms linked to them, form a double bond or a cyclopropyl bond. Each R6 independently contains H, F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, Structural unit [ka] teeth, [ka] Selected from, R71 is selected from 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R a ; R 81 is selected from H, F, Cl, Br, I and C 1-3 alkyl; Ring C is selected from Ring C1 and Ring C2, Ring C1 is selected from cyclohexyl substituted by one R9, and the R9 is -NHC(=O)-C 1-3 alkyl, -NH-C(=O)-5- to 6-membered heteroaryl, -NH-4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0011] The present invention provides a compound represented by formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] however, Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl, and the phenyl is optionally substituted with 1, 2, or 3 R6s. Ring B2 is selected from a 5-membered heteroaryl, and the 5-membered heteroaryl is optionally substituted with 1, 2, or 3 R6s. Ring A is selected from rings A1 and A2. Ring A1 is, [ka] Selected from, Ring A2 is, [ka] Selected from the above, [ka] Each of these can be independently and optionally replaced by one, two, or three R1s. E is selected from CH and N. T is selected from CH2, NH, and O. Ring C is selected from rings C1 and C2. Ring C1 is selected from a cyclohexyl substituted with one R9, and the R9 is selected from -NHC(=O)CH2CH3. Ring C2 is, [ka] Selected from the above, [ka] Each of them independently has 1, 2, or 3 R e It is optionally replaced by, Each R1 independently contains F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Selected from alkoxy and =NR, Each R6 independently contains F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, R c and R d C 3-5 Forms a cycloalkyl or 5-6 member heterocycloalkyl, Each R e These are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHC(=O)-C 1-3 Alkyl, -NHC(=O)-C 1-3 Alkoxy and -NHC(=O)-C1 1-3 Selected from alkylaminos, R f is = NR, [ka] Selected from, R is C 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy is optionally substituted with one, two, or three halogens. n is either 0 or 1. [ka] It is either a single bond or a double bond. In the aforementioned 5-membered heteroaryl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups each independently selected from O, S, N, and C (=O). The conditions are, If ring A is selected from A1 and ring B is selected from B1, then ring C is selected from C2.

[0012] In some embodiments of the present invention, R is selected from CH3, CH2CH3, CF3, OCH3, and OCF3, and the other variables are as defined in the present invention.

[0013] In some embodiments of the present invention, the R a The first variable is selected from -S(=O)2-CH2CH3, and the other variables are as defined in this invention.

[0014] In some embodiments of the present invention, each of the R b Each of these is independently selected from F, Cl, Br, I, CH3, -C(=O)-CH2CH3, and -NHC(=O)-CH2CH3, and the other variables are as defined in this invention.

[0015] In some embodiments of the present invention, the R c and R d Together with the carbon atoms linked to them, [ka] The following are formed, and the other variables are as defined in this invention.

[0016] In some embodiments of the present invention, the R e The first variable is selected from -NHC(=O)-CH2CH3, =NCH3, and =N-OCH3, and the other variables are as defined in this invention.

[0017] In some embodiments of the present invention, the R eEach is independently selected from F, Cl, Br, I, CH3, CH2CH3, OCH3, OCH2CH3, NCH3, NCH2CH3, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, -NHC(=O)-OCH3 and -NHC(=O)-NCH3, and the other variables are as defined in the present invention.

[0018] In some embodiments of the present invention, the R f is =NCH3, =N-OCH3,

Chemical formula

[0019] In some embodiments of the present invention, the R1 is selected from CH3, and the other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, each of the R1s is independently selected from F, Cl, Br, I, CH3, OCH3 and =N-OCH3, and the other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, each of the R2, R3, R4 and R5 is independently selected from H, F, Cl, Br, CH3, CHF2, CF3, CH2CH3, OCH3, OCH2CH3, where four of R2, R3, R4 and R5 cannot be H simultaneously, and the other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, the R2 is selected from H and F, and the other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, each of the R5s is selected from H, F, Cl, Br, CH3, CHF2, CF3, CH2CH3 and OCH3, and the other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, each R6 is independently selected from F, and the other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, each of the R6s is independently selected from F, Cl, Br, I, and CH3, and the other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, the R 71 teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0027] In some embodiments of the present invention, the R 81 is selected from H, and the other variables are as defined in this invention.

[0028] In some embodiments of the present invention, R9 is -NHC(=O)-CH2CH3, -NH-C(=O)-pyridyl, -NH-C(=O)-isoxazolyl, -NH-piperidinyl, -NH-pyrrolidinyl, -NH-azetidinyl, piperidinyl and [ka] Selected from -NHC(=O)-CH2CH3, -NH-C(=O)-pyridyl, -NH-C(=O)-isoxazolyl, -NH-piperidinyl, -NH-pyrrolidinyl, -NH-azetidinyl, and piperidinyl each independently have 1, 2, or 3 R b It is optionally substituted by and the other variables are as defined in this invention.

[0029] In some embodiments of the present invention, R9 is [ka] selected from, and the said

Chemical formula

[0030] In some embodiments of the present invention, the said R9 is

Chemical formula

[0031] In some embodiments of the present invention, the said ring B1 is

Chemical formula

[0032] In some embodiments of the present invention, the said ring B1 is

Chemical formula

[0033] In some embodiments of the present invention, the said ring B1 is selected from phenyl, and other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the said ring B2 is selected from thienyl, thiazolyl, imidazolyl and pyrazolyl, and the said thienyl, thiazolyl, imidazolyl and pyrazolyl are each independently optionally substituted by one, two or three R6, and other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the ring B2 is [ka] Selected from the above, [ka] Each of these can be independently substituted by one, two, or three R6 values ​​of any choice, and the other variables are as defined in this invention.

[0036] In some embodiments of the present invention, the ring B2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0037] In some embodiments of the present invention, the ring B2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0038] In some embodiments of the present invention, A2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0039] In some embodiments of the present invention, A2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the ring A2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0041] In some embodiments of the present invention, the ring C1 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0042] In some embodiments of the present invention, the ring C1 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0043] In some embodiments of the present invention, the ring C1 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0044] In some embodiments of the present invention, the ring C1 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0045] In some embodiments of the present invention, the ring C1 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0046] In some embodiments of the present invention, the ring C2 is [ka] Selected from the above, [ka] Each of these is independently one, two, or three R e This is optionally substituted, and the other variables are as defined in this invention.

[0047] In some embodiments of the present invention, the ring C2 of the compound represented by formula (I) is [ka] Selected from the above [ka] Each of these is independently one, two, or three R's g This is optionally substituted, and the other variables are as defined in this invention.

[0048] In some embodiments of the present invention, the ring C2 is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0049] In some embodiments of the present invention, the ring C2 of the compound represented by formula (I) is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0050] In some embodiments of the present invention, the ring C2 of the compound represented by formula (I) is [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0051] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0052] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0053] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is selected from the following formulas: [ka] however, [ka] It is either a single bond or a double bond. T2 is selected from CH and N. T4 is selected from CH and N. T3 is selected from C and N. Ring E is, [ka] Selected from, m is selected from 0, 1, 2, and 3. p is selected from 0, 1, and 2. Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl, pyridyl, and pyridazinyl. Ring B2 is selected from a 5-membered heteroaryl, T, T1, R1, R2, R3, R6, L, R7, and R8 are as defined in this invention.

[0054] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, Ring B is selected from phenyl, pyridyl, pyridazinyl, and 5-membered heteroaryl. R1 is H, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each of R2 and R5 is independently H, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Selected from haloalkoxys, Each R6 independently contains H, F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, R9 is -NHC(=O)-C 1-3Alkyl, -NH-C(=O)-5~6 member heteroaryl, -NH-4~6 member heterocycloalkyl, 4~6 member heterocycloalkyl, and [ka] Selected from, the -NHC(=O)-C 1-3 Alkyl, -NH-C(=O)-5~6 member heteroaryl, -NH-4~6 member heterocycloalkyl, and 4~6 member heterocycloalkyl each independently have 1, 2, or 3 R b It is optionally replaced by, Each R b These are F, Cl, Br, I, and C, respectively, independently. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl and -NH-C(=O)-C 1-3 Selected from alkyl groups, R is C 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy is independently and optionally substituted with one, two, or three halogens. m is selected from 0, 1, 2, and 3. [ka] It is either a single bond or a double bond. In the aforementioned 5-membered heteroaryl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups each independently selected from O, S, and N.

[0055] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, Ring B is selected from phenyl, pyridyl, pyridazinyl, and 5-membered heteroaryl. T1 is selected from O and CR4R5. R1 is H, =NR, C 1-3 Alkyl and C 1-3 Selected from haloalkyls, Each of R2, R3, R4, and R5 is independently H, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Selected from haloalkoxys, Alternatively, R2 and R3, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R4 and R5, together with the carbon atoms linked to them, form a cyclopropyl molecule. Alternatively, R3 and R4, together with the carbon atoms linked to them, form a double bond or a cyclopropyl bond. Each R6 independently contains H, F, Cl, Br, I, and C. 1-3 Selected from alkyl groups, Each R e These are F, Cl, Br, I, =O, and C, respectively, independently. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, -NHC(=O)-C 1-3 Alkyl, -NHC(=O)-C 1-3 Alkoxy, -NHC(=O)-C 1-3 Selected from alkylamino and =NR, R is C 1-3 Alkyl and C 1-3 Selected from alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy is independently and optionally substituted with one, two, or three halogens. m is selected from 0, 1, 2, and 3. [ka] It is either a single bond or a double bond. In the aforementioned five-membered heteroaryl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups, each independently selected from O, S, or N.

[0056] In some embodiments of the present invention, the formula (P-1) [ka] When a double bond is selected and T1 is selected from O, R3 and R4 do not exist, and the other variables are as defined in this invention.

[0057] In some embodiments of the present invention, the structural unit of formula (P-1) [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0058] In some embodiments of the present invention, the structural unit of formula (P-1) [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0059] In some embodiments of the present invention, the formula (III-2) [ka] R3 and R4 are selected from the double bonds, R3 and R4 are absent, and the other variables are as defined in this invention.

[0060] In some embodiments of the present invention, the structural unit of formula (III-2) [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0061] In some embodiments of the present invention, the structural unit of formula (III-2) [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0062] In some embodiments of the present invention, the structural unit of formula (III-2) [ka] teeth, [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0063] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, [ka] It is either a single bond or a double bond. T2 is selected from CH and N. T4 is selected from CH and N. T3 is selected from C and N. Ring E is, [ka] Selected from, m is selected from 0, 1, 2, and 3. p is selected from 0, 1, and 2. Ring B is selected from rings B1 and B2. Ring B1 is selected from phenyl, pyridyl, and pyridazinyl. Ring B2 is selected from a 5-membered heteroaryl, T, T1, R1, R2, R3, R6, L, R7, and R8 are as defined in this invention.

[0064] In some embodiments of the present invention, the formula (III'-2) [ka] The double bond is selected, T1 is selected from CR5, and the other variables are as defined in this invention.

[0065] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] T2 is selected from CH and N. T3 is selected from C and N. Ring E is [ka] Selected from, m is selected from 0, 1, 2, and 3. Ring B2 is selected from a 5-membered heteroaryl, T, T1, R1, R2, R3, R6, L, R7, and R8 are as defined in this invention.

[0066] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, [ka] It is either a single bond or a double bond. T2 is selected from CH and N. T4 is selected from CH and N. Ring B2 is selected from a 5-membered heteroaryl, R1, R2, R3, R4, R5, R6, L, R7, R8, and m are as defined in this invention.

[0067] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, [ka] It is either a single bond or a double bond. T5 is CR 61 Selected from N, R 61 H, F, Cl, Br, I and C 1-3 Selected from alkyl groups, R1, R2, R5, R6, Re And m are as defined in the present invention.

[0068] In some embodiments of the present invention, the above compound, its stereoisomer, or its pharmaceutically acceptable salt, the compound is selected from the following formula: [ka] however, [ka] It is either a single bond or a double bond. T5 is CR 61 Selected from N, R 61 H, F, Cl, Br, I and C 1-3 Selected from alkyl groups, R1, R2, R3, R5, R6, R9, R 71 , R 81 And m are as defined in the present invention.

[0069] Some embodiments of the present invention further consist of any combination of the above variables.

[0070] The present invention provides compounds represented by the following formula, stereoisomers thereof, or pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka]

[0071] The present invention provides compounds represented by the following formula, stereoisomers thereof, or pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0072] The present invention further provides the use of the above-mentioned compound, its stereoisomer, or its pharmaceutically acceptable salt in the manufacture of a pharmacopoeia for the treatment of aldosterone synthase inhibitor-related diseases.

[0073] The present invention further provides the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts in the manufacture of pharmaceuticals for the treatment of refractory hypertension. [Effects of the Invention]

[0074] (Technical effects) The compounds of the present invention possess higher CYP11B2 enzyme inhibitory activity, weak inhibitory effect on CYP11B1, excellent selectivity, minimal impact on cortisol synthesis, and excellent clinical safety. Furthermore, the compounds of the present invention have good in vivo pharmacokinetic properties, high bioavailability, slow in vivo clearance, long half-life, good oral absorption, and meet the requirements for once-daily oral administration. The compounds of the present invention are highly permeable and low efflux compounds, exhibit moderate binding to various plasma proteins, have an appropriate proportion of plasma-free drug, and possess good pharmacokinetic potential. The compounds of the present invention have low clearance in human liver microsomes, good metabolic stability, no inhibitory effect on CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and have an extremely low risk of drug interactions.

[0075] (Definitions and explanations)

[0076] Unless otherwise stated, the following terms and collocations used herein are intended to have the following meanings. Unless specifically defined, any particular term or collocation should not be interpreted as ambiguous or unclear, but rather should be understood as having its ordinary definition. Where a trade name appears herein, it refers to the corresponding product or its active ingredient.

[0077] As used herein, the term “pharmaceutically acceptable” applies to compounds, materials, compositions and / or dosage forms that are within the bounds of reliable medical judgment, suitable for use in contact with human and animal tissues, with little toxicity, irritation, allergic reaction or other problem or complication, and that meet a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared with a compound having a specific substituent discovered in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting these compounds with a sufficient amount of base in a single solution or a suitable inert solvent. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting these compounds with a sufficient amount of acid in a single solution or a suitable inert solvent. Since some specific compounds of the present invention contain basic and acidic functional groups, they can be converted into any base addition salt or acid addition salt.

[0079] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional methods from a parent compound containing an acidic or basic moiety. Typically, such salts are produced by reacting these compounds, in the form of free acids or bases, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0080] Unless otherwise specified, the term "isomer" includes geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers.

[0081] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds and includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures containing a large amount of enantiomers or diastereomers, all of which are within the scope of the present invention. Other chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0082] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0083] Unless otherwise explained, the terms "cis-trans isomer" or "geometric isomer" refer to the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely.

[0084] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

[0085] Unless otherwise specified, "(+)" indicates dextrorotatory properties, "(-)" indicates levorotatory properties, and "(±)" indicates a racemic mixture.

[0086] Unless otherwise explained, wedge-shaped solid line connections [ka] and wedge-shaped dotted line connections [ka] The absolute arrangement of the center of one solid is connected by a solid line. [ka] and line-dotted line combinations [ka] The relative arrangement of the center of the solid is shown by the wavy line. [ka] wedge-shaped solid line connection [ka] or wedge-shaped dotted line connection [ka] or a wavy line [ka] Linear solid line combination [ka] or a combination of straight and dotted lines [ka] It represents.

[0087] Unless otherwise specified, the terms “rich in one isomer,” “rich in isomers,” “rich in one enantiomer,” or “rich in enantiomers” mean that the content of one isomer or enantiomer is less than 100%, and that the content of this isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0088] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomer or enantiomer excess (ee value) is 80%.

[0089] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a compound of the present invention, it can be produced by asymmetric synthesis or derivatization with a chiral auxiliary agent, where the resulting diastereomer mixture can be separated and the auxiliary group cleaved to obtain the pure enantiomer of the desired type. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxy), a salt of the diastereomer can be formed with a suitable optically active acid or base, and then the diastereomer can be separated by conventional methods known in the art and recovered to obtain the pure enantiomer. Furthermore, the separation of enantiomers and diastereomers is usually performed using chromatography with a chiral stationary phase, and, if necessary, combined with chemical derivatization methods (e.g., producing a carbamate from an amine).

[0090] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, tritium ( 3 H), Iodine-125( 125 I), C-14( 14 Compounds labeled with radioactive isotopes such as C) may also be used.

[0091] Furthermore, for example, deuterated drugs can be formed by substituting hydrogen with deuterium. The bond formed between deuterium and carbon is stronger than the bond formed between ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic effects, and extended biological half-life. The conversion of the isotopic composition of the compounds of the present invention is included within the scope of the present invention, whether or not they are radioactive.

[0092] The terms "optional" and "at willing discretion" may appear in the events or situations described below, but are not necessarily so, and such descriptions include cases where the aforementioned events or situations occur, as well as cases where the aforementioned matters or situations do not occur.

[0093] The term "substituted" refers to the substitution of any one or more hydrogen atoms in a particular atom with a substituent. The substituent may include deuterium and hydrogen variants, provided that the specific valence state is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms have been substituted.

[0094] The term "optionally substituted" means that substitution is optional, and unless otherwise defined, the type and number of substituents are arbitrary as long as they can be chemically realized.

[0095] If any of the variables (e.g., R) appear once or more in the composition or structure of a compound, their definitions are independent in each case. Therefore, for example, if one group is substituted with 0 to 2 Rs, the group can be substituted with any two or fewer Rs, and in each case, Rs have independent choices. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0096] When the number of linking groups is 0, for example, -(CRR)0-, it means that the linking group is a single bond.

[0097] A value of 0 for the number of substituents indicates that the substituent is absent. For example, -A-(R)0 represents a structure that is actually -A.

[0098] If a substituent is empty, it means that substituent does not exist. For example, if X in AX is empty, it means that the structure is actually A.

[0099] When one of the variables is selected from a single bond, the two groups connected by it are directly linked. For example, if L in ALZ represents a single bond, then this structure is indeed AZ.

[0100] If the connection direction of the listed linking groups is not specified, the connection direction is arbitrary, for example, [ka] The linking group L in this case is -MW-, and in this case -MW- links ring A and ring B in the same direction as the reading order from left to right. [ka] It is possible to construct this, and also connect ring A and ring B in the reverse direction of the reading order from left to right. [ka] It is also possible to construct such a compound. The combination of the linking group, substituent and / or its variants is only permissible if such a combination results in a stable compound.

[0101] Unless otherwise specified, if a group has one or more bondable sites, any one or more of these sites can be bonded to other groups by chemical bonds. If the bonding mode of the chemical bond is delocalized and hydrogen atoms are present at the bondable sites, when a chemical bond is formed, the number of hydrogen atoms at the sites decreases to a group with a corresponding valency in proportion to the number of chemical bonds formed. The chemical bond formed by the bonding of the sites to other groups is a linear solid bond. [ka] , dashed line connection [ka] or wavy line [ka] It can be represented as follows. For example, the linear solid bond of -OCH3 represents a bond to another group via an oxygen atom within that group. [ka] The dashed line in the diagram indicates that the nitrogen atom within that group is bonded to another group via both ends. [ka] The wavy line indicates that the phenyl molecule is bonded to another group via the carbon atoms at positions 1 and 2.

[0102] [ka] This indicates that any bondable site of the piperidinyl can bond to another group via one chemical bond, at least [ka] This includes the four bonding methods, and even when the H atom is depicted as -N-, [ka] for [ka] The group contains a bonding method, however, when bonded to one chemical bond, the number of H atoms at that site decreases by one, resulting in the corresponding monovalent piperidinyl.

[0103] Unless otherwise specified, when rings A and B are fused, they share one bond, and the atom on that bond may be a carbon atom or a nitrogen atom, for example, [ka] In the condensed bond between A and B, the atom is either C or N. [ka] This includes, but is not limited to, these.

[0104] Unless otherwise explained, the number of atoms in a ring is generally defined as the number of ring members. For example, a "5- to 7-membered ring" refers to a "ring" in which 5 to 7 atoms are arranged around it.

[0105] Unless otherwise defined, the terms “halogen element” or “halogen” refer to a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0106] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl contains C 1-2 and C 2-3 Alkyl compounds may be monovalent (e.g., methyl), divalent (e.g., methylene), and polyvalent (e.g., methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0107] Unless otherwise defined, the term "C 1-3 "Alkoxy" represents an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via one oxygen atom. This may be monovalent, divalent, or polyvalent. 1-3 Alkoxy is C 1-2 , C 2-3 This includes C3 and C2 alkoxys. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy and isopropoxy).

[0108] Unless otherwise defined, the term "C 1-3 "Alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via a nitrogen atom. 1-3 Alkylamino is C 1-2 , including C3 and C2 alkylaminos.1-3 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0109] Unless otherwise defined, the term "C 1-3 "Haloalkyl" refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms. 1-3 Haloalkyl is C 1-2 , C 2-3 , including C3, C2 and C1 haloalkyls. 1-3 Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, and 3-bromopropyl.

[0110] Unless otherwise defined, the term "C 1-3 "Haloalkoxy" refers to monohaloalkoxy and polyhaloalkoxy containing 1 to 3 carbon atoms. 1-3 Haloalkoxy is C 1-2 , C 2-3 , including C3, C2 and C1 haloalkoxys. 1-3 Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, and 3-bromopropoxy.

[0111] Unless otherwise defined, "C 5-6 "Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which is a monocyclic ring system, and the C 5-6 Cycloalkyls include C5 and C6 cycloalkyls, and may be monovalent, divalent, or polyvalent. 5-6 Examples of cycloalkyl compounds include, but are not limited to, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.

[0112] Unless otherwise defined, "C 3-5 "Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, and the above C 3-5 Cycloalkyls include C3, C4, and C5 cycloalkyls, and they may be monovalent, divalent, or polyvalent. 3-5 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropenyl, cyclobutenyl, and cyclopentenyl.

[0113] Unless otherwise defined, the term "4-6 membered heterocycloalkyl" refers to a saturated cyclic group composed of 4-6 ring atoms, either by itself or in combination with other terms, wherein one, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the carbon atoms are optionally oxinated (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). P(where p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridging rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl," the heteroatom can occupy a linking position between the heterocycloalkyl and the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl. Examples of 4- to 6-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxynyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0114] Unless otherwise defined, the term "5-6 membered heterocycloalkyl" refers to a saturated cyclic group composed of 5-6 ring atoms, either by itself or in combination with other terms, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the carbon atoms are optionally oxinated (i.e., C(O)), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). P(where p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridging rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl," the heteroatom can occupy a linking position between the heterocycloalkyl and the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered or 6-membered heterocycloalkyl. Examples of 5-6 member heterocycloalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxynyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0115] Unless otherwise stated, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" in this invention are interchangeable, and the term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system composed of 5-6 ring atoms, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). 5- to 6-membered heteroaryls are linked to the rest of the molecule through heteroatoms or carbon atoms. The 5- to 6-membered heteroaryls include 5-membered and 6-membered heteroaryls. Examples of the 5- to 6-membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- This includes, but is not limited to, triazolyl, tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyridinyl and 4-pyridinyl, etc.).

[0116] Unless otherwise defined, the terms “5-membered heteroaryl ring” and “5-membered heteroaryl” in this invention are interchangeable, and the term “5-membered heteroaryl” refers to a monocyclic group having a conjugated π-electron system composed of five ring atoms, the 1st, 2nd, 3rd and 4th ring atoms being heteroatoms independently selected from O, S and N, and the remaining one being a carbon atom. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). Five-membered heteroaryls are linked to the rest of the molecule through heteroatoms or carbon atoms. Examples of the five-membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2 This includes, but is not limited to, 3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), and thienyl (including 2-thienyl and 3-thienyl, etc.).

[0117] The compounds of the present invention can be produced by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0118] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, in single-crystal X-ray diffraction (SXRD), the absolute configuration can be confirmed by collecting diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer with CuKα radiation as the light source and scanning method: φ / ω scanning, and then analyzing the crystal structure using a direct method (Shelxs97) after collecting the relevant data.

[0119] In this invention, the following abbreviations are used: eq represents equivalent, DCM represents dichloromethane, PE represents petroleum ether, DMSO represents dimethyl sulfoxide, ƒ represents ethyl acetate, EtOH represents ethanol, MeOH represents methanol, DMF represents N,N-dimethylformamide, Boc represents tert-butoxycarbonyl, an amine protecting group, rt represents room temperature, TFA represents trifluoroacetic acid, Eaton's reagent represents a 7.5% phosphorus pentoxide methanesulfonic acid solution, PEG represents polyethylene glycol, solutol represents polyoxyl 15-hydroxystearate, C max represents the maximum concentration, AUC represents the oral exposure, and T represents the maximum concentration. 1 / 2 V represents the half-life. dss represents the steady-state distributed volume, and CL represents the clearance.

[0120] All solvents used in this invention are commercially available.

[0121] Compounds are named according to the usual naming conventions in this art, or using ChemDraw® software, and commercial compounds use the supplier's catalog name. [Brief explanation of the drawing]

[0122] [Figure 1] This is a schematic diagram illustrating the binding of compound 1A to the CYP11B2 protein. [Figure 2] This is a schematic diagram illustrating the binding of compound 2A to the CYP11B2 protein. [Figure 3] This is a schematic diagram illustrating the binding of compound 3A to the CYP11B2 protein. [Modes for carrying out the invention]

[0123] The present invention will be described in detail below with reference to examples, but this does not mean that there will be any unfavorable limitations to the present invention. The compounds of the present invention can be produced by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0124] Calculation example 1 [ka]

[0125] The molecular docking process was performed using Maestro (Schrodinger version 2022-1) Glide SP[1] and default settings. The co-crystal structure of CYP11B2 (PDB ID: 4ZGX) was selected as the docking template. To produce the protein, hydrogen atoms were added using the Maestro[2] Protein Production Wizard module and the OPLS4 force field was used. For ligand production, the LigPrep module was used to generate the three-dimensional structure of the molecule, energy minimization[3] was performed, and the ConfGen module was used to explore small molecule conformations[4]. The Receptor Grid Generation module of Glide was used to generate the grid file required for docking, with the ligand of the crystal structure as the center of the docking box. The interaction types between the protein receptor and ligand were analyzed, and molecules with high potential were selected, synthesized, and tested based on the calculated docking score and binding mode. The binding modes of compounds 1A, 2A, and 3A are shown in Figures 1, 2, and 3.

[0126] [1] Glide, Schrodinger, LLC, New York, NY, 2020. [2] Maestro, Schrodinger, LLC, New York, NY, 2020. [3] LigPrep, Schrodinger, LLC, New York, NY, 2020. [4] ConfGen, Schrodinger, LLC, New York, NY, 2020.

[0127] Conclusion: The compounds of the present invention exhibit good binding to the CYP11B2 protein.

[0128] Reference Example 1: Fragment A-1

[0129] Synthesis pathway: [ka]

[0130] Step 1: Synthesis of Compound A-1-3 A-1-1 (19 g, 84.04 mmol) and tetrahydrofuran (250 mL) were added to the reaction flask and stirred to dissolve. Then A-1-2 (12.22 g, 100.85 mmol) was added, followed by the dropwise addition of tetraethyl titanate (57.51 g, 252.13 mmol). The reaction system was stirred at 75°C for 16 hours. 400 mL of ethyl acetate and 800 mL of saturated sodium bicarbonate aqueous solution were added, the mixture was filtered, and the cake was washed three times with ethyl acetate (100 mL each time). The filtrate was collected and separated. The aqueous phase was extracted twice with 400 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 800 mL of saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product A-1-3. 1 H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1 H), 8.71 (s, 1 H), 3.25 - 3.35 (m, 1 H), 3.10 - 3.18 (m, 1 H), 2.83 - 2.99 (m, 2 H), 1.96 - 2.16 (m, 2 H), 1.34 (s, 9 H).

[0131] Step 2: Synthesis of Compound A-1-4 A-1-3 (11.13 g, 33.80 mmol) and tetrahydrofuran (100 mL) were added to a reaction flask and the flask was purged with nitrogen gas. 9-borabicyclo[3.3.1]nonane (169.02 mL in a 0.5 M solution of tetrahydrofuran) was added dropwise at 0°C, and the temperature was slowly raised to 25°C for 16 hours. Saturated ammonium chloride aqueous solution (250 mL) and 250 mL of water were sequentially added to the reaction solution, and the aqueous phase was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 25%~100%) to obtain A-1-4. 1 H NMR (400 MHz, CDCl3) δ ppm 8.58 (d, J = 8.78 Hz, 2 H), 4.60 - 4.70 (m, 1 H), 3.18 - 3.31 (m, 1 H), 2.81 - 2.92 (m, 1 H), 2.62 (ddd, J = 18.51, 9.60, 6.53 Hz, 1H), 2.09 - 2.18 (m, 1H), 1.93 - 2.07 (m, 1H), 1.80 - 1.91 (m, 2H), 1.23 (s, 9H).

[0132] Step 3: Synthesis of Compound A-1-5 A-1-4 (8.31 g, 25.09 mmol) was dissolved in ethyl acetate (50 mL), and hydrogen chloride / ethyl acetate (2 M, 160 mL) was added at 28 °C. The mixture was stirred for 16 hours. The reaction solution was filtered, and the cake was rinsed with 3 mL of ethyl acetate. The cake was collected and dried to obtain the hydrochloride salt of the crude product A-1-5. ESI-LCMS: m / z = 226.8, 228.9 [M+1] + .

[0133] Step 4: Synthesis of Compound A-1 In a reaction flask, hydrochloride salt of A-1-5 (7.67 g), dichloromethane (150 mL), and triethylamine (8.83 g, 87.30 mmol) were added sequentially and stirred to dissolve. Then, propionic anhydride (5.68 g, 43.65 mmol) was added and the mixture was stirred at 28°C for 16 hours. 400 mL of saturated ammonium chloride aqueous solution was added and the mixture was separated. The aqueous phase was extracted three times with dichloromethane (200 mL each time), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain A-1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.54 (s, 1 H), 8.41 (s, 1 H), 5.74 (br d, J = 7.28 Hz, 1 H), 5.24 - 5.32 (m, 1 H), 2.69 - 2.82 (m, 2 H), 2.27 (q, J = 7.53 Hz, 2 H), 1.98 - 2.06 (m, 1 H), 1.91 (dt, J = 12.05, 6.02 Hz, 2 H), 1.78 - 1.86 (m, 1 H), 1.21 (t, J = 7.65 Hz, 3 H). [α] 20 D = +5.77 (c 1.0, MeOH).

[0134] Reference Example 2: Fragment A-2

[0135] Synthesis pathway: [ka]

[0136] Step 1: Synthesis of Compound A-2 In a reaction flask, A-1 (70 mg, 247.21 μmol), triisopropyl borate (155.75 mg, 828.14 μmol), and tetrahydrofuran (3.5 mL) were added sequentially. The flask was purged with nitrogen gas, and n-butyllithium (2.5 M, 247.21 μL) was added dropwise at -78°C. The mixture was stirred at -78°C for 2 hours. Methanol (3.5 mL) was added dropwise to the reaction solution to obtain a methanol solution of A-2, which was used immediately after preparation. ESI-LCMS: m / z = 249.3 [M+H] + .

[0137] Example 1

[0138] Synthesis pathway: [ka]

[0139] Step 1: Synthesis of Compound 001-2 001-1 (1 g, 4.16 mmol) and 1,2-dichloroethane (20 mL) were added to the reaction flask. After stirring to dissolve, N-bromosuccinimide (1.11 g, 6.25 mmol) and azobisisobutyronitrile (136.79 mg, 833.00 μmol) were added, and the reaction system was stirred at 80°C for 4 hours. 20 mL of water was added, the mixture was separated, and the aqueous phase was extracted three times with dichloromethane (20 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 001-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.73 (d, J = 2.26 Hz, 1 H), 7.68 (dd, J = 9.03, 2.26 Hz, 1 H), 7.62 (d, J = 9.54 Hz, 1 H), 7.30 (d, J = 2.51 Hz, 1 H), 6.78 (d, J = 9.54 Hz, 1 H), 3.73 (s, 3 H).

[0140] Step 2: Synthesis of Compounds 001-3 001-2 (1.6g, 6.72 mmol), bis(pinacolate)diborone (2.56g, 10.08 mmol), potassium acetate (1.98g, 20.16 mmol), and 1,4-dioxane (10 mL) were added to the reaction flasks. After purging with nitrogen gas, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (274.41 mg, 336.02 μmol) was added. The reaction system was stirred at 80°C for 2 hours. 30 mL of ethyl acetate was added, the mixture was stirred to dilute, and the mixture was filtered by suction. The cake was washed with 30 mL of ethyl acetate, the organic phase was collected, and the mixture was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 0%~20%) to obtain 001-3. ESI-LCMS: m / z = 286.1 [M+H] + .

[0141] Step 3: Synthesis of Compound 001 001-3 (191.33 mg, 670.99 μmol), A-1 (190 mg, 670.99 μmol), and ethanol (2.5 mL) were added to the reaction flask and dissolved. Then sodium carbonate (142.50 mg, 1.34 mmol) and water (0.5 mL) were added. After purging with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (38.77 mg, 33.55 μmol) was added. The reaction system was stirred at 80°C for 16 hours. The reaction system was quenched by adding 20 mL of semisaturated saline solution, extracted three times with ethyl acetate (10 mL each time), the organic phases were combined and washed with 20 mL of saturated saline solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1), and then chiral separation was performed [column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], ethanol (0.1% aqueous ammonia): 45%, isogradient elution] to obtain compound 001. 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1 H), 8.31 (s, 1 H), 7.69 (d, J=9.29 Hz, 1 H), 7.43 - 7.52 (m, 3 H), 6.77 (d, J=9.54 Hz, 1 H), 5.84 (br d, J=8.53 Hz, 1 H), 5.32 - 5.40 (m, 1 H), 3.77 (s, 3 H), 2.55 - 2.71 (m, 2 H), 2.29 (q, J=7.53 Hz, 2 H), 2.04 - 2.15 (m, 1 H), 1.82 - 1.90 (m, 2 H), 1.23 (t, J=7.65 Hz, 3 H); ESI-LCMS: m / z = 362.0 [M+H] + SFC detection method: Chromatography column: Chiralcel OD-3, 150 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% diethylamine), gradient: B% = 5%~40% (elute for 4 minutes), 40% (elute for 2 minutes), 5% (elute for 2 minutes), flow rate: 2.5 mL / min, column temperature: 35°C, pressure: 1500 psi. ee = 99.52%, retention time: 4.686 min.

[0142] Example 2

[0143] Synthesis pathway: [ka]

[0144] Step 1: Synthesis of Compound 002-2 Add 002-1 (6 g, 26.54 mmol) of 1,4-dioxane (60 mL) solution to a reaction flask, add Lawson's reagent (7.51 g, 18.58 mmol), purge with nitrogen gas, raise the temperature to 110°C and stir for 2 hours. Concentrate the reaction solution, add 10 mL of dichloromethane, and concentrate under reduced pressure to obtain the crude product. Add 12 mL of dichloromethane to the crude product, stir for 0.5 hours, and filter to obtain 002-2. 1H NMR (400 MHz, CDCl3) δ = 9.84 (br s, 1H), 7.39 - 7.31 (m, 2H), 6.81 - 6.71 (m, 1H), 3.14 - 3.05 (m, 2H), 2.93 - 2.83 (m, 2H).

[0145] Step 2: Synthesis of Compound 002-4 002-2 (540 mg, 2.23 mmol), 002-3 (198.26 mg, 2.68 mmol), and cyclohexanol (10.4 mL) were added to a reaction flask, the mixture was purged with nitrogen gas, and the temperature was raised to 120°C and stirred for 16 hours. 5 mL of water and 10 mL of ethyl acetate were added to the reaction solution, and the mixture was extracted and separated to collect the organic phase. The aqueous phase was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined and washed twice sequentially with saturated brine (10 mL each time). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:(ethyl acetate / methanol=5 / 1)=1:0~0:1) to obtain 002-4. 1 H NMR (400 MHz, CDCl3) δ = 7.57 - 7.48 (m, 2H), 7.37 (d,J= 8.5 Hz, 1H), 3.19 - 3.10 (m, 2H), 3.05 - 2.98 (m, 2H), 2.77 (s, 3H).

[0146] Step 3: Synthesis of Compound 002-5 In a reaction flask, 002-4 (475 mg, 1.80 mmol), bis(pinacolate)diborone (548.02 mg, 2.16 mmol), 1,4-dioxane (10 mL), potassium acetate (529.49 mg, 5.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (164.68 mg, 179.84 μmol), and tricyclohexylphosphine (100.87 mg, 359.68 μmol) were added, the flask was purged with nitrogen gas, and the temperature was raised to 80°C and stirred for 12 hours. 10 mL of saturated saline solution and 20 mL of ethyl acetate were added to the reaction solution, and the mixture was extracted and separated to collect the organic phase. The aqueous phase was extracted three times with ethyl acetate (20 mL each time). The organic phases were combined and washed three times sequentially with saturated saline solution (20 mL each time). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was obtained from 002-5 by column chromatography [petroleum ether:(ethyl acetate / methanol=5 / 1)=1:0~0:1]. 1 H NMR (400 MHz,CD3OD) δ = 7.84 - 7.78 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H), 3.12 - 3.03 (m, 4H), 2.78 (s, 3H), 1.36 (s, 12H); ESI-LCMS: m / z = 312.2 [M+H] + .

[0147] Step 4: Synthesis of compounds 002 and 003 A solution of 002-5 (56.92 mg, 127.13 μmol), A-1 (30 mg, 105.95 μmol), ethanol (1.6 mL), and sodium carbonate (12.35 mg, 116.54 μmol) in water (0.3 mL) was sequentially added to the reaction flask, purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (3.67 mg, 3.18 μmol) was added, purged with nitrogen gas again, and the temperature was raised to 85°C and stirred for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the crude product. Chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], ethanol (0.1% aqueous ammonia): 30%, isogradient elution) was performed to obtain 002 and 003. SFC detection method: Column: Chiralpak AD-3, 150 × 4.6 mm ID, 3 μm, mobile phase: A: supercritical CO2, B: ethanol (methanol solution of 0.2% 7 M ammonia, gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.5 min), 50 / 50 (3.5 min), 50 / 50 (4.5 min), 90 / 10 (5.0 min), flow rate: 2.5 mL / min, column temperature: 35 °C, pressure: 2000 psi) was used to measure the ee value.

[0148] Compound 002:ESI-LCMS: m / z = 388.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 8.32 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.32 - 7.29 (m, 2H), 5.73 - 5.66 (m, 1H), 5.41 - 5.34 (m, 1H), 3.22 - 3.16 (m, 2H), 3.10 - 3.04 (m, 2H), 2.82 (s, 3H), 2.71 - 2.55 (m, 2H), 2.30 (q, J = 7.6 Hz, 2H), 2.10 (br t, J = 5.1 Hz, 1H), 1.90 - 1.78 (m, 3H), 1.24 (t, J = 7.6 Hz, 3H), ee = 100%, holding time: 3.778 minutes.

[0149] Compound 003: ESI-LCMS: m / z = 388.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 8.32 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.32 - 7.29 (m, 2H), 5.73 - 5.66 (m, 1H), 5.41 - 5.34 (m, 1H), 3.22 - 3.16 (m, 2H), 3.10 - 3.04 (m, 2H), 2.82 (s, 3H), 2.71 - 2.55 (m, 2H), 2.30 (q, J = 7.6 Hz, 2H), 2.10 (br t, J = 5.1 Hz, 1H), 1.90 - 1.78 (m, 3H), 1.24 (t, J = 7.6 Hz, 3H), ee = 99.86%, holding time: 4.024 minutes.

[0150] Example 3

[0151] Synthetic road:

change

[0152] ステップ1:Synthesis of compound 004-2 Add 002-2 (2 g, 8.26 mmol), 004-1 (1.48 g, 12.39 mmol), silver acetate (2.76 g, 16.52 mmol, 846.06 μL), and acetonitrile (20 mL) to a reaction flask and stir at 25°C for 12 hours. Filter the reaction solution and rinse the cake with 10 mL of acetonitrile. The filtrate was collected and concentrated to obtain crude product 004-2. 1 H NMR (400 MHz, CDCl3) δ = 7.35 (br d, J = 8.3 Hz, 1H), 7.29 (br s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.51 (s, 2H), 3.26 (s, 6H), 3.22 (s, 4H), 1.42 (s, 3H).

[0153] Step 2: Synthesis of Compound 004-3 004-2 (3g, 9.17 mmol), hydrochloric acid (12M, 15mL), and water (5mL) were added to a reaction flask and stirred at 80°C for 5 hours. Saturated sodium bicarbonate aqueous solution was added dropwise to the reaction solution to adjust the pH to 7-8, and dichloromethane was added and extracted three times (10mL each time). The mixture was separated and the organic phase was collected. The mixture was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0-0:1) to obtain 004-3. 1 H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 2.0 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.38 - 7.33 (m, 1H), 6.79 (s, 1H), 3.07 - 2.91 (m, 4H), 2.51 (s, 3H).

[0154] Step 3: Synthesis of Compound 004-4 004-3 (230 mg, 874.08 μmol), bis(pinacolate)diborone (443.93 mg, 1.75 mmol), potassium acetate (257.35 mg, 2.62 mmol), tricyclohexylphosphine (49.02 mg, 174.82 μmol), tris(dibenzylideneacetone)dipalladium(0) (80.04 mg, 87.41 μmol), and 1,4-dioxane (7.5 mL) were added to a reaction flask, and after purging with nitrogen gas, the mixture was stirred at 80°C for 16 hours. Water (10 mL) and ethyl acetate (5 mL) were added to the reaction solution, and the mixture was filtered. The filtrate was extracted three times with ethyl acetate (5 mL each time), separated, and the organic phases were combined. The mixture was washed with saturated brine (5 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 004-4. ESI-LCMS: m / z = 311.4 [M+H] + .

[0155] Step 4: Synthesis of Compound 004 A solution of 004-4 (65.73 mg, 211.89 μmol), A-1 (40 mg, 141.26 μmol), ethanol (3.2 mL), and sodium carbonate (16.47 mg, 155.39 μmol) in water (0.52 mL) was sequentially added to the reaction flask, the flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (4.90 mg, 4.24 μmol) was added, the flask was purged with nitrogen gas again, and the mixture was stirred at 85°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was first separated by preparative thin-layer chromatography (ethyl acetate:methanol = 1:1), and then 004 was obtained by chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 30% isopropanol (0.1% ammonia)).

[0156] ESI-LCMS: m / z = 387.3[M+H] + ; 1HNMR (400 MHz, CDCl3) δ = 8.53 (s, 1H), 8.33 (s, 1H), 7.57 (br d, J = 8.5 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.84 (br s, 1H), 5.79 - 5.65 (m, 1H), 5.41 - 5.31 (m, 1H), 3.14 - 2.99 (m, 4H), 2.76 - 2.62 (m, 2H), 2.58 (s, 3H), 2.29 (q, J = 7.2 Hz, 2H), 2.14 - 2.06 (m, 1H), 1.86 - 1.78 (m, 3H), 1.23 (br t, J = 7.5 Hz, 3H), SFC detection method: Column: Chiralpak AD-3, 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Ethanol (methanol solution of 0.2% 7 M ammonia), Gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.5 min), 50 / 50 (3.5 min), 50 / 50 (4.5 min), 90 / 10 (5.0 min), Flow rate: 2.5 mL / min, Column temperature: 35 °C, Pressure: 2000 psi, ee = 100%, Retention time: 4.144 min.

[0157] Example 4

[0158] Synthesis pathway: [ka]

[0159] Step 1: Synthesis of Compound 005-1 Add A-1 (0.1 g, 353.15 μmol), methoxyamine hydrochloride (38.34 mg, 459.1 μmol), phosphorus oxychloride (119.12 mg, 776.94 μmol), and toluene (1 mL) to a reaction flask and stir at 90°C for 10 hours. The reaction solution was concentrated, and the concentrate was slowly poured into water (2 mL). The pH was adjusted to 9-10 by adding saturated sodium carbonate aqueous solution dropwise. The solution was extracted three times with dichloromethane (2 mL each time), the organic phases were combined, washed with saturated saline solution (2 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 005-1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.56 (s, 1 H), 8.49 (s, 1 H), 5.31 (s, 1 H), 4.53 - 4.62 (m, 1 H), 3.75 (s, 3 H), 2.72 - 2.80 (m, 2 H), 2.38 (qd, J = 7.48, 3.69 Hz, 2 H), 1.97 - 2.07 (m, 2 H), 1.77 - 1.91 (m, 2 H), 1.28 (t, J = 7.50 Hz, 3 H).

[0160] Step 2: Synthesis of compounds 005 and 006 O05-1 (100 mg, 320.30 μmol), O05-2 (110.37 mg, 384.36 μmol), ethanol (4.5 mL), water (1.5 mL), and sodium carbonate (37.34 mg, 352.33 μmol) were sequentially added to the reaction flask, the flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (11.10 mg, 9.61 μmol) was added, the flask was purged with nitrogen gas again, and the temperature was raised to 85°C and stirred for 12 hours. The reaction solution was filtered, the cake was rinsed with dichloromethane (5 mL), the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified to obtain 005 and 006 by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 0:1), preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: acetonitrile%: 20%~50%), and chiral separation (column: DAIEL CHIRALPAK AD (250mm×30mm, 10μm), mobile phase: [A: supercritical carbon dioxide-B: isopropanol (0.1% aqueous ammonia)], isogradation elution: 35% of B). SFC detection method: (Column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Methanol [methanol solution of 0.2% 7 M ammonia], Gradient: A:B = 60:40, Flow rate: 4 mL / min, Column temperature: 35 °C, Pressure: 1800 psi).

[0161] Compound 005: 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (s, 1 H), 8.33 (s, 1 H), 7.14 - 7.25 (m, 1 H), 7.00 - 7.14 (m, 2 H), 5.34 (br d, J = 10.13 Hz, 1 H), 4.66 (br s, 1 H), 3.73 - 3.81 (m, 3 H), 3.41 (s, 3 H), 2.91 - 3.00 (m, 2 H), 2.72 (br t, J = 7.32 Hz, 3 H), 2.33 - 2.45 (m, 2 H), 2.11 (br s, 1 H), 1.89 (br d, J = 7.00 Hz, 1 H), 1.74 - 1.87 (m, 3 H), 1.30 (t, J = 7.44 Hz, 3 H). ESI-LCMS: m / z = 393.2 [M+H] + ee=99.98%, retention time: 0.805 minutes.

[0162] Compound 006: 1 H NMR (400 MHz, CDCl3) δ ppm 8.59 (br s, 1 H), 8.22 - 8.37 (m, 1 H), 7.17 - 7.21 (m, 1 H), 7.05 - 7.11 (m, 2 H), 5.34 (br d, J = 10.39 Hz, 1 H), 4.60 - 4.66 (m, 1 H), 3.76 (s, 3 H), 3.41 (s, 3 H), 2.96 (t, J = 7.42 Hz, 2 H), 2.69 - 2.75 (m, 3 H), 2.36 - 2.42 (m, 2 H), 2.08 (br dd, J = 6.99, 1.92 Hz, 1H), 1.85 - 1.89 (m, 1 H), 1.74 - 1.83 (m, 3 H), 1.29 - 1.32 (m, 3 H); ESI-LCMS: m / z = 393.2 [M+H] + ee=100%, retention time 0.510 minutes.

[0163] Example 5

[0164] Synthesis pathway: [ka]

[0165] Step 1: Synthesis of Compound 007-3 007-1 (3g, 12.49 mmol) and tetrahydrofuran (15 mL) were added to a reaction flask, the mixture was purged with nitrogen gas, cooled to 0°C, lithium bis(trimethylsilyl)amide (1M, 14.99 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hour. A solution of 007-2 (5.38g, 37.48 mmol) in tetrahydrofuran (9 mL) was slowly added dropwise, the mixture was stirred at 0°C for 1 hour, and then the temperature was raised to 25°C and stirred for 1 hour. Saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL each time). The organic phase was collected, washed with saturated brine (20 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 6:1) to obtain 007-3. 1 H NMR (400 MHz, CDCl3) δ = 7.39 (dd, J = 2.2, 8.6 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.85 (d, J = 8.6 Hz, 1H), 3.34 (s, 3H), 2.79 (s, 2H), 1.33 - 1.28 (m, 2H), 0.76 - 0.68 (m, 2H).

[0166] Step 2: Synthesis of Compound 007-4 In a reaction flask, 007-3 (190 mg, 713.93 μmol), bis(pinacolate)diborone (271.94 mg, 1.07 mmol), 1,4-dioxane (4 mL), and potassium acetate (140.13 mg, 1.43 mmol) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (58.30 mg, 71.39 μmol) was added. The mixture was stirred at 80°C for 16 hours. Water (2 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (2 mL each time). The organic phase was collected, washed with saturated brine (2 mL), and the organic phase was collected again. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 007-4. 1 H NMR (400 MHz, CDCl3) δ = 7.73 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.37 (s, 3H), 2.81 (s, 2H), 1.35 (s, 12H), 1.31 - 1.27 (m, 2H), 0.74 - 0.66 (m, 2H).

[0167] Step 3: Synthesis of Compound 007 In a reaction flask, a solution of A-1 (100 mg, 353.15 μmol), 007-4 (132.73 mg, 423.78 μmol), ethanol (8.5 mL), and sodium carbonate (41.17 mg, 388.47 μmol) in water (1.42 mL) was added, the flask was purged with nitrogen gas, and then tetrakis(triphenylphosphine)palladium(0) (12.24 mg, 10.59 μmol) was added and the mixture was stirred at 85°C for 2 hours. Water (2 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (2 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (ethyl acetate:methanol = 10:1) and chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 40% isopropanol (0.1% aqueous ammonia)) to obtain 007. 1 H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 8.31 (s, 1H), 7.20 (dd, J = 1.6, 8.4 Hz, 1H), 7.08 - 7.01 (m, 2H), 5.85 (br d, J = 8.3 Hz, 1H), 5.39 - 5.29 (m, 1H), 3.40 (s, 3H), 2.86 (s, 2H), 2.69 (td, J = 6.0, 15.7 Hz, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.16 - 2.05 (m, 1H), 1.92 - 1.83 (m, 3H), 1.38 - 1.31 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.79 - 0.72 (m, 2H). ESI-LCMS: m / z = 390.2 [M+H] +SFC detection method: (Column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Isopropanol [0.2% 7 M ammonia methanol solution], Gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), Flow rate: 3.4 mL / min, Column temperature: 35 °C, Pressure: 1800 psi). ee = 100%, Retention time: 1.465 min.

[0168] Example 6

[0169] Synthesis pathway: [ka]

[0170] Step 1: Synthesis of Compound 008-3 008-1 (0.2 g, 1.23 mmol), N,N-dimethylformamide (4 mL), cesium carbonate (1.09 g, 3.33 mmol), and potassium iodide (20.50 mg, 123.47 μmol) were sequentially added to the reaction flask. While stirring, 008-2 (206.19 mg, 1.23 mmol) was added dropwise to the reaction flask, the flask was purged with nitrogen gas, and the mixture was stirred at 20°C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL) to collect the aqueous phase. Citric acid solution was added to the aqueous phase to adjust the pH to 3-4, and ethyl acetate was added and extracted three times (5 mL each time). The organic phases were combined and washed with saturated brine (5 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 008-3. 1 H NMR (400 MHz, DMSO-d6) δ = 11.02 - 10.68 (m, 1H), 5.68 (s, 1H), 4.20 (t, J = 7.1 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H).

[0171] Step 2: Synthesis of Compound 008-4 008-3 (180 mg, 833.20 μmol), N,N-dimethylformamide (3 mL), cesium carbonate (325.77 mg, 999.84 μmol), and methyl iodide (473.05 mg, 3.33 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and stirred at 25°C for 12 hours. 5 mL of water and 10 mL of ethyl acetate were added to the reaction solution, and the mixture was separated to collect the organic phase. The aqueous phase was extracted three times with ethyl acetate (30 mL each time), the organic phases were combined, and the mixture was washed twice with saturated brine (30 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 008-4. 1 H NMR (400 MHz, CDCl3) δ = 5.78 (s, 1H), 4.29 (t, J = 7.1 Hz, 2H), 3.24 (s, 3H), 2.94 (t, J = 7.1 Hz, 2H).

[0172] Step 3: Synthesis of Compound 008 In a reaction flask, 008-4 (28.28 mg, 122.94 μmol), water (0.7 mL), acetonitrile (2.1 mL), methanol (0.7 mL), potassium carbonate (67.96 mg, 491.77 μmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (7.57 mg, 18.44 μmol) were added sequentially, the mixture was purged with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (4.31 mg, 6.15 μmol) and palladium acetate (1.38 mg, 6.15 μmol) were added, the mixture was purged with nitrogen gas, and the crude product solution of A-2 (prepared according to the synthesis method of Reference Example 2, used immediately after preparation, added to the preparation according to the theoretical yield, the theoretical yield being 61 mg, 245.88 μmol) was added dropwise at 40°C, and the mixture was stirred at 75°C for 12 hours. The reaction solution was filtered, the filtrate was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:methanol = 3:1), and 008 was obtained by chiral separation (column:DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [A: supercritical carbon dioxide - B: methanol], isogradient elution: 45% methanol).

[0173] 1 H NMR (400 MHz, CDCl3) δ = 8.62 - 8.57 (m, 1H), 8.53 - 8.48 (m, 1H), 5.93 (s, 1H), 5.85 - 5.75 (m, 1H), 5.39 - 5.27 (m, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.34 (s, 3H), 3.02 (t, J = 7.1 Hz, 3H), 2.30 (br d, J = 7.6 Hz, 2H), 2.22 - 2.00 (m, 2H), 1.87 (br s, 2H), 1.22 (br t, J = 6.8 Hz, 3H); ESI-LCMS: m / z 354.2 [M+H] + SFC detection method: (Column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, Mobile phase: A: Supercritical CO2, B: Methanol [Methanol solution of 0.2% 7 M ammonia], Gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), Flow rate: 3.4 mL / min, Column temperature: 35 °C, Pressure: 1800 psi). ee = 99.02%, Retention time: 1.532 min.

[0174] Example 7

[0175] Synthesis pathway: [ka]

[0176] Step 1: Synthesis of Compound 009-3 009-1 (2g, 7.04 mmol), 009-2 (2.44g, 14.09 mmol), cesium carbonate (4.59g, 14.09 mmol), toluene (20 mL), and 1,10-phenanthroline (253.91 mg, 1.41 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, cuprous iodide (134.17 mg, 704.49 μmol) was added, and the mixture was stirred at 110°C for 24 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL each time). The organic phases were combined, washed three times with saturated brine (50 mL each time), and the organic phases were collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 009-3. 1 H NMR (400 MHz, CDCl3) δ = 8.35 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.23 (t, J = 2.2 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.34 (ddd, J = 0.8, 6.4, 9.8 Hz, 2H), 4.02 (dd, J = 3.9, 10.4 Hz, 2H), 1.46 (s, 9H).

[0177] Step 2: Synthesis of Compound 009-4 009-3 (60 mg, 182.27 μmol), dichloromethane (1 mL), and trifluoroacetic acid (5.38 mmol, 0.4 mL) were added sequentially to the reaction flask, and the mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated to obtain 009-4. 1 H NMR (400 MHz, CDCl3) δ = 8.56 - 8.33 (m, 2H), 8.04 (br s, 1H), 5.43 (br d, J = 1.3 Hz, 1H), 4.71 (br s, 2H), 4.37 (br s, 2H), 3.49 - 3.41 (m, 1H).

[0178] Step 3: Synthesis of Compound 009-6 009-4 (60 mg, 261.92 μmol), 009-5 (50.52 mg, 392.89 μmol), dichloromethane (1 mL), and N,N-diisopropylethylamine (67.70 mg, 523.85 μmol) were sequentially added to a reaction flask, and the mixture was stirred at 25°C for 12 hours. Water (1 mL) and dichloromethane (1 mL) were added to the reaction solution, and the mixture was extracted and separated. The organic phase was collected, and the aqueous phase was extracted three times with dichloromethane (1 mL each time). The organic phase was combined with the aqueous phase and washed twice with saturated brine (1 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 009-6. 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (d, J = 1.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 5.23 - 5.13 (m, 1H), 4.33 (dd, J = 6.5, 9.7 Hz, 2H), 3.92 (dd, J = 4.5, 9.8 Hz, 2H), 3.22 - 3.14 (m, 2H), 1.23 (t, J = 7.3 Hz, 3H).

[0179] Step 4: Synthesis of Compound 009 In a reaction flask, 002-5 (48.51 mg, 108.35 μmol), 009-6 (29 mg, 90.29 μmol), ethanol (2.4 mL), and an aqueous solution of sodium carbonate (10.53 mg, 99.32 μmol) (0.39 mL) were added, the flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (3.13 mg, 2.71 μmol) was added, the flask was purged with nitrogen gas again, and the mixture was stirred at 85°C for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 009. 1H NMR (400 MHz, CDCl3) δ = 8.54 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.59 - 7.55 (m, 2H), 7.29 - 7.27 (m, 1H), 5.12 - 5.06 (m, 1H), 4.36 (dd, J = 6.5, 9.4 Hz, 2H), 4.19 (dd, J = 4.8, 9.4 Hz, 2H), 3.24 - 3.17 (m, 2H), 3.14 - 3.08 (m, 2H), 3.04 (q, J = 7.4 Hz, 2H), 2.83 (s, 3H), 1.40 (t, J = 7.4 Hz, 3H); ESI-LCMS: m / z = 426.1 [M+H] + .

[0180] Example 8

[0181] Synthesis pathway: [ka]

[0182] Step 1: Synthesis of Compound 010-2 In a reaction flask, 010-1 (3g, 13.16 mmol), bis(pinacolate)diborone (5.08g, 20.02 mmol), potassium acetate (2.01g, 20.45 mmol), and dioxane (90 mL) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (512.73 mg, 627.85 μmol) was added. The mixture was stirred at 100°C for 4 hours. 50 mL of water and 50 mL of dichloromethane were added to the reaction solution, extracted, separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 010-2. ESI-LCMS: m / z = 276.1 [M+H] + .

[0183] Step 2: Synthesis of Compound 010-3 010-2 (2.0 g, 7.27 mmol), N,N-dimethylformamide (15 mL), potassium carbonate (3.01 g, 21.81 mmol), and methyl iodide (1.50 g, 10.54 mmol) were added sequentially to a reaction flask, and the mixture was stirred at 25°C for 16 hours. 10 mL of water and 15 mL of dichloromethane were added, and the mixture was extracted. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 010-3. ESI-LCMS: m / z = 290.1 ​​[M+H] + .

[0184] Step 3: Synthesis of compounds 010 and 011 Crude product 010-3 (0.1 g, 345.86 μmol), A-1 (97.94 mg, 345.86 μmol), ethanol (2 mL), water (0.4 mL), and sodium carbonate (36.66 mg, 345.86 μmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (19.98 mg, 17.29 μmol) was added. The mixture was stirred at 80°C for 2 hours. The reaction solution was transferred to another location, 5 mL of water and 5 mL of dichloromethane were added, and the mixture was extracted, separated, and the organic phase collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (dichloromethane:methanol = 20:1) and chiral separation (column:DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 45% ethanol (0.1% aqueous ammonia)) to obtain 010 and 011. The ee value was measured using the SFC detection method (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, mobile phase: A: supercritical carbon dioxide, B: ethanol (0.05% diethylamine), gradient: 40% B, flow rate: 4 mL / min, column temperature: 35 °C, pressure: 1500 psi).

[0185] Compound 010: 1H NMR (400MHz, CDCl3) δ = 8.43 (s, 1H), 8.21 (s, 1H), 7.03 - 6.93 (m, 1H), 6.92 - 6.82 (m, 2H), 5.65 (br d, J=8.5 Hz, 1H), 5.39 - 5.11 (m, 1H), 4.61 (s, 2H), 3.34 (s, 3H), 2.69 - 2.47 (m, 2H), 2.29 - 2.14 (q, J=7.7 Hz, 2H), 2.06 - 1.92 (m, 1H), 1.84 - 1.69 (m, 3H), 1.19 - 1.07 (t, J=7.7 Hz, 3H); ESI-LCMS: m / z = 366.1 [M+H] + ee=96.72%, duration: 0.582 minutes.

[0186] Compound 011: 1 H NMR (400MHz, CDCl3) δ = 8.41 (br s, 1H), 8.17 (br s, 1H), 7.04 - 6.70 (m, 3H), 5.87 (br s, 1H), 5.26 (br s, 1H), 4.59 (br s, 2H), 3.34 ( s, 3H), 2.56 (br s, 2H), 2.20 (br s, 2H), 1.99 (br s, 4H), 1.14 (br s, 3H); ESI-LCMS: m / z = 366.1 [M+H] + ee=99.98%, duration: 2.351 minutes.

[0187] Example 9

[0188] Synthetic road:

change

[0189] ステップ1:Synthesis of compound 012-2 010-1 (2.0 g, 8.77 mmol) and toluene (100 mL) were sequentially added to a reaction flask, and after purging with nitrogen, Lawson's reagent (7.09 g, 17.54 mmol) was added, and the mixture was stirred at 110°C for 16 hours. 50 mL of water and 50 mL of ethyl acetate were added to the reaction solution, and the mixture was extracted, separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation and purification by column chromatography (petroleum ether:ethyl acetate = 4:1) was performed to obtain 012-2. 1 H NMR (400MHz, CDCl3) δ = 9.61 (br s, 1H), 7.19 (s, 1H), 7.13 (dd, J=1.9, 8.4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 4.90 (s, 2H).

[0190] Step 2: Synthesis of Compound 012-4 012-2 (1.0 g, 4.10 mmol), 002-3 (364.17 mg, 4.92 mmol), and cyclohexanol (5 mL) were added sequentially to a reaction flask, and the mixture was stirred at 120°C for 16 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 012-4.

[0191] Step 3: Synthesis of Compound 012-5 In a reaction flask, 012-4 (0.3 g, 1.13 mmol), bis(pinacolate)diborone (429.44 mg, 1.69 mmol), and 1,4-dioxane (10 mL) were added sequentially, the flask was purged with nitrogen gas, and then potassium acetate (171.50 mg, 1.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (46.03 mg, 56.37 μmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 012-5. ESI-LCMS: m / z = 314.1 [M+H] + .

[0192] Step 4: Synthesis of compounds 012 and 013 To the reaction solution, 012-5 (0.1 g, 319.33 μmol), A-1 (90.42 mg, 319.33 μmol), ethanol (5 mL), water (1 mL), and sodium carbonate (33.85 mg, 319.33 μmol) were added sequentially, the mixture was purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (18.45 mg, 15.97 μmol) was added. The mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated, 50 mL of water and 50 mL of dichloromethane were added, and the mixture was extracted, separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified sequentially by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) and chiral separation (column: DAIEL CHIRALPAK IF (250 mm × 30 mm, 10 μm), mobile phase: [A: n-hexane, B: isopropanol / acetonitrile = 4:1], 100% B, isogradient elution) to obtain O12 and O13. The ee value was measured by SFC detection method (column: Chiralpak IF 100 × 4.6 mm, 3 μm, mobile phase: A: n-hexane (0.1% diethylamine), B: isopropanol / acetonitrile = 2:1, gradient elution: A / B = 20 / 8, flow rate: 1 mL / min, column temperature: 35 °C).

[0193] Compound 012:ESI-LCMS: m / z = 390.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ = 8.46 (s, 1H), 8.22 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 2.0, 8.3 Hz, 1H), 5.77 (br d, J = 8.5 Hz, 1H), 5.28 (s, 3H), 2.77 (m, 3H), 2.65 - 2.44 (m, 2H), 2.22 (q, J = 7.7 Hz, 2H), 2.08 - 1.96 (m, 1H), 1.84 - 1.76 (m, 3H), 1.15 (t, J = 7.5 Hz, 3H), ee=99.87%, holding time: 3.245 minutes.

[0194] Compound 013: 1 H NMR (400MHz, CDCl3) δ = 8.48 (s, 1H), 8.24 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.03 - 6.94 (m, 1H), 5.65 (br d, J=8.0 Hz, 1H), 5.29 (s, 3H), 2.77 (s, 3H), 2.68-2.47 (m, 2H), 2.22 (q, J=7.5 Hz, 2H), 2.09-1.89 (m, 1H), 1.85-1.69 (m, 3H), 0.77 (br s, 3H); ESI-LCMS: m / z = 390.1 [M+H] + ee=98.44%, duration: 2.328 minutes.

[0195] Example 10

[0196] Synthetic road:

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[0197] ステップ1:Synthesis of compound 014-2 O14-1 (120.00 mg, 761.64 μmol), N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (196.15 mg, 1.52 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (577.06 mg, 1.52 mmol) were sequentially added to the reaction flask. After stirring at 25°C for 5 minutes, A-1-5 hydrochloride (200 mg) was added, and the mixture was stirred at 25°C for 16 hours. 25 mL of water was added to the reaction solution, and the mixture was transferred to a separatory funnel. 20 mL of ethyl acetate was added, and the mixture was extracted three times. The organic phases were combined, washed with saturated brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain O14-2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1 H), 8.53 (s, 1 H), 8.43 (d, J = 3.26 Hz, 1 H), 8.18 (br s, 1 H), 7.86 (d, J = 8.28 Hz, 1 H), 7.39 (dd, J = 8.16, 4.39 Hz, 1H), 5.40 - 5.48 (m, 1H), 2.72 - 2.92 (m, 2H), 1.95 - 2.17 (m, 4H).

[0198] Step 2: Synthesis of Compound 014 O14-2 (204 mg, 556.40 μmol), O01-3 (317.32 mg, 1112.8 μmol), ethanol (10 mL), sodium carbonate (117.95 mg, 1.11 mmol), and water (2 mL) were sequentially added to the reaction flask. The flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (64.3 mg, 55.64 μmol) was added, and the reaction solution was stirred at 80°C for 20 hours. 40 mL of semi-saturated saline solution was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Extraction was performed three times with ethyl acetate (20 mL each time), the organic phases were combined, washed with 40 mL of saturated saline solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. O14 was obtained by sequential preparative thin-layer chromatography (dichloromethane:methanol = 20:1) and chiral separation (column:DAICEL CHIRALCEL OJ (250mm × 30mm, 10μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 30% ethanol (0.1% aqueous ammonia)) and detected by SFC method (column: Chiralcel OJ-3 50 × 4.6mm ID, 3μm, mobile phase: A: supercritical CO2, B: ethanol (0.05% diethylamine), gradient (B%): 5%~40% (0~2 mins), 40% (hold for 1.2 mins), 5% (hold for 0.8 mins), flow rate: 3 mL / min, column temperature: 35℃, column pressure: 1500 psi), with ee = 100% and retention time: 1.834 mins. ESI-LCMS: m / z = 445.0 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ ppm 8.64 (s, 1 H), 8.44 (dd, J =4.52, 1.26 Hz, 1 H), 8.35 (s, 1 H), 8.21 (br d, J = 8.53 Hz, 1 H), 7.87 (dd, J = 8.16, 1.38 Hz, 1 H), 7.71 (d, J = 9.54 Hz, 1 H), 7.50 - 7.55 (m, 2 H), 7.44 - 7.50 (m, 1 H), 7.40 (dd, J = 8.03, 4.52 Hz, 1 H), 6.79 (d, J = 9.54 Hz, 1 H), 5.49 - 5.56 (m, 1 H), 3.78 (s, 3 H), 2.60 - 2.77 (m, 2 H), 2.16 - 2.25 (m, 1 H), 1.99 - 2.08 (m, 1 H), 1.82 - 1.93 (m, 2 H).

[0199] Example 11

[0200] Synthetic road:

change

[0201] ステップ1:Synthesis of compound 015-2 O15-1 (192.76 mg, 1.37 mmol), N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (514.89 mg, 3.98 mmol), 1-hydroxybenzotriazole (76.90 mg, 569.13 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (109.10 mg, 569.13 μmol) were sequentially added to the reaction flask. The mixture was stirred at 25°C for 5 minutes, and A-1-5 hydrochloride (300 mg) was added. The reaction solution was stirred at 25°C for 16 hours. 25 mL of water was added to the reaction solution, and the solution was transferred to a separatory funnel. 20 mL of ethyl acetate was added and the mixture was extracted three times. The organic phases were combined and washed sequentially with semi-saturated saline and saturated saline (40 mL each time). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain O15-2.

[0202] Step 2: Synthesis of Compound 015 In a reaction flask, 015-2 (124 mg, 354.07 μmol), 001-3 (201.92 mg, 708.15 μmol), ethanol (5 mL), sodium carbonate (112.58 mg, 1.06 mmol), and water (1 mL) were added sequentially. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (40.92 mg, 35.41 μmol) was added. The reaction solution was stirred at 85°C for 16 hours. 20 mL of semi-saturated saline solution was added to the reaction solution, and the solution was transferred to a separatory funnel and extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with 20 mL of saturated saline solution, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Crude products were separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:methanol = 20:1), and 015 was obtained by chiral separation (column: ChiralPak IH, 250 mm × 30 mm, 10 μm, mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 45% ethanol (0.1% aqueous ammonia)). Detection was performed by SFC method (column: Chiralpak AS-3 50 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% diethylamine), gradient (B%): 5%~40% (0~2 mins), 40% (hold for 1.2 mins), 5% (hold for 0.8 mins), flow rate: 3 mL / min, column temperature: 35°C, column pressure: 1500 psi), with ee = 100% and retention time of 2.383 mins. ESI-LCMS: m / z = 429.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ ppm 8.60 (s, 1 H), 8.34 (s, 1 H), 7.69 (d, J = 9.54 Hz, 1 H), 7.42 - 7.56 (m, 3 H), 6.75 (d, J = 9.54 Hz, 1 H), 6.02 (br d, J = 8.28 Hz, 1 H), 5.46 - 5.57 (m, 1 H), 3.76 (s, 3 H), 2.58 - 2.74 (m, 5 H), 2.43 (s, 3 H), 2.15 - 2.25 (m, 1 H), 1.83 - 2.01 (m, 3 H).

[0203] Example 12

[0204] Synthesis pathway: [ka]

[0205] Step 1: Synthesis of Compound 016 In a reaction flask, 009-6 (217 mg, 675.61 μmol), 010-3 (195.34 mg, 675.61 μmol), ethanol (10 mL), sodium carbonate (143.22 mg, 1.35 mmol), and water (2 mL) were added sequentially. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (39.04 mg, 33.78 μmol) was added. The reaction solution was stirred at 80°C for 16 hours. 40 mL of semi-saturated saline solution was added to the reaction solution, and the solution was transferred to a separatory funnel. The organic phases were extracted three times with ethyl acetate (20 mL each time), combined, washed with 40 mL of saturated saline solution, and the organic phases were collected. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1), and 016 was obtained by preparative high-performance liquid chromatography (column: C18 100 × 40 mm, mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile], gradient: rinsed with 7% to 37% acetonitrile). ESI-LCMS: m / z = 404.0 [M+H] + . 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1 H), 8.18 (d, J = 2.26 Hz, 1 H), 7.22 - 7.35 (m, 3 H), 7.13 (d, J = 8.28 Hz, 1 H), 5.11 (quin, J = 5.58 Hz, 1 H), 4.73 (s, 2 H), 4.34 - 4.45 (m, 2 H), 4.22 (dd, J = 9.16, 4.64 Hz, 2 H), 3.47 (s, 3 H), 3.09 (q, J = 7.45 Hz, 2 H), 1.45 (t, J = 7.40 Hz, 3H).

[0206] Example 13

[0207] Synthesis pathway: [ka]

[0208] Step 1: Synthesis of Compound 017-3 Palladium acetate (480.24 mg, 2.14 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (2.04 g, 4.28 mmol), and N,N-dimethylformamide (89 mL) were added sequentially to the reaction flask. After purging with nitrogen gas, 017-1 (8.9 g, 42.78 mmol), triethylamine (34.63 g, 342.25 mmol, 47.64 mL), and 017-2 (41.63 g, 256.69 mmol) were added, and the flask was again purged with nitrogen gas. The reaction solution was stirred at 80°C for 12 hours. 10 mL of water was added to the reaction solution, the reaction solution was transferred to a separatory funnel, 20 mL of ethyl acetate was added, and the solution was extracted and separated. The aqueous phase was extracted three times with ethyl acetate, each time yielding 30 mL. The organic phase was combined with the aqueous phase and washed twice with saline solution, each time yielding 30 mL. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain O17-3. 1H NMR (400 MHz, CDCl3) δ = 8.49 (d, J = 16.1 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.46 - 7.34 (m, 5H), 7.29 (d, J = 5.7 Hz, 1H), 6.52 (d, J = 16.1 Hz, 1H), 5.29 (s, 2H).

[0209] Step 2: Synthesis of Compound 017-4 In a reaction flask, 017-3 (5g, 17.28 mmol), methanol (175 mL), ammonium chloride (1.02 g, 19.01 mmol), and water (50 mL) were added sequentially. The flask was then purged with nitrogen gas, and iron powder (4.83 g, 86.41 mmol) was slowly added. The reaction solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the reaction solution was transferred to a separatory funnel. 100 mL of dichloromethane was added, and the mixture was extracted and separated. The organic phase was collected, and the aqueous phase was extracted three times with dichloromethane (100 mL each time). The organic phases were combined and washed twice with saturated brine (100 mL each time). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 017-4, which was used directly in the next step without further purification. ESI-LCMS: m / z = 260.1 [M+H] + .

[0210] Step 3: Synthesis of Compound 017-5 017-4 (4g, 15.42 mmol), tributylphosphine (9.36g, 46.27 mmol), and methanol (70 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 70°C for 2 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 017-5. 1H NMR (400 MHz, CDCl3) δ = 7.88 (d, J = 9.3 Hz, 1H), 7.11 - 7.08 (m, 1H), 7.07 - 7.04 (m, 1H), 6.68 (d, J = 9.3 Hz, 1H). ESI-LCMS: m / z = 152.1 [M+H] + .

[0211] Step 4: Synthesis of Compound 017-6 In a reaction flask, 017-5 (1 g, 6.61 mmol), N,N-dimethylformamide (20 mL), cesium carbonate (2.59 g, 7.94 mmol), and methyl iodide (3.76 g, 26.46 mmol) were added sequentially, the flask was purged with nitrogen gas, and the reaction solution was stirred at 25°C for 2 hours. Water (30 mL) was added to the reaction solution, the solution was transferred to a separatory funnel, ethyl acetate (30 mL) was added, and the mixture was extracted and separated. The organic phase was collected, and the aqueous phase was extracted three times with ethyl acetate (30 mL each time). The organic phases were combined and washed twice with saturated brine (30 mL each time), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 017-6. 1 H NMR (400 MHz, CD3OD) δ = 7.91 (d, J = 9.3 Hz, 1H), 7.22 (q, J = 5.6 Hz, 2H), 6.53 (d, J = 9.3 Hz, 1H), 3.72 (s, 3H).

[0212] Step 5: Synthesis of Compound 017-7 017-6 (30 mg, 181.58 μmol) and tetrahydrofuran (0.5 mL) were sequentially added to a reaction flask, the flask was purged three times with nitrogen gas, and the mixture was cooled to -78°C. Lithium tri(sec-butyl)borohydride (1 M tetrahydrofuran solution, 297.80 μL) was added dropwise, and the reaction solution was stirred at -78°C for 1 hour, then slowly raised to 25°C and stirred for 12 hours. Water (1 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. 1 mL of dichloromethane was added, and the mixture was extracted and separated. The aqueous phase was extracted three times with dichloromethane (1 mL each time). The organic phases were combined and washed twice with saturated brine (1 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 017-7. 1 H NMR (400 MHz, CDCl3) δ = 6.80 - 6.77 (m, 1H), 6.76 - 6.73 (m, 1H), 3.32 (d, J = 2.3 Hz, 3H), 2.87 - 2.81 (m, 2H), 2.75 - 2.67 (m, 2H).

[0213] Step 6: Synthesis of Compound 017-8 017-7 (10 mg, 59.80 μmol) and dichloromethane (0.2 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, the reaction temperature was cooled to 0°C, N-bromosuccinimide (11.71 mg, 65.78 μmol) was added, and the reaction solution was stirred at 0°C for 0.5 hours. Water (1 mL) was added to the reaction solution, the solution was transferred to a separatory funnel, 1 mL of dichloromethane was added, and the mixture was extracted and separated to collect the organic phase. The aqueous phase was extracted three times with dichloromethane (1 mL each time). The organic phases were combined and washed twice with saturated brine (1 mL each time), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 017-8. 1H NMR (400 MHz, CDCl3) δ = 6.73 (s, 1H), 3.25 (s, 3H), 2.83 - 2.75 (m, 2H), 2.70 (d, J = 7.6 Hz, 2H).

[0214] Step 7: Synthesis of Compound 017 In a reaction flask, sequentially add 017-8 (20 mg, 81.26 μmol), potassium carbonate (44.92 mg, 325.04 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.00 mg, 12.19 μmol), water (0.4 mL), acetonitrile (1.2 mL), and methanol (0.4 mL), then purge with nitrogen gas and add bis(triphenylphosphine)palladium(II) dimethyl Lorid (2.85 mg, 4.06 μmol) and palladium acetate (912.17 μg, 4.06 μmol) were added, the mixture was purged with nitrogen gas, and the reaction solution was heated to 40°C. A solution of crude product A-2 (prepared according to the synthesis method in Reference Example 2, used immediately after preparation, added to the preparation according to the theoretical yield, which is 40.32 mg, 162.52 μmol) was added dropwise. After the addition was complete, the reaction solution was heated to 75°C and stirred for 12 hours. The reaction solution was filtered through diatomaceous earth and anhydrous sodium sulfate, the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (eluent:ethyl acetate:dichloromethane:methanol = 3:1:0.3) to obtain O17. 1H NMR (400 MHz, CDCl3) δ = 8.59 - 8.52 (m, 1H), 8.48 - 8.42 (m, 1H), 6.89 (s, 1H), 6.40 - 6.22 (m, 1H), 5.37 - 5.21 (m, 1H), 3.35 (s, 3H), 3.10 - 2.99 (m, 2H), 2.90 (br d, J = 8.0 Hz, 2H), 2.79 (br d, J = 7.8 Hz, 2H), 2.34 (br d, J = 7.4 Hz, 2H), 2.18 (br d, J = 2.9 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.23 - 1.20 (m, 3H); ESI-LCMS: m / z = 370.2 [M+H] + The substance was detected by SFC analysis (Method: Column: (S,S)-WHELK-O1, 100 × 4.6 mm ID, 3.5 μm, Mobile phase: A: CO2, B: Ethanol [Methanol solution of 0.2% 7 M ammonia], Isograin: A / B = 40 / 60, Flow rate: 4 mL / min, Column temperature: 35 °C, Pressure: 2000 psi), with ee = 94.22% and retention time of 2.467 minutes.

[0215] Example 14

[0216] Synthesis pathway: [ka]

[0217] Step 1: Synthesis of Compound 018-3 018-1 (10 g, 52.63 mmol), dichloromethane (200 mL), and pyridine (5.00 g, 63.15 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and 018-2 (7.79 g, 57.89 mmol) was added. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated to obtain the crude product, which was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 018-3. 1H NMR (400 MHz, CDCl3) δ = 8.30 (t, J = 8.7 Hz, 1H), 7.66 (d, J = 12.0 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.10 (br s, 1H), 5.34 (d, J = 12.1 Hz, 1H), 3.97 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[0218] Step 2: Synthesis of Compound 018-4 5 mL of 98% concentrated sulfuric acid was added to the reaction flask, then 500 mg (1.74 mmol) of 018-3 was added, the mixture was purged with nitrogen gas, and the reaction solution was stirred at 25°C for 3 hours. The temperature of the reaction solution was then raised to 80°C and stirred for 1 hour. The reaction solution was poured into ice water, filtered, the cake was washed with water, and dried under reduced pressure to obtain the crude product 018-4. This was used directly in the next step of the reaction without separation or purification.

[0219] Step 3: Synthesis of Compound 018-5 018-4 (0.2 g, 826.30 μmol), N,N-dimethylformamide (0.5 mL), and cesium carbonate (538.45 mg, 1.65 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, the reaction solution was allowed to stand at 0°C, methyl iodide (469.13 mg, 3.31 mmol) was slowly added dropwise, the flask was purged with nitrogen gas, and the mixture was stirred at 25°C for 2 hours. 2 mL of water was added to the reaction solution, the solution was transferred to a separatory funnel, extracted three times with ethyl acetate (3 mL each time), the organic phases were combined, washed three times with saturated brine (3 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 018-5. 1 H NMR (400 MHz, CDCl3) δ = 7.55 (d, J = 9.5 Hz, 1H), 7.50 - 7.37 (m, 2H), 6.76 (d, J = 9.5 Hz, 1H), 3.90 (d, J = 8.4 Hz, 3H).

[0220] Step 4: Synthesis of Compound 018-6 In a reaction flask, 018-5 (100 mg, 390.52 μmol), dioxane (2 mL), bis(pinacolate)diborone (148.75 mg, 585.78 μmol), potassium acetate (114.98 mg, 1.17 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (15.95 mg, 19.53 μmol) were added sequentially. The flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was filtered, washed with ethyl acetate, and the filtrate was collected and concentrated to obtain crude product 018-6, which was used directly in the next step without purification. ESI-LCMS: m / z = 304.2 [M+H] + .

[0221] Step 5: Synthesis of Compound 018 In a reaction flask, A-1 (0.05 g, 176.58 μmol), potassium carbonate (97.62 mg, 706.31 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (10.87 mg, 26.49 μmol), bis(triphenylphosphine)palladium(II) dichloride (6.20 mg, 8.83 μmol), palladium acetate (1.98 mg, 8.83 μmol), water (1.2 mL), acetonitrile (3.6 mL), and methanol (1.2 mL) were added sequentially. The flask was then purged with nitrogen gas, and a solution of 018-6 (107.05 mg, 353.15 μmol) in tetrahydrofuran (1.2 mL) was added dropwise to the reaction solution at 40°C. The reaction solution was then heated to 75°C and stirred for 2 hours. The reaction solution was allowed to return to room temperature, 20 mL of water was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. The organic phase was extracted three times with dichloromethane (30 mL each time), the organic phase was combined, and the mixture was washed three times with saturated brine (30 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.1) and SFC chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical CO2-methanol (0.1% aqueous ammonia)], isogradient elution: 45% methanol (0.1% aqueous ammonia)) to obtain O18. 1H NMR (400 MHz, CD3OD) δ = 8.41 (s, 1H), 8.26 (s, 1H), 7.95 (dd, J = 1.5, 9.5 Hz, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.46 (dd, J = 1.9, 15.3 Hz, 1H), 6.76 (d, J = 9.4 Hz, 1H), 5.22 (t, J = 5.7 Hz, 1H), 3.96 (d, J = 8.0 Hz, 3H), 2.83 - 2.63 (m, 2H), 2.29 (dq, J = 1.9, 7.6 Hz, 2H), 2.13 - 2.00 (m, 1H), 1.94 - 1.72 (m, 3H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 380.2 [M+H] + The substance was detected by SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: methanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, column pressure: 1800 psi), with ee = 100% and retention time of 1.504 minutes.

[0222] Example 15

[0223] Synthesis pathway: [ka]

[0224] Step 1: Synthesis of Compound 019-2 Add 019-1 (0.96 g, 5.81 mmol) and N,N-dimethylformamide (10 mL) to a reaction flask, purge with nitrogen gas, and cool the reaction solution to 0°C. Add N-bromosuccinimide (1.24 g, 6.97 mmol), and after the addition is complete, stir the reaction solution at 25°C for 8 hours. Add water (20 mL) and saturated sodium thiosulfate aqueous solution (2 mL) sequentially to the reaction solution, stir for 10 minutes, filter, collect the cake, add dichloromethane (20 mL), transfer to a separatory funnel, wash with saturated brine (20 mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate to obtain crude product 019-2, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 8.32 (br s, 1 H), 7.34 (d, J=7.03 Hz, 1 H), 6.61 (d, J = 8.94 Hz, 1 H), 2.95 (t, J = 7.57 Hz, 2 H), 2.59 - 2.69 (m, 2 H).

[0225] Step 2: Synthesis of Compound 019-3 019-2 (1.3g, 5.33 mmol), N,N-dimethylformamide (13 mL), and cesium carbonate (3.47 g, 10.65 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (2.27 g, 15.98 mmol) was added dropwise, and the reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. It was extracted three times with ethyl acetate (20 mL each time), the organic phases were combined, washed twice with saturated brine (20 mL each time), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 019-3. This product was not further purified and was used directly in the next step of the reaction.

[0226] Step 3: Synthesis of Compound 019-4 019-3 (1.3g, 5.04 mmol), dichloroethane (26 mL), N-bromosuccinimide (1.34 g, 7.56 mmol), and 2,2'-azobis(isobutyronitrile) (165.42 mg, 1.01 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 2 hours. Water (30 mL) was added to the reaction solution, the solution was transferred to a separatory funnel, ethyl acetate (30 mL x 2) was added for extraction and separation, the organic phases were combined, washed with saturated brine (30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 30:1~3:1) to obtain 019-4. 1 H NMR (400 MHz, CDCl3) δ ppm 7.76 (d, J=7.25 Hz, 1 H), 7.58 (d, J=9.51 Hz, 1 H), 7.13 (d, J=10.38 Hz, 1 H), 6.69 (d, J=9.51 Hz, 1 H), 3.67 (s, 3 H).

[0227] Step 4: Synthesis of Compound 019-5 019-4 (500 mg, 1.95 mmol), 1,4-dioxane (20 mL), bis(pinacolate)diborone (743.75 mg, 2.93 mmol), potassium acetate (574.88 mg, 5.86 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (82.64 mg, 97.63 μmol) were added sequentially to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was filtered through diatomaceous earth, the cake was rinsed with ethyl acetate:methanol = 10:1 (10 mL), the filtrate was collected and concentrated to obtain crude product 019-5, which was used directly in the next step of the reaction without further purification.

[0228] Step 5: Synthesis of Compound 019 In a reaction flask, A-1 (100 mg, 353.15 μmol), water (1.2 mL), acetonitrile (3.6 mL), methanol (1.2 mL), potassium carbonate (195.23 mg, 1.41 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (21.75 mg, 52.97 μmol) were added sequentially, and the flask was purged with nitrogen gas. Bis(triphenylphosphine)palladium(II) dichloride (12.39 mg, 17.66 μmol) and palladium acetate (3.96 mg, 17.66 μmol) were added, and the flask was purged with nitrogen gas. The reaction solution was brought to 40°C, and a solution of crude product 019-5 (156.09 mg, 706.31 μmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction solution was stirred at 75°C for 2 hours. The reaction solution was allowed to return to room temperature, anhydrous sodium sulfate (5g) was added to the reaction solution, filtered through diatomaceous earth, the cake was rinsed with ethyl acetate (10mL), the filtrate was collected and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.1) and SFC chiral separation (column:DAICEL CHIRALPAK AD (250mm × 30mm, 10μm), mobile phase: [supercritical carbon dioxide - methanol (0.1% aqueous ammonia)], isogradient elution: 50% methanol (0.1% aqueous ammonia)) to obtain O19. 1 H NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1 H), 8.25 (s, 1 H), 7.95 (d, J = 9.51 Hz, 1 H), 7.69 (d, J = 7.88 Hz, 1 H), 7.52 (d, J = 11.88 Hz, 1 H), 6.69 (d, J = 9.38 Hz, 1 H), 5.24 (t, J = 5.75 Hz, 1 H), 3.76 (s, 3 H), 2.54 - 2.70 (m, 2 H), 2.29 (qd, J = 7.61, 2.19 Hz, 2 H), 2.01 - 2.10 (m, 1 H), 1.78 - 1.95 (m, 3 H), 1.20 (t, J=7.63 Hz, 3 H); ESI-LCMS: m / z = 380.2 [M+H] +SFC analysis (column: Chiralpak AD-3, 150 × 4.6 mm ID, 3 μm, mobile phase: A: supercritical carbon dioxide, B: methanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 50 / 50, flow rate: 2.5 mL / min, column temperature: 35 °C, pressure: 2000 psi) detected ee = 100% and retention time was 1.797 minutes.

[0229] Example 16

[0230] Synthesis pathway: [ka]

[0231] Step 1: Synthesis of Compound 020-2 To the reaction solution, A-1-1 (0.2 g, 880.67 μmol), dichloromethane (10 mL), and N,N-diisopropylethylamine (682.92 mg, 5.28 mmol) were added sequentially, the mixture was purged with nitrogen gas, and 020-1 (140.53 mg, 880.67 μmol) was added. The reaction solution was stirred at 25°C for 1 hour. Water (10 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. Dichloromethane was added and extracted twice (10 mL each time), separated, and the organic phases were combined. The mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 020-2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.41 - 8.71 (m, 2 H), 5.97 (br d, J=6.31 Hz, 1 H), 5.39 - 5.53 (m, 1 H), 2.80 - 2.86 (m, 2 H), 2.63 (s, 3 H), 2.42 (s, 3H), 2.12 - 2.18 (m, 1H), 1.90 - 1.96 (m, 3H).

[0232] Step 2: Synthesis of Compound 020 Compound 020-2 (50 mg, 142.77 μmol), water (0.6 mL), acetonitrile (1.8 mL), methanol (0.6 mL), potassium carbonate (78.93 mg, 571.09 μmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (8.79 mg, 21.42 μmol) were added to a reaction flask, and the flask was purged with nitrogen gas. Bis(triphenylphosphine)palladium(II) dichloride (5.01 mg, 7.14 μmol) and palladium acetate (1.60 mg, 7.14 μmol) were added, and the flask was purged with nitrogen gas. To the reaction solution, a solution of 019-5 (63.10 mg, 285.54 μmol) in tetrahydrofuran (1 mL) was added dropwise at 40°C, and the reaction solution was heated to 75°C and stirred for 2 hours. The reaction solution was allowed to return to room temperature, anhydrous sodium sulfate (5g) was added to the reaction solution, filtered through diatomaceous earth, the cake was rinsed with ethyl acetate (10mL), the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 1:1) and SFC chiral separation (column: DAIEL CHIRALPAK AD (250mm × 30mm, 10μm), mobile phase: [supercritical carbon dioxide - methanol (0.1% aqueous ammonia)], isogradient elution: 50% methanol (0.1% aqueous ammonia)) to obtain O20. 1 H NMR (400 MHz, CD3OD) δ ppm 8.58 (s, 1 H), 8.29 (s, 1 H), 7.95 (d, J = 9.51 Hz, 1 H), 7.70 (d, J = 7.88 Hz, 1 H), 7.53 (d, J = 11.88 Hz, 1 H), 6.69 (d, J = 9.51 Hz, 1 H), 5.43 (t, J = 6.50 Hz, 1 H), 3.76 (s, 3 H), 2.60 - 2.72 (m, 2 H), 2.54 (s, 3 H), 2.38 (s, 3 H), 2.12 - 2.23 (m, 1 H), 1.85 - 2.02 (m, 3 H); ESI-LCMS: m / z = 447.3 [M+H] +SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: methanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100%, and retention time was 1.566 minutes.

[0233] Example 17

[0234] Synthesis pathway: [ka]

[0235] Step 1: Synthesis of Compound 021-2 In a reaction flask, 021-1 (0.3 g, 1.03 mmol), potassium carbonate (283.93 mg, 2.05 mmol), and N,N-dimethylformamide (6 mL) were added sequentially, the flask was purged with nitrogen gas, the reaction solution was cooled to 0°C, methyl iodide (583.21 mg, 4.11 mmol) was added, and the reaction solution was heated to 25°C and stirred for 3 hours. Water (30 mL) was added to the reaction solution, and ethyl acetate was added to the reaction solution three times (10 mL each time) for extraction. The organic phases were combined, washed with saturated brine (20 mL), and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 021-2. 1 H NMR (400 MHz, CDCl3) δ = 7.97 (s, 1H), 7.76 (dd, J = 1.8, 9.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.14 (s, 1H), 3.74 (s, 3H).

[0236] Step 2: Synthesis of Compound 021-3 In a reaction flask, 021-2 (100 mg, 326.71 μmol), bis(pinacolate)diborone (124.45 mg, 490.07 μmol), potassium acetate (96.19 mg, 980.14 μmol), and 1,4-dioxane (2 mL) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (26.68 mg, 32.67 μmol) was added. The reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated to obtain crude product 021-3, which was used directly in the next step without further purification.

[0237] Step 3: Synthesis of Compound 021 Crude product 021-3 (109.75 mg, 310.77 μmol), A-1 (80 mg, 282.52 μmol), sodium carbonate (59.89 mg, 565.04 μmol), water (0.3 mL), and ethanol (1.8 mL) were added sequentially to a reaction flask, the flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (32.65 mg, 28.25 μmol) was added, and the reaction solution was stirred at 85°C for 2.5 hours. The reaction solution was concentrated to obtain the crude product, which was then separated and purified to obtain O21 by sequential preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 5:5:1) and SFC chiral separation (column:DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradient elution: 30% isopropanol (0.1% aqueous ammonia)). 1H NMR (400 MHz, CD3OD) δ = 8.42 (s, 1H), 8.25 (s, 1H), 7.89 - 7.82 (m, 1H), 7.80 - 7.73 (m, 2H), 7.17 (s, 1H), 5.24 (t, J = 5.9 Hz, 1H), 3.84 (s, 3H), 2.78 - 2.60 (m, 2H), 2.28 (dq, J = 2.0, 7.6 Hz, 2H), 2.12 - 2.00 (m, 1H), 1.95 - 1.76 (m, 3H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 430.2 [M+H] + SFC analysis (column: Chiralpak AD-3, 150 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: isopropanol [0.2% 7M ammonia methanol solution], gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.5 min), 50 / 50 (3.5 min), 50 / 50 (4.5 min), 90 / 10 (5.0 min), flow rate: 2.5 mL / min, column temperature: 35 °C, pressure: 2000 psi) detected ee = 100%, retention time was 3.591 minutes.

[0238] Example 18

[0239] Synthesis pathway: [ka]

[0240] Step 1: Synthesis of Compound 022-2 022-1 (0.4 g, 1.78 mmol), N,N-dimethylformamide (8 mL), and cesium carbonate (694.95 mg, 2.13 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (1.01 g, 7.11 mmol) was added dropwise, and the reaction solution was stirred at 0°C for 1 hour. Water (10 mL) was added to the reaction solution, the reaction solution was transferred to a separatory funnel, 10 mL of ethyl acetate was added, and the mixture was extracted and separated. The organic phase was collected, the aqueous phase was extracted three times with ethyl acetate (15 mL each time), the organic phases were combined, and the mixture was washed twice with saturated brine (10 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 022-2, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 8.63 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 6.81 (d, J = 9.5 Hz, 1H), 3.81 (s, 3H).

[0241] Step 2: Synthesis of Compound 022-3 Crude product 022-2 (0.32 g, 1.34 mmol), 1,4-dioxane (12.8 mL), bis(pinacolate)diborone (509.85 mg, 2.01 mmol), potassium acetate (394.09 mg, 4.02 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (56.65 mg, 66.93 μmol) were added sequentially to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was filtered, the cake was rinsed with ethyl acetate, the filtrate was collected and concentrated to obtain crude product 022-3, which was used directly in the next step of the reaction without further purification. ESI-LCMS: m / z = 205.1 [M+H] + .

[0242] Step 3: Synthesis of Compound 022 Add A-1 (0.14 g, 494.41 μmol), water (1.6 mL), acetonitrile (4.8 mL), methanol (1.6 mL), potassium carbonate (273.33 mg, 1.98 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (30.45 mg, 74.16 μmol) to a reaction flask, purge with nitrogen gas, add bis(triphenylphosphine)palladium(II) dichloride (17.35 mg, 24.72 μmol) and palladium acetate (5.55 mg, 24.72 μmol), purge with nitrogen gas, raise the temperature of the reaction solution to 40°C, add 022-3 (201.71 mg, 988.83 μmol) in tetrahydrofuran (2.8 mL) solution, raise the temperature of the reaction solution to 75°C, and stir for 12 hours. The reaction solution was allowed to return to room temperature, anhydrous sodium sulfate was added, and the mixture was filtered. The filtrate was collected and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 1:1:0.1) and SFC chiral separation (column:DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide-isopropanol], isogradation: 55% isopropanol) to obtain O22. 1 H NMR (400 MHz, CDCl3) δ = 8.61 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 9.5 Hz, 1H), 6.85 (d, J = 9.4 Hz, 1H), 5.83 (br d, J = 8.5 Hz, 1H), 5.44 - 5.31 (m, 1H), 3.89 (s, 3H), 2.76 - 2.60 (m, 2H), 2.31 (q, J = 7.5 Hz, 2H), 2.17 - 2.09 (m, 1H), 1.93 (br s, 6H), 1.24 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z =363.2 [M+H] +SFC analysis (column: Chiralpak IG-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: isopropanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100%, retention time was 2.145 minutes.

[0243] Example 19

[0244] Synthesis pathway: [ka]

[0245] Step 1: Synthesis of Compound 023-1 017-6 (75 mg, 410.36 μmol) and tetrahydrofuran (3 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, and the reaction solution was cooled to 0°C. N-bromosuccinimide (58.43 mg, 328.29 μmol) was added, and the reaction solution was stirred at 0°C for 0.5 hours. Semi-saturated sodium thiosulfate aqueous solution (3 mL) was added to the reaction solution, and the mixture was stirred at 25°C for 5 minutes. The reaction solution was transferred to a separatory funnel, and ethyl acetate was added and extracted three times (3 mL each time). The organic phases were combined, washed with saturated brine (3 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 023-1. 1 H NMR (400 MHz, CDCl3) δ = 7.58 (d, J = 9.4 Hz, 1H), 7.10 (s, 1H), 6.55 (d, J = 9.4 Hz, 1H), 3.64 (s, 3H).

[0246] Step 2: Synthesis of Compound 023 Add 023-1 (70 mg, 286.76 μmol), potassium carbonate (158.53 mg, 1.15 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17.66 mg, 43.01 μmol), water (1.4 mL), acetonitrile (4.2 mL), and methanol (0.4 mL) sequentially to the reaction flask, purge with nitrogen gas, and bis(triphenylphosphine)palladium(II) Dichloride (10.06 mg, 14.34 μmol) and palladium acetate (3.22 mg, 14.34 μmol) were added, the mixture was purged with nitrogen gas, and the reaction solution was brought to 40°C. A solution of crude product A-2 (prepared according to the synthesis method in Reference Example 2, used immediately after preparation, added to the preparation according to the theoretical yield, which is 142.28 mg, 573.52 μmol) was added, and the reaction solution was heated to 75°C and stirred for 12 hours. The reaction solution was filtered through diatomaceous earth and anhydrous sodium sulfate, the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified to obtain O23 by sequential preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 3:1:0.3) and SFC chiral separation (column:DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradation elution: 50% ethanol (0.1% aqueous ammonia)). 1 H NMR (400 MHz, CDCl3) δ = 8.58 - 8.37 (m, 2H), 7.69 (d, J = 9.4 Hz, 1H), 7.05 (s, 1H), 6.61 (d, J = 9.4 Hz, 1H), 5.81 (br d, J = 8.4 Hz, 1H), 5.35 (br d, J = 7.8 Hz, 1H), 3.71 (s, 3H), 2.95 - 2.78 (m, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.10 (br dd, J = 5.5, 8.6 Hz, 1H), 1.88 (br dd, J = 3.6, 5.8 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 368.2 [M+H] +SFC analysis (column: Chiralpak IG-3 100×4.6mm ID, 3μm, mobile phase: A: supercritical carbon dioxide, B: ethanol [methanol solution of 0.2% 7M ammonia], gradient: A / B=60 / 40, flow rate: 4mL / min, column temperature: 35℃, pressure: 1800psi) detected ee=100% and retention time was 2.762 minutes.

[0247] Example 20

[0248] Synthesis pathway: [ka]

[0249] Step 1: Synthesis of Compound 024-2 024-1 (500 mg, 2.51 mmol) and hydrogen chloride / ethyl acetate (4 M, 7.50 mL) were added sequentially to the reaction flask, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain the hydrochloride salt of 024-2, which was used directly in the next step of the reaction without further purification. 1 H NMR (400 MHz, CDCl3) δ = 3.62 - 3.50 (m, 4H), 2.89 (t, J = 6.4 Hz, 4H).

[0250] Step 2: Synthesis of Compound 024-3 260 mg of O24-2 hydrochloride and 2.6 mL of dichloromethane were sequentially added to a reaction flask, and the reaction solution was cooled to 0°C. N,N-diisopropylethylamine (1.02 g, 7.87 mmol) and propionyl chloride (364.01 mg, 3.93 mmol) were added, and the reaction solution was stirred at 0°C for 1 hour. 2 mL of water was added to the reaction solution, and the solution was transferred to a separatory funnel. The organic phases were extracted three times with ethyl acetate (2 mL each time), the organic phases were combined, washed with saturated brine (2 mL), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 6:1) to obtain O24-3. 1H NMR (400 MHz, CDCl3) δ = 3.99 - 3.66 (m, 4H), 2.56 - 2.33 (m, 6H), 1.21 (t, J = 7.4 Hz, 3H).

[0251] Step 3: Synthesis of Compound 024-4 In a reaction flask, A-1-5 hydrochloride (140 mg), triethylamine (161.25 mg, 1.59 mmol), and methanol (1.4 mL) were added sequentially. The reaction solution was stirred at 25°C, then O24-3 (123.66 mg, 796.78 μmol) and acetic acid (76.56 mg, 1.27 mmol) were added. After 10 minutes, sodium borohydride cyanohydride (100.14 mg, 1.59 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The pH of the reaction solution was adjusted to 8-9 by adding saturated sodium bicarbonate solution. The reaction solution was transferred to a separatory funnel, and ethyl acetate was added and extracted three times (2 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 1:0 to 15:1) to obtain O24-4. 1 H NMR (400 MHz, CDCl3) δ = 8.53 (br s, 2H), 4.59 - 4.36 (m, 1H), 4.18 - 4.03 (m, 1H), 3.75 (br d, J = 16.9 Hz, 1H), 3.60 - 3.41 (m, 1H), 3.27 - 3.15 (m, 1H), 2.98 (br s, 1H), 2.85 (br d, J = 14.3 Hz, 1H), 2.69 - 2.58 (m, 1H), 2.39 - 2.36 (m, 2H), 2.17 - 1.94 (m, 4H), 1.87 (br d, J = 4.4 Hz, 3H), 1.60 (br s, 2H), 1.18 - 1.15 (m, 3H).

[0252] Step 4: Synthesis of Compound 024 In a reaction flask, 024-4 (60 mg, 163.80 μmol), water (0.2 mL), acetonitrile (0.6 mL), methanol (0.2 mL), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (10.09 mg, 24.57 μmol), and potassium carbonate (90.56 mg, 655.21 μmol) were added sequentially, and the flask was purged with nitrogen gas. Bis(triphenylphosphine)palladium(II) dichloride (5.75 mg, 8.19 μmol) and palladium acetate (1.84 mg, 8.19 μmol) were added, and the flask was purged with nitrogen gas. The reaction solution was brought to 40°C, and 001-3 (56.05 mg, 196.56 μmol) in tetrahydrofuran (1.2 mL) solution was added. The reaction solution was heated to 75°C and stirred for 12 hours. The reaction solution was concentrated to obtain the crude product. O24 was obtained by sequentially eluting the crude product using preparative thin-layer chromatography (petroleum ether:ethyl acetate:methanol = 1:1:0.1), preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: 15%~55% acetonitrile), and SFC chiral separation (column: ChiralPak IH, 250×30mm, 10μm, mobile phase: [supercritical carbon dioxide-methanol (0.1% aqueous ammonia)], isogradient elution: 50% methanol (0.1% aqueous ammonia)). 1H NMR (400 MHz, CDCl3) δ = 8.62 (br s, 1H), 8.30 (s, 1H), 7.69 (br d, J = 9.5 Hz, 1H), 7.55 - 7.41 (m, 3H), 6.78 (br d, J = 9.5 Hz, 1H), 4.56 - 4.34 (m, 1H), 4.05 (br d, J = 13.0 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.16 (br t, J = 11.6 Hz, 1H), 3.06 - 2.97 (m, 1H), 2.96 - 2.85 (m, 1H), 2.76 - 2.63 (m, 1H), 2.61 - 2.50 (m, 1H), 2.44 - 2.33 (m, 2H), 2.05 (br s, 1H), 1.90 (br s, 4H), 1.79 - 1.30 (m, 7H), 1.17 (br t, J = 6.6 Hz, 3H); ESI-LCMS: m / z = 445.3 [M+H] + SFC analysis (column: Chiralpak IH-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: methanol (methanol solution of 0.2% 7 M ammonia), gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, column pressure: 1800 psi) detected ee = 100%, retention time was 2.051 minutes.

[0253] Example 21

[0254] Synthesis pathway: [ka]

[0255] Step 1: Synthesis of Compound 025-1 Tetrahydrofuran (2 mL) and trimethylsulfoxonium iodide (554.62 mg, 2.52 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. 2.5 M n-hexane solution of n-butyllithium (940.86 μL) was added, and the reaction solution was stirred at 0°C for 0.5 hours. 1 mL of tetrahydrofuran solution of 001-2 (200 mg, 840.05 μmol) was added dropwise, and the reaction solution was heated to 25°C and stirred for 15.5 hours. Water (2 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Ethyl acetate was added and extracted twice (2 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 025-1. 1 H NMR (400 MHz, CDCl3) δ = 7.49 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 2.4, 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 3.31 (s, 3H), 2.49 (dt, J = 5.2, 8.0 Hz, 1H), 2.32 (ddd, J = 4.8, 7.6, 9.5 Hz, 1H), 1.65 - 1.61 (m, 1H), 0.64 (q, J = 4.8 Hz, 1H).

[0256] Step 2: Synthesis of 025-2 In a reaction flask, 025-1 (140 mg, 555.32 μmol), 1,4-dioxane (2.8 mL), bis(pinacolate)diborone (211.53 mg, 832.98 μmol), potassium acetate (163.50 mg, 1.67 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (22.67 mg, 27.77 μmol) were added, the flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was allowed to return to room temperature, 4 mL of water was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Extraction was performed three times with ethyl acetate (3 mL each time), the organic phases were combined, washed three times with saturated brine (3 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain O25-2. 1 H NMR (400 MHz, CDCl3) δ = 7.81 (d, J = 1.3 Hz, 1H), 7.67 (dd, J = 1.4, 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 3.34 (s, 3H), 2.56 (dt, J = 5.2, 8.0 Hz, 1H), 2.38 - 2.26 (m, 2H), 1.58 - 1.53 (m, 1H), 1.36 (s, 12H).

[0257] Step 3: Synthesis of 025 and 026 In a reaction flask, A-1 (75 mg, 264.86 μmol), water (1.2 mL), acetonitrile (3.6 mL), methanol (1.2 mL), potassium carbonate (146.43 mg, 1.06 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (16.31 mg, 39.73 μmol) were added sequentially, the flask was purged with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (9.30 mg, 13.24 μmol) and palladium acetate (2.97 mg, 13.24 μmol) were added, the flask was purged with nitrogen gas, the reaction solution was heated to 40°C, and 025-2 (95.09 mg, 317.84 μmol) in tetrahydrofuran (1.2 mL) solution was added. The reaction solution was heated to 75°C and stirred for 2 hours. The reaction solution was allowed to return to room temperature, 2 mL of water was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. The organic phase was extracted three times with dichloromethane (3 mL each time), the organic phase was combined, and the mixture was washed three times with saturated brine (3 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.3) and chiral separation (column: ChiralPak IH, 250 mm × 30 mm, 10 μm, mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 35% ethanol (0.1% aqueous ammonia)) to obtain O25 and O26. The ee value was measured by detection using SFC analysis (column: Chiralpak IH-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: supercritical CO2, B: ethanol (methanol solution of 0.2% 7 M ammonia), gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.2 min), 50 / 50 (2.4 min), 50 / 50 (3.4 min), 90 / 10 (4.0 min), flow rate: 3.4 mL / min, column temperature: 35°C, pressure: 2000 psi).

[0258] Compound 025: 1H NMR (400 MHz, CD3OD) δ ppm 8.35 (s, 1 H) 8.20 (s, 1 H) 7.40 (d, J = 1.43 Hz, 1 H) 7.18 - 7.25 (m, 2 H) 5.22 (t, J = 5.84 Hz, 1 H) 3.37 (s, 3 H) 2.62 - 2.82 (m, 3 H) 2.22 - 2.37 (m, 3 H) 1.99 - 2.08 (m, 1 H) 1.76 - 1.92 (m, 3 H) 1.69 (td, J = 9.00, 4.29 Hz, 1 H) 1.19 (t, J = 7.63 Hz, 3 H) 0.62 (q, J = 4.65 Hz, 1 H); ESI-LCMS: m / z = 376.2 [M+H] + ee=99.90%, duration: 2.458 minutes.

[0259] Compound 026: 1 H NMR (400 MHz, CD3OD) δ ppm 8.35 (s, 1 H) 8.20 (s, 1 H) 7.40 (d, J = 1.43 Hz, 1 H) 7.18 - 7.26 (m, 2 H) 5.22 (t, J = 5.84 Hz, 1 H) 3.37 (s, 3 H) 2.60 - 2.82 (m, 3 H) 2.21 - 2.36 (m, 3 H) 1.98 - 2.10 (m, 1 H) 1.74 - 1.95 (m, 3 H) 1.69 (td, J = 9.00, 4.29 Hz, 1 H) 1.19 (t, J=7.63 Hz, 3 H) 0.62 (q, J=4.81 Hz, 1 H); ESI-LCMS: m / z = 376.2 [M+H] + ee=99.88%, duration: 2.804 minutes.

[0260] Example 22

[0261] Synthetic road:

change

[0262] Step 1: Synthesis of Compound 027-2 027-1 (300 mg, 1.26 mmol), N,N-dimethylformamide (3 mL), and cesium carbonate (821.12 mg, 2.52 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (715.41 mg, 5.04 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. Water (15 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. The organic phases were extracted three times with ethyl acetate (5 mL each time), the organic phases were combined, washed twice with saturated brine (5 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 6:1) to obtain 027-2. 1 H NMR (400 MHz, CDCl3) δ = 7.81 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 2.3, 9.0 Hz, 1H), 7.24 (s, 1H), 6.63 (s, 1H), 3.69 (s, 3H), 2.45 (s, 3H).

[0263] Step 2: Synthesis of Compound 027-3 In a reaction flask, 027-2 (210 mg, 832.98 μmol), bis(pinacolate)diborone (423.05 mg, 1.67 mmol), 1,4-dioxane (8.4 mL), and potassium acetate (245.25 mg, 2.50 mmol) were added sequentially, the flask was purged with nitrogen gas, and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (35.25 mg, 41.65 μmol) was added. The reaction solution was stirred at 80°C for 16 hours to obtain the reaction solution of 027-3, which was used directly in the next step without workup. ESI-LCMS: m / z = 300.0 [M+H] + .

[0264] Step 3: Synthesis of Compound 027 In a reaction flask, A-1 (58.68 mg, 207.24 μmol), water (1 mL), acetonitrile (3 mL), methanol (1 mL), potassium carbonate (114.57 mg, 828.96 μmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (12.76 mg, 31.09 μmol) were added sequentially, and the flask was purged with nitrogen gas. Bis(triphenylphosphine)palladium(II) dichloride (7.27 mg, 10.36 μmol) and palladium acetate (2.33 mg, 10.36 μmol) were added, the flask was purged with nitrogen gas, and the reaction solution was heated to 40°C. The reaction solution of O27-3 was added, and the reaction solution was heated to 75°C and stirred for 4 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated to obtain the crude product. O27 was obtained by sequential preparative thin-layer chromatography (petroleum ether:ethyl acetate:ethanol = 1:1:0.1) and chiral separation (column:DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 50% ethanol (0.1% aqueous ammonia)) of the crude product. 1 H NMR (400 MHz, CD3OD) δ = 8.40 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.67 - 7.63 (m, 1H), 6.65 (d, J = 1.1 Hz, 1H), 5.23 (t, J = 6.0 Hz, 1H), 4.58 (s, 3H), 3.79 (s, 3H), 2.80 - 2.59 (m, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.29 (dq, J = 2.0, 7.6 Hz, 2H), 2.12 - 1.98 (m, 1H), 1.91 - 1.87 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 376.2 [M+H] +The substance was detected by SFC analysis (column: Chiralpak IG-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: ethanol (methanol solution of 0.2% 7 M ammonia), gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi), with ee = 100% and retention time of 2.133 minutes.

[0265] Example 23

[0266] Synthesis pathway: [ka]

[0267] Step 1: Synthesis of Compound 028-2 028-1 (2 g, 11.59 mmol) and diethyl oxalate (16.94 g, 115.90 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (2.03 g, 13.33 mmol) was added. The reaction solution was stirred at 25°C for 15 hours. The reaction solution was poured into ice water (20 mL), 1 M hydrochloric acid (15 mL) was added, the mixture was filtered, and the cake was collected. The cake was added to anhydrous methanol (10 mL), stirred for 10 minutes, filtered, and the cake was collected to obtain 028-2. 1 H NMR (400 MHz, CDCl3) δ = 8.96 (s, 1H), 8.26 (s, 1H), 7.26 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 0.9 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0268] Step 2: Synthesis of Compound 028-3 028-2 (1.7 g, 6.24 mmol), water (3 mL), and tetrahydrofuran (12 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Sodium borohydride (259.49 mg, 6.86 mmol) was added in batches, and the reaction solution was stirred at 0°C for 0.5 hours. Ice water (5 mL) and saturated ammonium chloride aqueous solution (5 mL) were added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Extraction was performed three times with ethyl acetate (10 mL each time), the organic phases were combined, washed with saturated brine (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1) to obtain 028-3. 1 H NMR (400 MHz, CDCl3) δ = 8.97 (s, 1H), 7.48 (s, 1H), 4.50 (td, J = 4.2, 8.4 Hz, 1H), 4.30 (dq, J = 3.6, 7.1 Hz, 2H), 3.60 (dd, J = 3.9, 14.0 Hz, 1H), 3.24 (dd, J = 8.4, 13.9 Hz, 1H), 3.01 (d, J = 4.8 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H).

[0269] Step 3: Synthesis of Compound 028-4 In a reaction flask, 028-3 (0.8g, 2.91 mmol), iron powder (650.70 mg, 11.65 mmol), and acetic acid (12 mL) were added sequentially. The flask was purged with nitrogen gas, and the reaction solution was stirred at 70°C for 0.5 hours. 1,4-dioxane (8 mL) and hydrochloric acid (6 M, 5.83 mL) were added, the temperature of the reaction solution was raised to 90°C, and the mixture was stirred for 3.5 hours. The reaction solution was cooled to 25°C, and the reaction solution was poured into saturated sodium bicarbonate aqueous solution (200 mL). The mixture was stirred for 0.5 hours, filtered, and the cake was collected. 028-4 was obtained and used directly in the next step without purification. ESI-LCMS: m / z = 181.0 [M+H] + .

[0270] Step 5: Synthesis of Compound 028-5 In a reaction flask, 028-4 (0.2 g, 1.11 mmol), cesium carbonate (541.25 mg, 1.66 mmol), and N,N-dimethylformamide (4 mL) were added sequentially, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (628.77 mg, 4.43 mmol) was added, and the reaction solution was stirred at 0°C for 1 hour. Water (20 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. It was extracted three times with ethyl acetate (10 mL each time), the organic phases were combined, washed with saturated brine (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 028-5. 1 H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.48 (s, 1H), 6.95 (d, J = 9.6 Hz, 1H), 3.77 (s, 3H).

[0271] Step 6: Synthesis of Compound 028 Add 028-5 (60 mg, 308.30 μmol), sodium carbonate (98.03 mg, 924.89 μmol), water (0.3 mL), and 1,4-dioxane (1.8 mL) sequentially to the reaction flask, purge with nitrogen gas, and add (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (26.10 mg, 30.83 μmol) of 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (29.39 mg, 61.66 μmol, 0.2 eq) was added, the reaction solution was heated to 85°C, and the solution of crude product A-2 (prepared according to the synthesis method of Reference Example 2, used immediately after preparation, added to the preparation according to the theoretical yield, the theoretical yield is 114.73 mg, 462.45 μmol) was added, and the reaction solution was stirred at 85°C for 0.5 hours. The reaction solution was cooled to room temperature, water (2 mL) was added to the reaction solution, the reaction solution was transferred to a separatory funnel, extracted three times with dichloromethane (2 mL each time), the organic phases were combined, washed with saturated brine (2 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified to obtain O28 by sequential preparative thin-layer chromatography (dichloromethane:ethyl acetate:ethanol = 5:5:1) and chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradient elution: 50% isopropanol (0.1% aqueous ammonia)). 1H NMR (400 MHz, CD3OD) δ = 9.05 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.83 (s, 1H), 6.97 (d, J = 9.5 Hz, 1H), 5.24 (t, J = 6.1 Hz, 1H), 3.86 (s, 3H), 2.96 - 2.85 (m, 1H), 2.82 - 2.71 (m, 1H), 2.29 (dq, J = 2.1, 7.6 Hz, 2H), 2.13 - 2.00 (m, 1H), 1.96 - 1.76 (m, 3H), 1.20 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 363.2 [M+H] + The substance was detected by SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: isopropanol (methanol solution of 0.2% 7 M ammonia), gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi), with ee = 100% and retention time of 1.827 minutes.

[0272] Example 24

[0273] Synthesis pathway: [ka]

[0274] Step 1: Synthesis of Compound 029-2 In a reaction flask, 029-1 (0.45 g, 1.99 mmol), acetic acid (956.25 mg, 15.92 mmol), and isopropanol (4 mL) were added sequentially, the flask was purged with nitrogen gas, and sodium borohydride cyanohydride (375.26 mg, 5.97 mmol) was added in batches. The reaction solution was stirred at 75°C for 14 hours. The pH of the reaction solution was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution. The reaction solution was transferred to a separatory funnel and extracted three times with dichloromethane (5 mL each time). The organic phases were combined, washed with saturated brine (5 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 029-2. This product was used directly in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ = 8.60 (s, 1H), 8.57 (s, 1H), 4.88 (t, J = 4.9 Hz, 1H), 2.88 - 2.83 (m, 1H), 2.72 - 2.65 (m, 1H), 2.10 - 1.79 (m, 5H).

[0275] Step 2: Synthesis of Compound 029-3 029-2 (0.4 g, 1.75 mmol) and dichloromethane (4 mL) were sequentially added to the reaction flask, the mixture was purged with nitrogen gas, the reaction solution was cooled to 0°C, thionyl chloride (312.96 mg, 2.63 mmol) was added, the reaction solution was stirred at 0°C for 1 hour, the temperature was raised to 25°C and the solution was stirred for 1.5 hours, and the reaction solution was concentrated to obtain crude product 029-3, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 8.83 (s, 1H), 8.74 (s, 1H), 5.52 - 5.36 (m, 1H), 3.15 (td, J = 4.5, 19.6 Hz, 1H), 2.93 - 2.80 (m, 1H), 2.40 - 2.22 (m, 3H), 2.15 - 2.05 (m, 1H).

[0276] Step 3: Synthesis of Compound 029-5 In a reaction flask, 029-3 (0.36 g, 1.46 mmol), 029-4 (350.95 mg, 1.75 mmol), N,N-diisopropylethylamine (566.19 mg, 4.38 mmol), potassium iodide (242.41 mg, 1.46 mmol), and acetonitrile (5 mL) were added sequentially. The flask was then purged with nitrogen gas, and the reaction solution was stirred at 40°C for 2 hours. The temperature of the reaction solution was then raised to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 029-5. 1 H NMR (400 MHz, CDCl3) δ = 8.79 (s, 1H), 8.51 (s, 1H), 4.49 (br s, 1H), 3.88 (br d, J = 2.5 Hz, 1H), 3.47 (br d, J = 1.3 Hz, 1H), 2.81 (br d, J = 17.3 Hz, 2H), 2.73 - 2.52 (m, 3H), 2.22 (br d, J = 7.5 Hz, 1H), 2.11 (br d, J = 9.3 Hz, 1H), 1.99 (br dd, J = 5.1, 9.3 Hz, 2H), 1.87 (br d, J = 9.9 Hz, 1H), 1.59 - 1.32 (m, 13H).

[0277] Step 4: Synthesis of Compound 029-6 O29-5 (0.2 g, 487.39 μmol) and hydrogen chloride / ethyl acetate (4 M, 10.00 mL) were sequentially added to the reaction flask, the mixture was purged with nitrogen gas, and the reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated to obtain the hydrochloride salt of O29-6, which was used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ = 8.98 (s, 1H), 8.75 (s, 1H), 4.69 (br s, 1H), 3.43 - 3.19 (m, 4H), 3.18 - 3.04 (m, 1H), 2.91 - 2.66 (m, 2H), 2.36 - 2.22 (m, 2H), 2.19 - 1.99 (m, 4H), 1.97 - 1.92 (m, 1H), 1.86 - 1.73 (m, 1H).

[0278] Step 5: Synthesis of Compound 029-7 220 mg of hydrochloride of O29-6, 410.07 mg (3.17 mmol) of N,N-diisopropylethylamine, and 5 mL of dichloromethane were sequentially added to a reaction flask. The flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. 99.10 mg (761.48 μmol) of propionic anhydride was added, and the reaction solution was stirred at 0°C for 1 hour. 2 mL of water was added to the reaction solution, and the solution was extracted three times with dichloromethane (2 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product O29-7. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 5:5:1) to obtain O29-7. 1 H NMR (400 MHz, CDCl3) δ = 8.80 (s, 1H), 8.51 (s, 1H), 5.34 (br d, J = 4.6 Hz, 1H), 3.97 - 3.73 (m, 2H), 2.90 - 2.70 (m, 3H), 2.66 - 2.49 (m, 2H), 2.32 - 2.24 (m, 1H), 2.20 (q, J = 7.7 Hz, 2H), 2.11 (br d, J = 5.0 Hz, 1H), 2.04 - 1.95 (m, 2H), 1.90 - 1.82 (m, 1H), 1.67 (br s, 1H), 1.59 - 1.53 (m, 2H), 1.46 (d, J = 6.6 Hz, 1H), 1.17 - 1.12 (m, 3H).

[0279] Step 6: Synthesis of compounds 029 and 030 In a reaction flask, 029-7 (0.1 g, 273.00 μmol), 001-3 (93.41 mg, 327.60 μmol), sodium carbonate (57.87 mg, 546.01 μmol), water (0.7 mL), and ethanol (2 mL) were added sequentially. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (31.55 mg, 27.30 μmol) was added. The reaction solution was stirred at 85°C for 2 hours. The reaction solution was allowed to return to room temperature, water (5 mL) was added, and the reaction solution was transferred to a separatory funnel. It was extracted three times with dichloromethane (5 mL each time), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified to obtain O29 and O30 by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 3:3:1) and SFC chiral separation (column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, mobile phase: A: supercritical carbon dioxide, B: ethanol (methanol solution of 0.2% 7 M ammonia), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi). SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: carbon dioxide, B: ethanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35°C, pressure: 1800 psi) was performed.

[0280] Compound 029: 1H NMR (400 MHz, CD3OD) δ = 8.83 (s, 1H), 8.21 (s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.67 - 7.63 (m, 1H), 6.74 (d, J = 9.5 Hz, 1H), 4.03 (br dd, J = 5.5, 9.6 Hz, 1H), 3.80 (s, 3H), 3.73 - 3.61 (m, 1H), 3.00 - 2.90 (m, 1H), 2.80 - 2.68 (m, 2H), 2.64 - 2.52 (m, 2H), 2.38 - 2.28 (m, 1H), 2.19 (q, J = 7.5 Hz, 2H), 2.06 - 1.90 (m, 3H), 1.87 - 1.76 (m, 2H), 1.71 - 1.58 (m, 2H), 1.44 (dq, J = 3.7, 11.6 Hz, 1H), 1.13 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 445.3 [M+H] + , ee=100%, retention time: 1.489 minutes.

[0281] Compound 030: 1H NMR (400 MHz, CD3OD) δ = 8.83 (s, 1H), 8.21 (s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.67 - 7.63 (m, 1H), 6.74 (d, J = 9.5 Hz, 1H), 4.03 (br dd, J = 5.6, 9.5 Hz, 1H), 3.80 (s, 3H), 3.72 - 3.61 (m, 1H), 2.95 (br d, J = 11.3 Hz, 1H), 2.82 - 2.68 (m, 2H), 2.65 - 2.51 (m, 2H), 2.32 (dt, J = 2.1, 11.4 Hz, 1H), 2.19 (q, J = 7.6 Hz, 2H), 2.09 - 1.90 (m, 3H), 1.88 - 1.76 (m, 2H), 1.72 - 1.57 (m, 2H), 1.44 (dq, J = 3.9, 11.6 Hz, 1H), 1.12 (t, J = 7.7 Hz, 3H); ESI-LCMS: m / z = 445.3 [M+H] + , ee=100%, holding time: 1.806 minutes.

[0282] Example 25

[0283] Synthetic road:

change

[0284] ステップ1:Synthesis of compound 031-2 In a reaction flask, 031-1 (0.3 g, 1.46 mmol), potassium carbonate (402.52 mg, 2.91 mmol), and N,N-dimethylformamide (3 mL) were added sequentially, the flask was purged with nitrogen gas, chloroacetyl chloride (180.92 mg, 1.60 mmol) was added, and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was allowed to return to room temperature, water (30 mL) was added to the reaction solution, the reaction solution was transferred to a separatory funnel, extracted three times with ethyl acetate (10 mL each time), the organic phases were combined, washed with saturated brine (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 031-2. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 031-2. 1 H NMR (400 MHz, DMSO-d6) δ = 11.01 (br s, 1H), 7.22 (dd, J = 2.0, 9.8 Hz, 1H), 7.08 (t, J = 1.7 Hz, 1H), 4.64 (s, 2H).

[0285] Step 2: Synthesis of Compound 031-3 In a reaction flask, 031-2 (0.1 g, 406.45 μmol), cesium carbonate (198.64 mg, 609.67 μmol), and N,N-dimethylformamide (2 mL) were added sequentially, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (230.76 mg, 1.63 mmol) was added, the reaction solution was cooled to 0°C, and the mixture was stirred for 1 hour. Water (10 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. The organic phases were extracted three times with ethyl acetate (3 mL each time), the organic phases were combined, washed with saturated brine (5 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 031-3. 1 H NMR (400 MHz, DMSO-d6) δ = 7.34 (dd, J = 1.9, 12.1 Hz, 1H), 7.19 (s, 1H), 4.67 (s, 2H), 3.33 (br s, 3H).

[0286] Step 3: Synthesis of Compound 031-4 In a reaction flask, 031-3 (100 mg, 384.53 μmol), bis(pinacolate)diborone (146.47 mg, 576.79 μmol), potassium acetate (113.21 mg, 1.15 mmol), and 1,4-dioxane (2 mL) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28.14 mg, 38.45 μmol) was added. The reaction solution was stirred at 80°C for 4 hours. The reaction solution was allowed to return to room temperature, concentrated to obtain crude product 031-4, which was used directly in the next step without purification.

[0287] Step 4: Synthesis of Compound 031 In a reaction flask, A-1 (100 mg, 353.15 μmol), 031-4 (108.46 mg, 353.15 μmol), sodium carbonate (74.86 mg, 706.31 μmol), water (0.5 mL), and ethanol (3 mL) were added sequentially. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (40.81 mg, 35.32 μmol) was added. The reaction solution was stirred at 85°C for 1 hour. The reaction solution was allowed to return to room temperature, diluted with water (5 mL), extracted with dichloromethane (5 mL x 3), the organic phases were combined, washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified sequentially by column chromatography (ethyl acetate:methanol = 1:0 to 10:1) and SFC chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 50% isopropanol (0.1% aqueous ammonia)) to obtain O31. 1H NMR (400 MHz, CD3OD) δ = 8.37 (s, 1H), 8.19 (s, 1H), 6.93 (dd, J = 1.8, 13.1 Hz, 1H), 6.88 (d, J = 1.3 Hz, 1H), 5.20 (t, J = 5.8 Hz, 1H), 4.64 (s, 2H), 3.51 (d, J = 5.9 Hz, 3H), 2.78 - 2.62 (m, 2H), 2.27 (dq, J = 1.7, 7.6 Hz, 2H), 2.07 - 1.98 (m, 1H), 1.92 - 1.76 (m, 3H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 384.2 [M+H] + SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: isopropanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100% and retention time was 1.479 minutes.

[0288] Example 26

[0289] Synthesis pathway: [ka]

[0290] Step 1: Synthesis of Compound 032-2 In a reaction flask, 032-1 (0.3 g, 1.46 mmol), potassium carbonate (402.53 mg, 2.91 mmol), and N,N-dimethylformamide (3 mL) were added sequentially, the flask was purged with nitrogen gas, chloroacetyl chloride (180.92 mg, 1.60 mmol) was added, and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was allowed to return to room temperature, water (30 mL) was added to the reaction solution, the reaction solution was transferred to a separatory funnel, extracted three times with ethyl acetate (10 mL each time), the organic phases were combined, washed with saturated brine (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 032-2. 1 H NMR (400 MHz, DMSO-d6) δ = 10.88 (br s, 1H), 7.31 (d, J = 6.4 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.59 (s, 2H).

[0291] Step 2: Synthesis of Compound 032-3 In a reaction flask, 032-2 (100 mg, 406.45 μmol), cesium carbonate (198.64 mg, 609.67 μmol), and N,N-dimethylformamide (1.5 mL) were added sequentially, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Methyl iodide (230.76 mg, 1.63 mmol) was added, and the reaction solution was stirred at 0°C for 1 hour. Water (10 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. It was extracted three times with ethyl acetate (5 mL each time), the organic phases were combined, washed with saturated brine (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 032-3. 1 H NMR (400 MHz, DMSO-d6) δ = 7.36 (d, J = 6.5 Hz, 1H), 7.30 (d, J = 10.1 Hz, 1H), 4.67 (s, 2H), 3.24 (s, 3H).

[0292] Step 3: Synthesis of Compound 032-4 In a reaction flask, 032-3 (120 mg, 461.43 μmol), bis(pinacolate)diborone (175.76 mg, 692.15 μmol), potassium acetate (135.86 mg, 1.38 mmol), and 1,4-dioxane (3 mL) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.76 mg, 46.14 μmol) was added. The reaction solution was stirred at 85°C for 16 hours. The reaction solution was allowed to return to room temperature, concentrated to obtain crude product 032-4, which was used directly in the next step without purification.

[0293] Step 4: Synthesis of Compound 032 In a reaction flask, A-1 (120 mg, 423.78 μmol), O32-4 (130.15 mg, 423.78 μmol), sodium carbonate (89.83 mg, 847.57 μmol), water (0.5 mL), and ethanol (3 mL) were added sequentially. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (48.97 mg, 42.38 μmol) was added. The reaction solution was stirred at 85°C for 1 hour. The reaction solution was allowed to return to room temperature, water (5 mL) was added to the reaction solution, and the solution was extracted three times with dichloromethane (5 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phases were collected. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. O32 was obtained by sequential column chromatography (ethyl acetate:methanol = 1:0 to 10:1) and SFC chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 50% isopropanol (0.1% aqueous ammonia)) of the crude product. 1H NMR (400 MHz, CD3OD) δ = 8.39 (s, 1H), 8.18 (s, 1H), 7.11 (d, J = 10.6 Hz, 1H), 6.92 (d, J = 6.6 Hz, 1H), 5.22 (br t, J = 5.8 Hz, 1H), 4.66 (s, 2H), 3.39 (s, 3H), 2.73 - 2.51 (m, 2H), 2.27 (dq, J = 2.0, 7.6 Hz, 2H), 2.11 - 1.97 (m, 1H), 1.94 - 1.75 (m, 3H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 384.2 [M+H] + The substance was detected by SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: isopropanol (methanol solution of 0.2% 7 M ammonia), gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, column pressure: 1800 psi), with ee = 100% and retention time of 1.795 minutes.

[0294] Example 27

[0295] Synthesis pathway: [ka]

[0296] Step 1: Synthesis of Compound 033-2 033-1 hydrochloride (2 g, 16.45 mmol), dichloromethane (20 mL), and N,N-diisopropylethylamine (5.32 g, 41.13 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. A solution of propionic anhydride (3.00 g, 23.03 mmol) in dichloromethane (10 mL) was added, and the reaction solution was stirred at 0°C for 1 hour. Water (10 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. The solution was extracted with 10 mL of dichloromethane, separated, and the organic phase was collected. The aqueous phase was further extracted three times (10 mL each time) with a mixed solvent (dichloromethane:methanol = 10:1), the organic phases were combined, and the mixture was washed twice (10 mL each time) with saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to dichloromethane:methanol = 20:1) to obtain O33-2. 1 H NMR (400 MHz, CDCl3) δ = 3.94 - 3.85 (m, 4H), 2.70 (t, J = 7.9 Hz, 1H), 2.62 (t, J = 7.9 Hz, 1H), 2.41 - 2.34 (m, 1H), 2.27 (q, J = 7.4 Hz, 1H), 1.21 - 1.16 (m, 3H).

[0297] Step 2: Synthesis of Compound 033-3 In a reaction flask, A-1-5 hydrochloride (0.7 g), methanol (7 mL), triethylamine (631.53 mg, 6.24 mmol), O33-2 (734.19 mg, 5.20 mmol), and acetic acid (249.85 mg, 4.16 mmol) were added sequentially, and the mixture was stirred for 15 minutes. Then sodium borohydride cyanohydride (653.64 mg, 10.40 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was adjusted to a pH of 8-9 by adding saturated sodium bicarbonate aqueous solution, the reaction solution was transferred to a separatory funnel, extracted three times with ethyl acetate (20 mL each time), the organic phases were combined, washed with saturated saline solution (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 033-3. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to dichloromethane:methanol = 20:1) to obtain 033-3. 1 H NMR (400 MHz, CDCl3) δ = 8.53 (d, J = 3.4 Hz, 1H), 8.51 - 8.47 (m, 1H), 3.98 - 3.83 (m, 1H), 3.73 - 3.57 (m, 3H), 3.52 - 3.44 (m, 1H), 3.12 (s, 2H), 2.88 - 2.78 (m, 1H), 2.70 - 2.59 (m, 1H), 2.31 - 2.25 (m, 2H), 2.19 - 2.10 (m, 1H), 2.02 - 1.96 (m, 1H), 1.92 (br d, J = 4.0 Hz, 1H), 1.89 - 1.82 (m, 2H), 1.38 (s, 3H).

[0298] Step 3: Synthesis of compounds 033 and 034 In a reaction flask, 001-3 (553.67 mg, 1.94 mmol), potassium carbonate (894.51 mg, 6.47 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (99.64 mg, 242.71 μmol), bis(triphenylphosphine)palladium(II) dichloride (56.79 mg, 80.90 μmol), palladium acetate (18.16 mg, 80.90 μmol), water (5.5 mL), acetonitrile (16.5 mL), and methanol (5.5 mL) were added sequentially. The flask was then purged with nitrogen gas. To the reaction solution, 033-3 (0.57 g, 1.62 mmol) in tetrahydrofuran (5.5 mL) solution was added at 40°C, and the reaction solution was heated to 75°C and stirred for 2 hours. The reaction solution was allowed to return to room temperature, filtered over anhydrous sodium sulfate, and the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 1:1:0.3), SFC chiral separation (column:ChiralPak IH, 250 mm × 30 mm, 10 μm, mobile phase: supercritical carbon dioxide - ethanol:acetonitrile = 1:1 (0.1% aqueous ammonia)), and isogradient elution: 50% ethanol:acetonitrile = 1:1 (0.1% aqueous ammonia)) to obtain O33 and O34. The ee value was detected by SFC detection (column: Chiralpak IH-3, 50 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol: acetonitrile (methanol solution of 0.1% 7 M ammonia), gradient: A / B = 65 / 35, flow rate: 4 mL / min, column temperature: 35 °C, pressure: 1800 psi).

[0299] Compound 033: 1H NMR (400 MHz, CD3OD) δ = 8.58 (d, J = 10.6 Hz, 1H), 8.21 (d, J = 3.1 Hz, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.75 - 7.61 (m, 3H), 6.74 (d, J = 9.5 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.80 (s, 3H), 3.79 - 3.50 (m, 4H), 3.49 - 3.33 (m, 2H), 2.81 - 2.71 (m, 1H), 2.68 - 2.57 (m, 1H), 2.43 - 2.31 (m, 2H), 2.28 - 2.13 (m, 1H), 2.02 (br d, J = 12.1 Hz, 1H), 1.98 - 1.79 (m, 3H), 1.79 - 1.68 (m, 1H), 1.15 (dt, J = 0.8, 7.5 Hz, 3H); ESI-LCMS: m / z = 431.3 [M+H] + ee=100%, retention time 2.289 minutes.

[0300] Compound 034: 1H NMR (400 MHz, CD3OD) δ = 8.60 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.72 - 7.60 (m, 3H), 6.74 (d, J = 9.4 Hz, 1H), 4.03 (td, J = 4.8, 9.6 Hz, 1H), 3.80 (s, 3H), 3.77 (br d, J = 3.1 Hz, 4H), 3.45 (td, J = 7.5, 12.2 Hz, 1H), 3.29 - 3.22 (m, 1H), 2.79 - 2.71 (m, 1H), 2.68 - 2.58 (m, 1H), 2.36 (qd, J = 7.5, 11.7 Hz, 2H), 2.25 - 2.15 (m, 1H), 2.05 - 1.90 (m, 4H), 1.73 (br dd, J = 2.1, 5.7 Hz, 1H), 1.13 (dt, J = 3.5, 7.5 Hz, 3H); ESI-LCMS: m / z = 431.2 [M+H] + , ee=100%, holding time 3.580 minutes.

[0301] Example 28

[0302] Synthetic road:

change

[0303] ステップ1:Synthesis of compound 035-3 035-1 (2.2 g, 11.82 mmol) and dichloromethane (34 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Then, a solution of 035-2 (1.94 g, 14.19 mmol) in dichloromethane (34 mL) was added, and the reaction solution was heated to 25°C and stirred for 12 hours. Water (10 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. The solution was extracted three times with dichloromethane (30 mL each time), separated, and the organic phases were combined. The organic phases were washed twice with saturated brine (20 mL each time), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 035-3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, J=8.50 Hz, 2 H) 7.13 (d, J=8.63 Hz, 2 H) 3.69 (s, 3 H) 3.29 (s, 3 H) 3.23 (s, 2 H).

[0304] Step 2: Synthesis of Compound 035-4 035-3 (3.3 g, 11.53 mmol) and tetrahydrofuran (33 mL) were added sequentially to a reaction flask, followed by the addition of an aqueous solution of lithium hydroxide monohydrate (967.98 mg, 23.07 mmol) (33 mL). The reaction solution was stirred at 25°C for 12 hours. 12 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2, water (15 mL) was added, and ethyl acetate was added to the reaction solution for extraction twice (30 mL each time). The organic phases were combined, washed with saturated brine (30 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. 25 mL of a mixed solvent (petroleum ether:ethyl acetate = 10:1) was added to the crude product, stirred for 0.5 hours, filtered, the cake was collected, and dried to obtain 035-4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (br d, J=7.63 Hz, 2 H) 7.32 (br d, J=7.63 Hz, 2 H) 3.17 (br s, 3 H) 3.11 (br s, 2 H).

[0305] Step 3: Synthesis of Compound 035-5 035-4 (2.8 g, 10.29 mmol) and Eaton's reagent (30.30 g, 127.28 mmol) were sequentially added to the reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 70°C for 12 hours. The reaction solution was added to ice water (100 mL), stirred at 0°C for 0.5 hours, filtered, and the cake was collected. The cake was added to acetonitrile (28 mL), stirred at 25°C for 1 hour, filtered, and the cake was collected to obtain 035-5. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (s, 1 H) 7.95 (d, J = 2.38 Hz, 1 H) 7.76 (dd, J = 9.01, 2.38 Hz, 1 H) 7.44 (d, J = 9.01 Hz, 1 H) 5.89 (s, 1 H) 3.51 (s, 3 H).

[0306] Step 4: Synthesis of Compound 035-6 035-5 (0.4 g, 1.57 mmol) and N,N-dimethylformamide (10 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, sodium carbonate (166.86 mg, 1.57 mmol) was added, the flask was purged with nitrogen gas, the reaction solution was cooled to 0°C, methyl iodide (335.18 mg, 2.36 mmol) was added, the reaction solution was stirred at 0°C for 2 hours, and the reaction solution was heated to 25°C and stirred for 10 hours. 10 mL of water was added to the reaction solution, the reaction solution was transferred to a separatory funnel, extracted three times with ethyl acetate (30 mL each time), the organic phases were combined, washed twice with saturated brine (30 mL each time), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 035-6. 1 H NMR (400 MHz, DMSO-d6) δ = 7.95 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 2.2, 9.1 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 6.09 (s, 1H), 3.94 (s, 3H), 3.54 (s, 3H).

[0307] Step 5: Synthesis of Compound 035-7 In a reaction flask, 035-6 (0.16 g, 596.78 μmol), 1,4-dioxane (7 mL), bis(pinacolate)diborone (227.32 mg, 895.17 μmol), potassium acetate (175.70 mg, 1.79 mmol), and (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II)methanesulfonate (25.26 mg, 29.84 μmol) were added sequentially. The flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 6 hours. The reaction solution was filtered, the cake was rinsed with ethyl acetate, the filtrate was collected and concentrated to obtain crude product 035-7. This was used directly in the next step without purification. ESI-LCMS: m / z = 316.2 [M+H] + .

[0308] Step 6: Synthesis of Compound 035 In a reaction flask, A-1 (80 mg, 282.52 μmol), water (1.7 mL), acetonitrile (5.1 mL), methanol (1.7 mL), potassium carbonate (156.18 mg, 1.13 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17.40 mg, 42.38 μmol) were added sequentially, and the flask was purged with nitrogen gas. Bis(triphenylphosphine)palladium(II) dichloride (9.92 mg, 14.13 μmol) and palladium acetate (3.17 mg, 14.13 μmol) were added, the flask was purged with nitrogen gas, and the reaction solution was heated to 40°C. O35-7 (178.09 mg, 565.04 μmol) in tetrahydrofuran (2.6 mL) solution was added, and the reaction solution was heated to 75°C and stirred for 12 hours. The reaction solution was filtered, the filtrate was collected and concentrated to obtain the crude product. O35 was obtained by preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 1:1:0.3) and SFC chiral separation (column:DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide-methanol (0.1% aqueous ammonia)], isogloss: 50% methanol (0.1% aqueous ammonia)) of the crude product. 1 H NMR (400 MHz, CDCl3) δ = 8.54 (br s, 1H), 8.33 (br s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 2.0, 8.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.09 (s, 1H), 5.81 (br d, J = 8.6 Hz, 1H), 5.40 - 5.33 (m, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 2.74 - 2.54 (m, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.15 - 2.07 (m, 1H), 1.87 - 1.80 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 392.2 [M+H] +SFC analysis (column: Chiralpak IG-3, 100 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 50 / 50, flow rate: 4 mL / min, column temperature: 35 °C, pressure: 2000 psi) detected ee = 100%, retention time was 2.119 minutes.

[0309] Example 29

[0310] Synthesis pathway: [ka]

[0311] Step 1: Synthesis of Compound 036-2 In a reaction flask, hydrochloride salt of 036-1 (2 g, 18.60 mmol), dichloromethane (20 mL), and N,N-diisopropylethylamine (4.49 g, 34.72 mmol) were added sequentially, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. A solution of propionic anhydride (2.53 g, 19.44 mmol) in dichloromethane (5 mL) was added, and the reaction solution was stirred at 0°C for 1 hour. The reaction solution was poured into 2 mL of water, separated, and the organic phase was collected and concentrated to obtain crude product 036-2, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 4.81 (br d, J = 13.8 Hz, 4H), 2.31 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).

[0312] Step 2: Synthesis of Compound 036-3 In a reaction flask, A-1-5 hydrochloride (0.5 g), methanol (5 mL), triethylamine (451.09 mg, 4.46 mmol), O36-2 (472.31 mg, 3.71 mmol), and acetic acid (178.46 mg, 2.97 mmol) were added sequentially. The reaction solution was stirred at 25°C for 0.5 hours, then sodium borohydride cyanohydride (466.89 mg, 7.43 mmol) was added, the flask was purged with nitrogen gas, and the mixture was stirred at 25°C for 15.5 hours. The reaction solution was poured into 5 mL of saturated sodium bicarbonate aqueous solution, extracted three times with dichloromethane (5 mL each time), the organic phases were combined, washed three times with saturated brine (5 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.1) to obtain O36-3. ESI-LCMS: m / z = 338.0 [M+H] + .

[0313] Step 3: Synthesis of Compound 036 In a reaction flask, 001-3 (50.58 mg, 177.39 μmol), potassium carbonate (81.72 mg, 591.29 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (9.10 mg, 22.17 μmol), bis(triphenylphosphine)palladium(II) dichloride (5.19 mg, 7.39 μmol), palladium acetate (1.66 mg, 7.39 μmol), water (0.4 mL), acetonitrile (1.2 mL), and methanol (0.4 mL) were added sequentially. The flask was then purged with nitrogen gas, the reaction solution was heated to 40°C, and 036-6 (50 mg, 147.82 μmol) in tetrahydrofuran (0.4 mL) solution was added. The reaction solution was then heated to 75°C and stirred for 1 hour. The reaction solution was allowed to return to room temperature, added to 2 mL of water, transferred to a separatory funnel, extracted three times with dichloromethane (3 mL each time), combined with the organic phase, washed three times with saturated saline solution (3 mL each time), collected the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.3), preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150×40mm×10μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: 5%~45%, 10mM ammonium bicarbonate), and SFC chiral separation (column: REGIS(S,S)WHELK-O1 (250mm×25mm, 10μm), mobile phase: [supercritical carbon dioxide-isopropanol:acetonitrile = 1:1 (0.1% aqueous ammonia)], isogradient: 50%, isopropanol:acetonitrile = 1:1 (0.1% aqueous ammonia)) to obtain O36. 1H NMR (400 MHz, CD3OD) δ = 8.56 (d, J = 3.8 Hz, 1H), 8.24 (s, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.67 - 7.61 (m, 1H), 6.74 (d, J = 9.4 Hz, 1H), 4.47 - 4.33 (m, 1H), 4.27 - 4.13 (m, 1H), 4.01 - 3.87 (m, 3H), 3.78 (br s, 3H), 3.78 - 3.68 (m, 1H), 2.83 - 2.70 (m, 1H), 2.69 - 2.58 (m, ESI-LCMS: m / z = 417.3 [M+H] + The substance was detected by SFC analysis (column: (S,S)-WHELK-O1, 50 × 4.6 mm ID., 3.5 μm, mobile phase: A: CO2, B: 0.1% isopropylamine (isopropanol:acetonitrile = 1:1), gradient: A / B = 55:45, flow rate: 4 mL / min, column temperature: 35 °C, pressure: 1800 psi), with an ee = 99.62% and a retention time of 2.720 minutes.

[0314] Example 30

[0315] Synthesis pathway: [ka]

[0316] Step 1: Synthesis of Compound 037-3 037-2 (26.43 g, 366.51 mmol) and tetrahydrofuran (450 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Potassium tert-butoxide (38.38 g, 342.07 mmol) was added, and the mixture was stirred at 0°C for 30 minutes. Then, a solution of 037-1 (43 g, 244.34 mmol) in tetrahydrofuran (22.5 mL) was added, and the mixture was stirred at 0°C for 10 minutes. The reaction solution was diluted with aqueous ammonium chloride (300 mL), and the reaction solution was transferred to a separatory funnel. It was extracted three times with ethyl acetate (300 mL each time), the organic phases were combined, washed with saturated brine (300 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 6:1) to obtain 037-3. 1 H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 6.79 (d, J = 5.6 Hz, 1H), 5.91 (tdd, J = 6.8, 10.3, 17.1 Hz, 1H), 5.25 - 5.12 (m, 2H), 4.13 (t, J = 6.6 Hz, 2H), 2.62 (q, J = 6.6 Hz, 2H).

[0317] Step 2: Synthesis of Compound 037-4 037-3 (28.1 g, 123.20 mmol) and N,N-dimethylformamide (281 mL) were added sequentially to the reaction flask, and the flask was purged with nitrogen gas. Acetic acid (60.46 g, 616.00 mmol), 1,2-bis(diphenylphosphin)ethane (9.82 g, 24.64 mmol), and palladium acetate (2.77 g, 12.32 mmol) were added, the flask was purged with nitrogen gas, and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was allowed to return to room temperature, 1.4 L of water was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Extraction was performed three times with ethyl acetate (500 mL each time), the organic phases were combined, and the mixture was washed twice with saturated brine (500 mL each time). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain O37-4. 1 H NMR (400 MHz, CDCl3) δ = 8.72 (s, 1H), 8.26 (d, J = 5.7 Hz, 1H), 6.76 (d, J = 5.7 Hz, 1H), 5.62 (s, 1H), 5.00 (s, 1H), 4.37 - 4.26 (m, 2H), 2.69 (t, J = 5.7 Hz, 2H).

[0318] Step 3: Synthesis of Compound 037-5 In a reaction flask, 037-4 (2g, 13.59 mmol), tert-butanol (10 mL), acetonitrile (10 mL), and water (10 mL) were added sequentially, the flask was purged with nitrogen gas, osmium(VIII) oxide (345.48 mg, 1.36 mmol) was added, and the reaction solution was stirred at 25°C for 0.5 hours. Sodium periodate (5.81 g, 27.18 mmol) was added, and the mixture was stirred at 25°C for 4 hours. Water (20 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. The mixture was extracted twice (20 mL each time) with a mixed solvent (ethyl acetate:ethanol = 5:1), the organic phases were combined, washed with saturated brine (50 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0~2:1) to obtain 037-5. 1H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 6.91 (d, J = 5.9 Hz, 1H), 4.70 - 4.56 (m, 2H), 2.93 - 2.79 (m, 2H).

[0319] Step 4: Synthesis of Compound 037-6 037-5 (400 mg, 2.68 mmol), tetrahydrofuran (4 mL), A-1-2 (325.05 mg, 2.68 mmol), and tetraethyl titanate (1.84 g, 8.05 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 50°C for 16 hours. The reaction solution was allowed to return to room temperature, ethyl acetate (4 mL) was added to the reaction solution, and then aqueous sodium glycolate solution (3.4 mL) was added. The mixture was stirred at 25°C for 30 minutes, separated, and the aqueous phase was extracted twice with ethyl acetate (2 mL each time). The organic phases were combined, washed with saturated brine (2 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 037-6. 1 H NMR (400 MHz, CDCl3) δ = 9.10 (s, 1H), 8.44 (d, J = 5.8 Hz, 1H), 6.86 (d, J = 5.8 Hz, 1H), 4.53 - 4.35 (m, 2H), 3.62 - 3.50 (m, 1H), 3.45 - 3.33 (m, 1H), 1.34 (s, 9H).

[0320] Step 5: Synthesis of Compound 037-7 037-6 (420 mg, 1.66 mmol) and tetrahydrofuran (4.2 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. 9-borabicyclo[3.3.1]nonane (0.5 M, 9.99 mL) was added, and the reaction solution was heated to 25°C and stirred for 1 hour. 23 mL of 20% aqueous citric acid solution was added to the reaction solution, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The reaction solution was transferred to a separatory funnel and extracted three times with ethyl acetate (20 mL each time). The organic phases were combined, washed with saturated brine (20 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 1:0-20:1) to obtain 037-7. 1 H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 6.79 (d, J = 5.8 Hz, 1H), 5.31 (s, 1H), 4.73 - 4.61 (m, 1H), 4.40 - 4.31 (m, 2H), 2.25 - 2.10 (m, 2H), 1.25 (s, 9H).

[0321] Step 6: Synthesis of Compound 037-8 037-7 (270 mg, 1.06 mmol) and ethanol (5.4 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. Chlorotrimethylsilane (230.66 mg, 2.12 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain crude product 037-8, which was used directly in the next step without purification. ESI-LCMS: m / z = 151.3 [M+H] + .

[0322] Step 7: Synthesis of Compound 037-9 Crude product 037-8, dichloromethane (2 mL), and N,N-diisopropylethylamine (289.16 mg, 2.24 mmol) were sequentially added to a reaction flask. The flask was purged with nitrogen gas, and the reaction solution was cooled to 0°C. A solution of propionic anhydride (194.11 mg, 1.49 mmol) in dichloromethane (1 mL) was added, and the mixture was stirred at 0°C for 1 hour. Water (5 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. The mixture was extracted three times with dichloromethane (2 mL each time), the organic phases were combined, washed with saturated brine (2 mL), and the organic phases were collected. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 037-9. ESI-LCMS: m / z = 207.1 [M+H] + .

[0323] Step 8: Synthesis of Compound 037-10 037-9 (95 mg, 460.63 μmol) and sulfuric acid (1 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, and the reaction solution was cooled to 0°C. N-bromosuccinimide (163.96 mg, 921.25 μmol) was added, and the reaction solution was heated to 25°C and stirred for 19 hours. The reaction solution was added to saturated sodium bicarbonate aqueous solution (ice water mixture), the pH was adjusted to 7-8, and the mixture was extracted three times with ethyl acetate (5 mL each time). The organic phases were combined, washed with saturated brine (5 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 037-10. 1 H NMR (400 MHz, CD3OD) δ ppm 8.40 (s, 1 H), 8.21 (s, 1 H), 5.18 (t, J=5.63 Hz, 1 H), 4.41 - 4.55 (m, 2 H), 2.23 - 2.32 (m, 2 H), 2.05 - 2.22 (m, 2 H), 1.16 (t, J = 7.63 Hz, 3 H).

[0324] Step 9: Synthesis of Compound 037 Add 005-2 (58.01 mg, 202.01 μmol), 037-10 (48 mg, 168.34 μmol), ethanol (3 mL), and a solution of sodium carbonate (19.63 mg, 185.17 μmol) in water (0.5 mL) to a reaction flask, purge with nitrogen gas, add (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II)methanesulfonate (4.27 mg, 5.05 μmol), purge with nitrogen gas, stir the reaction solution at 85°C for 2 hours, concentrate the reaction solution to obtain the crude product. Separate and purify the crude product by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to obtain 037. 1 H NMR (400 MHz, CD3OD) δ = 8.24 (d, J = 3.2 Hz, 2H), 7.44 (dd, J = 1.6, 8.4 Hz, 1H), 7.40 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.21 (t, J = 5.5 Hz, 1H), 4.47 - 4.28 (m, 2H), 3.39 (s, 3H), 2.97 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.28 (dq, J = 2.3, 7.6 Hz, 2H), 2.24 - 2.04 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 366.2 [M+H] + SFC analysis (column: Chiralpak IG-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: ethanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected a ee of 98.96% and a retention time of 2.179 minutes.

[0325] Example 31

[0326] Synthesis pathway: [ka]

[0327] Step 1: Synthesis of Compound 038-3 In a reaction flask, 038-2 (18.72 g, 77.29 mmol) and tetrahydrofuran (140 mL) were added sequentially, the flask was purged with nitrogen gas, triethylamine (15.64 g, 154.57 mmol) and magnesium bromide (14.23 g, 77.29 mmol) were added, and a solution of 038-1 (14 g, 77.29 mmol) in tetrahydrofuran (70 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was added to 20 mL of water and extracted three times with dichloromethane (30 mL each time). The organic phases were combined and washed three times with saturated brine (30 mL each time). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 038-3. 1 H NMR (400 MHz, CDCl3) δ = 8.22 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 17.6 Hz, 1H), 6.97 (dd, J = 2.8, 9.1 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H).

[0328] Step 2: Synthesis of Compound 038-4 In a reaction flask, 038-3 (1 g, 3.71 mmol), methanol (35 mL), ammonium chloride (218.55 mg, 4.09 mmol) in water (10 mL), and iron powder (1.04 g, 18.57 mmol) were added sequentially. The reaction solution was heated to 60°C and stirred for 2 hours. The reaction solution was allowed to return to room temperature, filtered, and the cake was collected to obtain crude product 038-4. Without purification, the next step was carried out directly. ESI-LCMS: m / z = 194.1 [M+H] + .

[0329] Step 3: Synthesis of Compound 038-5 038-4 (0.4 g, 2.07 mmol) and N,N-dimethylformamide (5 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, cesium carbonate (1.35 g, 4.14 mmol) was added, the mixture was purged with nitrogen gas, the reaction solution was cooled to 0°C, methyl iodide (1.18 g, 8.28 mmol) was added, the mixture was stirred at 0°C for 1 hour, and then the temperature was raised to 30°C and stirred for 2 hours. 5 mL of water was added to the reaction solution, the reaction solution was filtered through diatomaceous earth, the filtrate was collected and transferred to a separatory funnel, extracted three times with ethyl acetate (30 mL each time), the organic phases were combined, washed twice with saturated brine (30 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 038-5. ESI-LCMS: m / z = 208.0 [M+H] + .

[0330] Step 4: Synthesis of Compound 038-6 038-5 (564.51 mg, 2.72 mmol) and dichloromethane (4 mL) were sequentially added to the reaction flask, the mixture was purged with nitrogen gas, the reaction solution was cooled to 0°C, boron tribromide (2 M, 5.45 mL) was added, and the mixture was stirred at 0°C for 1 hour. The reaction solution was added to ice water, concentrated to remove dichloromethane, filtered, and the cake was collected to obtain crude product 038-6. Without purification, the next step was carried out directly. 1 H NMR (400 MHz, CD3OD) δ = 7.59 (d, J = 9.9 Hz, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.13 (dd, J = 2.6, 9.1 Hz, 1H), 7.03 (d, J = 2.7 Hz, 1H), 3.76 (s, 3H).

[0331] Step 5: Synthesis of Compound 038-7 038-6 (197.93 mg, 1.02 mmol) and dichloromethane (2 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, and the reaction solution was cooled to -20°C. Pyridine (129.68 mg, 1.64 mmol) was added, followed by trifluoromethanesulfonic anhydride (346.91 mg, 1.23 mmol). The mixture was stirred at -20°C for 0.5 hours, then raised to 0°C and stirred for 2 hours. Water (10 mL) was added to the reaction solution, and the solution was transferred to a separatory funnel. The mixture was extracted four times with dichloromethane (10 mL each time). The organic phases were combined, washed twice with saturated brine (10 mL each time), and the organic phases were collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 038-7. ESI-LCMS: m / z = 325.9 [M+H] + .

[0332] Step 6: Synthesis of Compound 038-8 In a reaction flask, 038-7 (90 mg, 276.72 μmol), 1,4-dioxane (1 mL), bis(pinacolate)diborone (105.41 mg, 415.08 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.37 mg, 41.51 μmol), and potassium acetate (81.47 mg, 830.17 μmol, 3 eq) were added sequentially. The flask was purged with nitrogen gas, and the reaction solution was stirred at 100°C for 3 hours. The reaction solution was filtered, the filtrate was collected, concentrated to obtain crude product 038-8, purified, and used directly in the next step. ESI-LCMS: m / z = 304.0 [M+H] + .

[0333] Step 7: Synthesis of Compound 038 In a reaction flask, A-1 (50 mg, 176.58 μmol), water (1 mL), acetonitrile (3 mL), methanol (1 mL), potassium carbonate (97.62 mg, 706.31 μmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (10.87 mg, 26.49 μmol) were added, and the flask was purged with nitrogen gas. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.20 mg, 8.83 μmol) and palladium acetate (1.98 mg, 8.83 μmol) were added, the flask was purged with nitrogen gas, and the reaction solution was heated to 40°C. A solution of crude product 038-8 (80.29 mg, 264.86 μmol) in tetrahydrofuran (1.5 mL) was added, and the reaction solution was heated to 75°C and stirred for 12 hours. The reaction solution was allowed to return to room temperature, filtered through anhydrous sodium sulfate, and the filtrate was collected and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 1:1:0.5) and SFC chiral separation (column:DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradation elution: 50% ethanol (0.1% aqueous ammonia)) to obtain O38. 1 H NMR (400 MHz, CD3OD) δ = 8.40 (s, 1H), 8.25 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.74 - 7.68 (m, 2H), 7.66 - 7.59 (m, 1H), 5.23 (br t, J = 5.8 Hz, 1H), 3.86 (s, 3H), 2.78 - 2.63 (m, 2H), 2.29 (dq, J = 2.2, 7.6 Hz, 2H), 2.09 - 2.00 (m, 1H), 1.94 - 1.77 (m, 3H), 1.20 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 380.1 [M+H] +SFC analysis (column: Chiralpak IG-3, 50 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol [methanol solution of 0.2% 7 M ammonia], isogradient: 50%), flow rate: 4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected a ee of 100% and a retention time of 1.345 minutes.

[0334] Example 32

[0335] Synthesis pathway: [ka]

[0336] Step 1: Synthesis of Compound 039-3 039-1 (0.5 g, 2.69 mmol) and 039-2 (892.90 mg, 5.37 mmol) were sequentially added to the reaction flask, the flask was purged with nitrogen gas, and the reaction solution was stirred at 130°C for 12 hours. The reaction solution was allowed to return to room temperature, and the reaction solution was concentrated to obtain crude product 039-3. This product was used directly in the next step without purification.

[0337] Step 2: Synthesis of Compound 039-4 039-3 (822.6 mg, 2.69 mmol) and sulfuric acid (4.60 g, 45.96 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the reaction solution was heated to 95°C and stirred for 1 hour. The reaction solution was allowed to return to room temperature, water (7.5 mL) was added to the reaction solution, and the reaction solution was transferred to a separatory funnel. Extraction was performed twice with ethyl acetate (7.5 mL each time), the organic phases were combined, washed with saturated brine (7.5 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1~5:1) to obtain 039-4. 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.74 (dd, J = 8.97, 2.17 Hz, 1 H), 7.33 (d, J = 9.16 Hz, 1 H), 6.97 (s, 1 H), 6.64 - 6.93 (m, 1 H), 3.73 (s, 3H).

[0338] Step 3: Synthesis of Compound 039-5 In a reaction flask, 039-4 (0.33 g, 1.15 mmol), 1,4-dioxane (6 mL), bis(pinacolate)diborone (436.32 mg, 1.72 mmol), potassium acetate (337.25 mg, 3.44 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (83.82 mg, 114.54 μmol) were added. The flask was purged with nitrogen gas, and the reaction solution was stirred at 80°C for 18 hours. The reaction solution was allowed to return to room temperature, filtered through diatomaceous earth, the cake was rinsed with ethyl acetate (5 mL), the filtrate was collected, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1~3:1) to obtain 039-5. ESI-LCMS: m / z = 336.0 [M+H] + .

[0339] Step 4: Synthesis of Compound 039 In a reaction flask, A-1 (100 mg, 353.15 μmol), 039-5 (177.54 mg, 529.73 μmol), ethanol (5 mL), and sodium carbonate (74.86 mg, 706.31 μmol) were added sequentially, the flask was purged with nitrogen gas, tetrakis(triphenylphosphine)palladium(0) (40.81 mg, 35.32 μmol) was added, the flask was purged with nitrogen gas, and the reaction solution was stirred at 85°C for 2 hours. The reaction solution was allowed to return to room temperature, anhydrous sodium sulfate (5 g) was added to the reaction solution, the solution was filtered through diatomaceous earth, the cake was rinsed with ethyl acetate (10 mL), the filtrate was collected, and the crude product was obtained by concentration. The crude product was separated and purified to obtain O39 by sequential preparative thin-layer chromatography (dichloromethane:ethyl acetate:ethanol = 1:1:0.1) and chiral separation (column: DAIEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 50% isopropanol (0.1% aqueous ammonia)). 1 H NMR (400 MHz, CD3OD) δ ppm 8.41 (s, 1 H), 8.26 (s, 1 H), 7.87 (s, 1 H), 7.80 (d, J = 8.80 Hz, 1 H), 7.73 (br d, J = 8.80 Hz, 1 H), 7.05 - 7.33 (m, 1 H), 6.99 (s, 1 H), 5.24 (br t, J = 5.56 Hz, 1 H), 3.83 (s, 3 H), 2.62 - 2.76 (m, 2 H), 2.24 - 2.31 (m, 2 H), 2.03 (br d, J = 11.98 Hz, 1 H), 1.78 - 1.91 (m, 3 H), 1.20 (t, J = 7.64 Hz, 3 H). ESI-LCMS: m / z = 412.2 [M+H] +SFC analysis (column: Chiralpak IG-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: CO2, B: isopropanol [0.2% 7 M ammonia methanol solution], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100% and retention time was 1.808 minutes.

[0340] Example 33

[0341] Synthesis pathway: [ka]

[0342] Step 1: Synthesis of Compound 040-2 040-1 (5 g, 36.45 mmol), triethylamine (4.06 g, 40.09 mmol), and dichloromethane (100 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and a solution of 035-2 (5.47 g, 40.09 mmol) in dichloromethane (7.5 mL) was added. The mixture was stirred at 25°C for 10 minutes. The reaction solution was rotated dry, dissolved in ethyl acetate (100 mL), and washed sequentially once with 1 N citric acid (50 mL) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 040-2. The crude product was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ = 7.19 - 7.11 (m, 2H), 6.97 - 6.88 (m, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 3.27 (s, 3H), 3.22 (s, 2H).

[0343] Step 2: Synthesis of Compound 040-3 Crude product 040-2 (8.5 g), aqueous sodium hydroxide solution (1 M, 42.50 mL), and methanol (42.5 mL) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated, extracted once with ethyl acetate (30 mL), the aqueous phase was collected, the pH was adjusted to 3-4 with 1 N hydrochloric acid, and the solution was extracted three times with ethyl acetate (50 mL each time). The organic phases were combined, washed with saturated brine (50 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 040-3, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ = 7.14 - 7.07 (m, 2H), 7.00 - 6.94 (m, 2H), 3.85 (s, 3H), 3.32 (s, 3H), 3.13 (s, 2H).

[0344] Step 3: Synthesis of Compound 040-4 Crude product 040-3 (8 g) and Eaton's reagent (60.60 g, 254.57 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and the mixture was stirred at 70°C for 3 hours. The reaction solution was cooled to 25°C, poured into ice water (250 mL), filtered, and the cake was collected. Acetonitrile (100 mL) was added, the mixture was stirred for 0.5 hours, filtered, and the cake was collected to obtain 040-4. 1 H NMR (400 MHz, DMSO-d6) δ = 11.52 (br s, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.27 (dd, J = 3.0, 9.1 Hz, 1H), 5.95 (s, 1H), 3.81 (s, 3H), 3.54 (s, 3H).

[0345] Step 4: Synthesis of Compound 040-5 Phosphorus oxybromide (8.59 g, 29.97 mmol) and N,N-dimethylformamide (41 mL) were sequentially added to the reaction flask, the mixture was purged with nitrogen gas, and 040-4 (4.1 g, 19.98 mmol) was added in batches. The mixture was stirred at 80°C for 3 hours. The reaction solution was cooled to 25°C, poured into ice water (200 mL), filtered, the cake was collected and dried to obtain 040-5, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 2.9 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.26 - 7.22 (m, 1H), 7.17 (s, 1H), 3.92 (s, 3H), 3.71 (s, 3H).

[0346] Step 5: Synthesis of Compound 040-6 040-5 (1 g, 3.73 mmol), N-fluorobenzenesulfonimide (2.35 g, 7.46 mmol), and tetrahydrofuran (30 mL) were sequentially added to a reaction flask. After purging with nitrogen gas, the flask was cooled to -78°C, n-butyllithium (2.5 M, 4.48 mL) was added, and the mixture was stirred at -78°C for 1 hour. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL each time), the organic phases were combined, washed with saturated brine (10 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 040-6. 1 H NMR (400 MHz, CDCl3) δ = 7.38 - 7.32 (m, 1H), 7.28 (d, J = 2.9 Hz, 1H), 7.26 - 7.24 (m, 1H), 6.43 (d, J = 11.3 Hz, 1H), 3.90 (s, 3H), 3.70 (s, 3H).

[0347] Step 6: Synthesis of Compound 040-7 040-6 (170 mg, 820.46 μmol) and dichloromethane (4 mL) were added sequentially to the reaction flask, the mixture was purged with nitrogen gas, cooled to 0°C, and boron tribromide (2 M dichloromethane solution, 1.64 mL) was added. The mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated to obtain 040-7, and the crude product was used directly in the next step.

[0348] Step 7: Synthesis of Compound 040-8 Crude product 040-7 (0.16 g) and dichloromethane (6 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, and the flask was left at 0°C. Pyridine (196.55 mg, 2.48 mmol) and trifluoromethanesulfonic anhydride (467.37 mg, 1.66 mmol) were sequentially added, and the mixture was stirred at 0°C for 0.5 hours. Water (2 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (2 mL each time). The organic phases were combined, washed with saturated brine (5 mL), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 040-8. 1 H NMR (400 MHz, CDCl3) δ = 7.75 (d, J = 2.8 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.51 - 7.46 (m, 1H), 6.52 (d, J = 10.9 Hz, 1H), 3.72 (s, 3H).

[0349] Step 8: Synthesis of Compound 040-9 In a reaction flask, 040-8 (150 mg, 461.20 μmol), bis(pinacolate)diborone (175.68 mg, 691.81 μmol), potassium acetate (135.79 mg, 1.38 mmol), and 1,4-dioxane (3 mL) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.75 mg, 46.12 μmol) was added, and the mixture was stirred at 90°C for 4 hours. The reaction solution was concentrated to obtain crude product 040-9, which was used directly in the next step.

[0350] Step 9: Synthesis of Compound 040 Crude product 040-9 (135.42 mg), A-1 (115 mg, 406.13 μmol), sodium carbonate (86.09 mg, 812.25 μmol), water (0.5 mL), and ethanol (3 mL) were added sequentially to a reaction flask. The flask was then purged with nitrogen gas, and tetrakis(triphenylphosphine)palladium(0) (46.93 mg, 40.61 μmol) was added. The mixture was stirred at 85°C for 1 hour. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified sequentially by column chromatography (ethyl acetate:methanol = 1:0 to 20:1), preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 5:5:1), preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100×30mm×10um, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: 20% to 50% acetonitrile), and SFC chiral separation (column: DAIEL CHIRALPAK AD (250mm×30mm, 10μm), mobile phase: [supercritical carbon dioxide-isopropanol (0.1% aqueous ammonia)], isogradient elution: 50% isopropanol (0.1% aqueous ammonia)) to obtain O40. 1 H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1H), 8.33 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.53 - 7.46 (m, 1H), 6.46 (d, J = 11.0 Hz, 1H), 5.80 (br d, J = 8.7 Hz, 1H), 5.46 - 5.32 (m, 1H), 3.75 (s, 3H), 2.74 - 2.55 (m, 2H), 2.30 (q, J = 7.6 Hz, 2H), 2.15 - 2.08 (m, 1H), 1.91 - 1.76 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 380.2 [M+H] +SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: isopropanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100% and retention time was 1.484 minutes.

[0351] Example 34

[0352] Synthesis pathway: [ka]

[0353] Step 1: Synthesis of Compound 041-2 041-1 (0.85 g, 4.98 mmol) and sodium methoxide (5.4 M methanol solution, 8.5 mL) were added sequentially to the reaction flask and stirred at 80°C for 1 hour. The reaction solution was allowed to cool to 25°C, water (5 mL) was added to the reaction solution, and 10 mL of dichloromethane was added for extraction. The organic phase was collected, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 041-2, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ = 8.88 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H).

[0354] Step 2: Synthesis of Compound 041-3 Crude product 041-2 (0.26 g) and hydrobromic acid (58.70 g, 239.40 mmol) were sequentially added to the reaction flask, the flask was purged with nitrogen gas, and the mixture was stirred at 130°C for 2 hours. The reaction solution was allowed to cool to 25°C, concentrated to obtain crude product 041-3, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H).

[0355] Step 3: Synthesis of Compound 041-4 Crude product 041-3 (0.38 g), N,N-dimethylformamide (8 mL), and potassium carbonate (690.26 mg, 4.99 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, the temperature was cooled to 0°C, methyl iodide (1.42 g, 9.99 mmol) was added dropwise, and the mixture was stirred at 0°C for 2 hours. 10 mL of water was added to the reaction solution, and 10 mL of ethyl acetate was added for extraction and separation. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:0) to obtain compound 041-4. 1 H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 8.00 (d, J = 9.7 Hz, 1H), 6.68 (d, J = 9.5 Hz, 1H), 3.74 (s, 3H).

[0356] Step 4: Synthesis of Compound 041-5 041-4 (50 mg, 300.84 μmol) and tetrahydrofuran (1 mL) were added sequentially to the reaction flask, the mixture was purged with nitrogen gas, zinc chloride (0.7 M tetrahydrofuran solution, 429.77 μL) was added, the mixture was cooled to -5°C, lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 601.68 μL) was added dropwise, the temperature was raised to 10°C and the mixture was stirred for 1 hour. The reaction solution of 041-5 was obtained and used directly in the next step without further processing.

[0357] Step 5: Synthesis of Compound 041 In a reaction flask, A-1 (85.15 mg, 300.71 μmol) and N,N-dimethylformamide (3 mL) were added sequentially, the flask was purged with nitrogen gas, (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (7.04 mg, 9.02 μmol) was added, the flask was purged with nitrogen gas, the temperature was raised to 100°C, the reaction solution of 041-5 was added, and the mixture was stirred at 100°C for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified to obtain O41 by sequential preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol = 1:1:0.3) and SFC chiral separation (column:DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - methanol (0.1% aqueous ammonia)], gradient: 45%~54% methanol (0.1% aqueous ammonia)). 1 H NMR (400 MHz, CD3OD) δ = 8.71 (s, 1H), 8.48 (s, 1H), 8.13 (d, J = 9.5 Hz, 1H), 6.69 (d, J = 9.5 Hz, 1H), 5.24 (br s, 1H), 3.80 (s, 3H), 3.18 (br s, 1H), 3.15 - 3.10 (m, 1H), 2.29 (dq, J = 1.5, 7.6 Hz, 2H), 2.09 - 1.84 (m, 5H), 1.19 (t, J = 7.7 Hz, 3H); ESI-LCMS: m / z = 369.1 [M+H] +SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: methanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi) detected ee = 100% and retention time was 1.968 minutes.

[0358] Example 35

[0359] Synthesis pathway: [ka]

[0360] Step 1: Synthesis of Compound 042-3 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (530.70 mg, 1.11 mmol), palladium acetate (124.97 mg, 556.62 μmol), and N,N-dimethylformamide (74 mL) were sequentially added to a reaction flask, and the flask was purged with nitrogen gas. Then, 042-1 (3.7 g, 11.13 mmol), triethylamine (9.01 g, 89.06 mmol), and 042-2 (10.83 g, 66.79 mmol) were sequentially added, the flask was purged with nitrogen gas, and the mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to 25°C, water (370 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), and the organic phases were collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain 042-3. 1H NMR (400 MHz, DMSO-d6) δ = 7.71 (d, J = 16.5 Hz, 1H), 7.47 - 7.33 (m, 6H), 6.68 (d, J = 8.9 Hz, 1H), 6.48 (d, J = 16.4 Hz, 1H), 5.85 (s, 2H), 5.24 (s, 2H).

[0361] Step 2: Synthesis of Compound 042-4 042-3 (2.18 g, 5.95 mmol), methanol (22 mL), and triphenylphosphine (3.61 g, 17.84 mmol) were sequentially added to the reaction flask, and the mixture was stirred at 70°C for 1.5 hours. The reaction solution was directly concentrated to obtain crude product 042-4, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ = 12.14 (br s, 1H), 8.10 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.31 (s, 1H), 6.66 (d, J = 9.8 Hz, 1H).

[0362] Step 3: Synthesis of Compound 042-5 Crude product 042-4 (5.5 g), N,N-dimethylformamide (55 mL), and potassium carbonate (5.88 g, 42.55 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and methyl iodide (12.08 g, 85.11 mmol) was added. The mixture was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution, the mixture was filtered, and the cake was collected to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to obtain 042-5. 1 H NMR (400 MHz, DMSO-d6) δ = 8.14 (d, J = 9.9 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.49 (d, J = 9.3 Hz, 1H), 6.78 (d, J = 9.9 Hz, 1H), 3.61 (s, 3H).

[0363] Step 4: Synthesis of Compound 042-6 In a reaction flask, 042-5 (200 mg, 733.88 μmol), bis(pinacolate)diborone (279.54 mg, 1.10 mmol), 1,4-dioxane (4 mL), and potassium acetate (144.05 mg, 1.47 mmol) were added sequentially, the flask was purged with nitrogen gas, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (53.70 mg, 73.39 μmol) was added, the flask was purged with nitrogen gas, and the mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to 25°C, filtered, the cake was rinsed with dichloromethane, the filtrate was collected, and the crude product 042-6 was obtained by concentrating under reduced pressure and used directly in the next step.

[0364] Step 5: Synthesis of Compound 042 In a reaction flask, A-1 (141.76 mg, 500.64 μmol), water (1.2 mL), acetonitrile (3.6 mL), methanol (1.2 mL), potassium carbonate (276.77 mg, 2.00 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (30.83 mg, 75.10 μmol) were added, the mixture was purged with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (17.57 mg, 25.03 μmol) and palladium acetate (5.62 mg, 25.03 μmol) were added, the temperature was raised to 40°C, a solution of crude product 042-6 (240 mg) in tetrahydrofuran (7.2 mL) was added, the mixture was purged with nitrogen gas, and the temperature was raised to 75°C and stirred for 2 hours. The reaction mixture was filtered, rinsed with dichloromethane, the filtrate was collected, and the mixture was concentrated under reduced pressure. Separation and purification of O42 was performed by preparative high-performance liquid chromatography (column: 2_Phenomenex Gemini C18 75×40mm×3μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: 10%~40% acetonitrile) to obtain O42. 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.38 - 8.25 (m, 1H), 8.25 - 8.17 (m, 2H), 7.70 - 7.63 (m, 1H), 7.62 - 7.46 (m, 1H), 6.82 (d, J = 9.9 Hz, 1H), 5.11 (br d, J = 6.3 Hz, 1H), 3.69 (s, 3H), 2.40 - 2.31 (m, 2H), 2.23 - 2.13 (m, 2H), 1.92 - 1.65 (m, 4H), 1.07 (dt, J = 3.8, 7.6 Hz, 3H); ESI-LCMS: m / z = 396.1 [M+H] + .

[0365] Example 36

[0366] Synthesis pathway: [ka]

[0367] Step 1: Synthesis of Compound 043-3 043-1 (500 mg, 1.97 mmol), dichloromethane (5 mL), and pyridine (187.19 mg, 2.37 mmol) were sequentially added to a reaction flask, the flask was purged with nitrogen gas, and 043-2 (291.91 mg, 2.17 mmol) was added. The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated to obtain the crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain 043-3. 1 H NMR (400 MHz, CDCl3) δ = 7.74 - 7.57 (m, 3H), 7.42 (dd, J = 1.8, 8.2 Hz, 1H), 5.29 (d, J = 12.0 Hz, 1H), 3.96 (q, J = 7.0 Hz, 2H), 1.36 (s, 15H).

[0368] Step 2: Synthesis of Compound 043-4 In a reaction flask, 043-3 (149.02 mg, 423.78 μmol), potassium carbonate (195.24 mg, 1.41 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (21.75 mg, 52.97 μmol), bis(triphenylphosphine)palladium(II) dichloride (12.39 mg, 17.66 μmol), palladium acetate (3.96 mg, 17.66 μmol), water (1.6 mL), acetonitrile (4.8 mL), and methanol (1.6 mL) were added sequentially. The mixture was then purged with nitrogen gas, the temperature was raised to 45°C, and a solution of A-1 (100 mg, 353.15 μmol) in tetrahydrofuran (1.6 mL) was added. The temperature was then raised to 75°C and the mixture was stirred for 2 hours. 2 mL of water was added to the reaction solution, extracted with dichloromethane (3 mL x 3), combined the organic phases, washed with saturated brine (3 mL x 3), collected the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol = 1:1:0.3) to obtain O43-4. 1 H NMR (400 MHz, CDCl3) δ = 8.57 (br d, J = 2.1 Hz, 1H), 8.41 - 8.09 (m, 1H), 7.69 (dd, J = 3.1, 12.0 Hz, 1H), 7.62 - 7.49 (m, 1H), 7.40 - 7.32 (m, 1H), 5.54 - 5.42 (m, 1H), 5.40 - 5.32 (m, 1H), 5.31 - 5.23 (m, 1H), 4.14 - 3.91 (m, 2H), 3.02 - 2.91 (m, 2H), 2.44 - 2.28 (m, 4H), 2.21 - 2.12 (m, 2H), 1.39 (br t, J = 6.7 Hz, 3H), 1.23 - 1.19 (m, 3H).

[0369] Step 3: Synthesis of Compound 043-5 Concentrated sulfuric acid (1.5 mL) was added to the reaction flask, cooled to 0°C, 043-4 (90 mg, 210.32 μmol) was added, the mixture was purged with nitrogen gas, and stirred at 25°C for 2 hours. Water was added to the reaction solution, the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, ethyl acetate (3 mL x 3) was added for extraction, the organic phases were combined, washed with saturated brine (3 mL x 3), the organic phases were combined again, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 043-5, which was used directly in the next step. 1 H NMR (400 MHz, CD3OD) δ = 8.44 (s, 1H), 8.25 (d, J = 4.5 Hz, 1H), 8.17 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.18 (d, J = 5.4 Hz, 1H), 5.31 - 5.18 (m, 1H), 2.88 - 2.79 (m, 2H), 2.56 - 2.47 (m, 2H), 2.27 - 2.22 (m, 2H), 2.05 - 1.99 (m, 2H), 1.18 (s, 3H).

[0370] Step 4: Synthesis of Compound 043 Crude product 043-5 (40 mg), N,N-dimethylformamide (0.5 mL), and cesium carbonate (68.26 mg, 209.50 μmol) were sequentially added to a reaction flask, cooled to 0°C, methyl iodide (22.30 mg, 157.13 μmol) was added, the flask was purged with nitrogen gas, and stirred at 0°C for 1 hour. The reaction solution was poured into 2 mL of water, extracted three times with ethyl acetate (3 mL each time), the organic phases were combined, washed three times with saturated brine (3 mL each time), the organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified to obtain O43 by sequential preparative thin-layer chromatography (dichloromethane:ethyl acetate:ethanol = 1:1:0.3) and SFC chiral separation (column: ChiralPak IH, 250 mm × 30 mm, 10 μm, mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradation elution: 50% isopropanol (0.1% aqueous ammonia)). 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.39 - 8.25 (m, 1H), 8.21 (s, 1H), 7.93 (dd, J = 9.7, 18.6 Hz, 1H), 7.82 - 7.61 (m, 2H), 6.74 - 6.62 (m, 1H), 5.18 - 5.04 (m, 1H), 3.65 (s, 3H), 2.42 - 2.33 (m, 2H), 2.25 - 2.10 (m, 2H), 1.95 - 1.74 (m, 2H), 1.74 - 1.61 (m, 2H), 1.07 (dt, J = 3.4, 7.5 Hz, 3H); ESI-LCMS: m / z = 396.1 [M+H] + The substance was detected by SFC analysis (column: Chiralpak IH-3, 100 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: isopropanol [0.2% 7M ammonia methanol solution], gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.2 min), 50 / 50 (2.4 min), 50 / 50 (3.4 min), 90 / 10 (4.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 2000 psi), with ee = 93.92% and retention time of 3.194 minutes.

[0371] Example 37

[0372] Synthesis pathway: [ka]

[0373] Step 1: Synthesis of Compound 044 In a reaction flask, 001-3 (120.00 mg, 420.85 μmol), water (1 mL), acetonitrile (3 mL), methanol (1 mL), potassium carbonate (193.89 mg, 1.40 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (21.60 mg, 52.61 μmol) were added sequentially, the mixture was purged with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (12.31 mg, 17.54 μmol) and palladium acetate (3.94 mg, 17.54 μmol) were added, the mixture was purged with nitrogen gas, the temperature was raised to 45°C, and 037-10 (100 mg, 350.71 μmol) in tetrahydrofuran (6 mL) solution was added. The temperature was then raised to 75°C and the mixture was stirred for 16 hours. The reaction solution was concentrated to obtain the crude product, which was then subjected to preparative thin-layer chromatography (petroleum ether:ethyl acetate = 0:1), a second preparative thin-layer chromatography (dichloromethane:methanol = 10:1), and SFC chiral separation (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - isopropanol (0.1% aqueous ammonia)], isogradient elution: 40% isopropanol (0.1% aqueous ammonia)) to obtain O44. 1 H NMR (400 MHz, CD3OD) δ = 8.31 (d, J = 15.0 Hz, 2H), 7.98 (d, J = 9.5 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.68 (s, 1H), 6.72 (d, J = 9.5 Hz, 1H), 5.24 (s, 1H), 4.53 - 4.28 (m, 2H), 3.79 (s, 3H), 2.33 - 2.26 (m, 2H), 2.25 - 2.07 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 364.2 [M+H] +SFC analysis (column: Chiralcel AD-3, 150 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: isopropanol [methanol solution of 0.2% 7 M ammonia], gradient: A / B = 90 / 10 (0 min), 90 / 10 (0.5 min), 50 / 50 (3.5 min), 50 / 50 (4.5 min), 90 / 10 (5.0 min), flow rate: 2.5 mL / min, column temperature: 35 °C, pressure: 2000 psi) detected ee = 100%, retention time was 3.894 minutes.

[0374] Example 38

[0375] Synthesis pathway: [ka]

[0376] Step 1: Synthesis of Compound 045-1 In a reaction flask, 023-1 (120 mg, 491.59 μmol), triisopropyl borate (309.72 mg, 1.65 mmol), and tetrahydrofuran (1.2 mL) were added sequentially, the flask was purged with nitrogen gas, and the mixture was cooled to -5°C. Isopropyl magnesium chloride-lithium chloride (1.3 M, 567.21 μL) was added, and the mixture was stirred at -5°C for 0.5 hours. Isopropyl magnesium chloride-lithium chloride complex (1.3 M tetrahydrofuran solution, 378.14 μL) was added, and the mixture was stirred at -5°C for 1 hour. Isopropyl magnesium chloride-lithium chloride complex (1.3 M tetrahydrofuran solution, 567.21 μL) and triisopropyl borate (92.45 mg, 491.59 μmol) were added, and the mixture was stirred at 0°C for 0.5 hours. 0.9 mL of methanol was added to the reaction solution to obtain reaction solution 045-1, which was used directly in the next step.

[0377] Step 2: Synthesis of Compound 045 In a reaction flask, 037-10 (69.57 mg, 243.98 μmol), tetrahydrofuran (0.9 mL), water (0.3 mL), acetonitrile (0.3 mL), potassium carbonate (134.88 mg, 975.94 μmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (15.02 mg, 36.60 μmol) were added sequentially, the flask was purged with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (8.56 mg, 12.20 μmol) and palladium acetate (2.74 mg, 12.20 μmol) were added, the flask was purged with nitrogen gas, the reaction solution of 045-1 was added at 45°C, the temperature was raised to 75°C, and the mixture was stirred for 16 hours. The reaction solution was concentrated to obtain the crude product, which was then separated and purified to obtain O45 by sequential preparative thin-layer chromatography (petroleum ether:ethyl acetate = 0:1), a second preparative thin-layer chromatography (dichloromethane:methanol = 10:1), and preparative high-performance liquid chromatography (column:Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], gradient: 10%~43% acetonitrile). 1 H NMR (400 MHz, CD3OD) δ = 8.67 (s, 1H), 8.28 - 8.19 (m, 1H), 7.97 - 7.90 (m, 1H), 7.74 (s, 1H), 6.56 (d, J = 9.3 Hz, 1H), 5.23 (s, 1H), 4.66 - 4.46 (m, 2H), 3.76 (s, 3H), 2.32 - 2.27 (m, 2H), 2.26 (br s, 2H), 1.19 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z = 370.1 [M+H] +The substance was detected by SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: methanol solution of 0.2% 7 M ammonia, gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi), with ee = 100% and retention time of 1.479 minutes.

[0378] Example 39

[0379] Synthesis pathway: [ka]

[0380] Step 1: Synthesis of Compound 046-1 0.25 g, 1.02 mmol of 017-8 and 6.25 mL of tetrahydrofuran were added sequentially to the reaction flask, the flask was purged with nitrogen gas, and cooled to -15 to -20°C. Isopropyl magnesium chloride-lithium chloride complex (1.3 M solution of tetrahydrofuran, 1.95 mL) was added dropwise, and the mixture was stirred at -15 to -20°C for 0.5 hours. Triisopropyl borate (353.59 mg, 3.40 mmol) was added, and stirring was continued for another 0.5 hours. After adding 0.5 mL of methanol to the reaction solution, the reaction solution of 046-1 was obtained and used directly in the next step.

[0381] Step 2: Synthesis of Compound 046 In a reaction flask, 037-10 (0.13 g, 455.92 μmol), potassium phosphate (193.56 mg, 911.84 μmol), isopropanol (7.2 mL), and water (1.2 mL) were added sequentially, and the flask was purged with nitrogen gas. Dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (32.28 mg, 45.59 μmol) was added, the flask was again purged with nitrogen gas, and the temperature was raised to 45°C. The reaction solution of 046-1 was added dropwise, and after the addition was complete, the temperature was raised to 75°C and the mixture was stirred for 2 hours. The reaction solution was filtered over anhydrous sodium sulfate, the filtrate was collected and concentrated to obtain the crude product. The crude product was separated and purified sequentially by column chromatography (petroleum ether:ethyl acetate = 10:1 to dichloromethane:methanol = 1:1) and preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], 15%~50% acetonitrile, isogram) to obtain O46. 1 H NMR (400 MHz, CD3OD) δ = 8.57 (br s, 1H), 8.14 (br s, 1H), 7.36 (s, 1H), 5.19 (t, J = 5.5 Hz, 1H), 4.64 - 4.42 (m, 2H), 3.34 (s, 3H), 2.93 - 2.84 (m, 2H), 2.77 - 2.66 (m, 2H), 2.34 - 2.08 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H); ESI-LCMS: m / z =372.2 [M+H] +The substance was detected by SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: methanol solution of 0.2% 7 M ammonia), gradient: A / B = 95 / 5 (0 min), 95 / 5 (0.2 min), 50 / 50 (1.2 min), 50 / 50 (2.2 min), 95 / 5 (2.6 min), 95 / 5 (3.0 min), flow rate: 3.4 mL / min, column temperature: 35 °C, pressure: 1800 psi), with ee = 100% and retention time of 1.431 minutes.

[0382] Example 40

[0383] Synthesis pathway: [ka]

[0384] Step 1: Synthesis of Compound 047-2 047-1 (350 mg, 2.06 mmol), methanol (7 mL), and sodium methoxide (5.4 M methanol solution, 2 mL) were sequentially added to a reaction flask, placed in a microwave reactor, heated to 100°C, and stirred for 5 hours. The same scale reaction was carried out in parallel in three batches and the mixture was worked together. The reaction mixtures were combined and concentrated, 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was extracted and separated. The aqueous phase was collected and extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with saturated brine, and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 047-2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J = 8.53 Hz, 1H), 7.67 (d, J = 5.52 Hz, 1H), 7.41 (d, J = 5.52 Hz, 1H), 6.77 (d, J = 8.53 Hz, 1H), 4.02 (s, 3H).

[0385] Step 2: Synthesis of Compound 047-3 047-2 (0.9 g), acetic acid (9 mL), and hydrobromic acid (9 mL, 66.29 mmol, 40% concentration) were added sequentially to the reaction flask. After gas purging with nitrogen, the mixture was stirred at 85°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 047-3. 1 H NMR (400 MHz, CD3OD) δ ppm 8.73 (d, J = 9.29 Hz, 1H), 8.32 (d, J = 5.52 Hz, 1H), 7.44 (d, J = 5.52 Hz, 1H), 7.07 (d, J = 9.03 Hz, 1H).

[0386] Step 3: Synthesis of Compound 047-4 047-3 (1.43 g) and N,N-dimethylformamide (30 mL) were sequentially added to a reaction flask, and potassium tert-butoxide (3.18 g, 28.38 mmol) was added at 0°C. After stirring at 0°C for 15 minutes, methyl iodide (1.47 mL, 23.65 mmol) was added dropwise, and the temperature was raised to 20°C and stirred for 18 hours. The mixture was diluted with 40 mL of ethyl acetate, extracted with 80 mL of hydrochloric acid (concentration: 1 M), separated, and the aqueous phase was extracted with ethyl acetate (40 mL x 5). The organic phases were combined, washed with saturated brine (140 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10-100%) to obtain 047-4. 1 H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J = 9.29 Hz, 1H), 7.89 (d, J = 5.52 Hz, 1H), 7.32 (d, J = 5.52 Hz, 1H), 6.55 (d, J = 9.29 Hz, 1H), 3.75 (s, 3H).

[0387] Step 4: Synthesis of Compound 047-5 047-4 (213 mg, 1.29 mmol) and tetrahydrofuran (12 mL) were sequentially added to a reaction flask, the mixture was purged with nitrogen gas, and cooled to 0°C. A solution of N-bromosuccinimide (210 mg, 1.18 mmol) in tetrahydrofuran (12 mL) was added, and the mixture was stirred at 0°C for 1 hour. A semi-saturated aqueous sodium thiosulfate solution (40 mL) was added to the reaction solution, and the mixture was stirred at 25°C for 5 minutes. The mixture was extracted with ethyl acetate (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:5) to obtain 047-5. 1 H NMR (400 MHz, CDCl3) δ ppm 8.14 (s, 1H), 7.62 (d, J = 5.52 Hz, 1H), 7.06 (d, J = 5.52 Hz, 1H) ,3.81 (s, 3H).

[0388] Step 5: Synthesis of Compound 047-6 047-5 (174 mg, 712.80 μmol) and tetrahydrofuran (4 mL) were added sequentially to the reaction flask, and the mixture was purged with nitrogen gas. The mixture was cooled to 0°C, and isopropylmagnesium chloride-lithium chloride complex (2 M tetrahydrofuran solution, 534.60 μL) was added dropwise, and the mixture was stirred at 20°C for 0.5 hours. The mixture was cooled to 0°C, and a tetrahydrofuran solution of trimethyl borate (161.02 μL, 1.43 mmol) was added dropwise, and the mixture was heated to 20°C and stirred for 0.5 hours. After adding 1 mL of methanol to the reaction solution, the reaction solution of 047-6 was obtained and used directly in the next step.

[0389] Step 6: Synthesis of Compound 047 A-1 (222.03 mg, 784.10 μmol), potassium carbonate (394.06 mg, 2.85 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (43.89 mg, 106.92 μmol), acetonitrile (8 mL), and water (1.6 mL) were added sequentially to the reaction flask. After purging with nitrogen gas, bis(triphenylphosphine)palladium(II) dichloride (25.02 mg, 35.64 μmol) and palladium acetate (8.00 mg, 35.64 μmol) were added. After purging with nitrogen gas, the reaction solution of 047-6 described above was added dropwise, and after the addition was complete, the temperature was raised to 75°C and the mixture was stirred for 1 hour. The reaction solution was filtered through a funnel containing anhydrous sodium sulfate, the filtrate was collected, and the mixture was concentrated to obtain the crude product. The crude product was separated and purified sequentially by preparative thin-layer chromatography (dichloromethane:methanol = 15:1), SFC chiral separation [column: DAIEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 25% ethanol (0.1% aqueous ammonia)], and preparative high-performance liquid chromatography [column: Welch Xtimate C18 150 × 30 mm × 5 μm, mobile phase: [water (0.225% formic acid) - acetonitrile], gradient: 5%~35% acetonitrile] to obtain O47. 1 H NMR (400 MHz, CDCl3) δ ppm 8.51 (br s, 1H), 8.28 (s, 1H), 7.72 (s, 1H), 7.65 - 7.70 (m, 1H), 7.13 (d, J = 5.52 Hz, 1H), 5.92 (br s, 1H), 5.30 - 5.37 (m, 1H), 3.80 (s, 3H), 2.41 (br s, 2H), 2.27 (q, J = 7.53 Hz, 2H), 2.00 - 2.10 (m, 1H), 1.73 - 1.93 (m, 3H), 1.21 (t, J = 7.53 Hz, 3H); ESI-LCMS: m / z = 368.1 [M+H] +SFC analysis (column: Chiralcel OJ-3, 50×4.6mm ID., 3μm, mobile phase: A: supercritical carbon dioxide, B: ethanol [0.05% diethylamine], gradient: 5%~40% B (2 min), 40% B (hold for 1.2 min), 5% B (hold for 0.5 min), flow rate: 3.0 mL / min, column temperature: 35°C, column pressure: 1500 psi) detected ee = 98.58% and retention time was 1.394 minutes.

[0390] Example 41

[0391] Synthesis pathway: [ka]

[0392] Step 1: Synthesis of Compound 048-2 048-1 (0.819 g, 3.86 mmol) and tetrahydrofuran (10 mL) were sequentially added to a reaction flask and stirred to dissolve. Then tetraethyl titanate (1.60 mL, 7.72 mmol) was added, and a solution of A-1-2 (468.13 mg, 3.86 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred at 75°C for 1 hour. The reaction solution was allowed to return to room temperature, and 40 mL of ethyl acetate and 40 mL of saturated sodium bicarbonate aqueous solution were sequentially added. The mixture was filtered through diatomaceous earth, and the cake was sequentially rinsed with ethyl acetate, water, and ethyl acetate (40 mL x 2). The filtrate was collected and separated, and the organic phase was collected and washed sequentially with saturated sodium bicarbonate aqueous solution and saturated brine (100 mL each time). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10-30%) to obtain 048-2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.90 (s, 1H), 8.73 (s, 1H), 3.50 - 3.63 (m, 2H), 3.10 - 3.22 (m, 2H), 1.34 (s, 9H).

[0393] Step 2: Synthesis of Compound 048-3 048-2 (255 mg, 808.94 μmol) and tetrahydrofuran (10 mL) were sequentially added to a reaction flask, and the flask was purged with nitrogen gas. 9-borabicyclo[3.3.1]nonane (0.5 M tetrahydrofuran solution, 4.04 mL) was added dropwise at 0°C, and the temperature was raised to 20°C for 16 hours. Saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 3). The organic phase was collected, washed with saturated brine (30 mL), and the organic phase was collected again. It was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 048-3.

[0394] Step 3: Synthesis of Compound 048-4 048-3 (170 mg, 535.86 μmol) and ethanol (9 mL) were sequentially added to the reaction flask. Chlorotrimethylsilane (136.02 μL, 1.07 mmol) was added at 0°C, and the temperature was raised to 20°C and the mixture was stirred for 2 hours. The reaction solution was concentrated to obtain crude product 048-4. This product was used directly in the next step without purification. ESI-LCMS: m / z = 213.0 [M+H] + .

[0395] Step 4: Synthesis of Compound 048-5 048-4 (115 mg, 539.72 μmol), dichloromethane (9 mL), and N,N-diisopropylethylamine (159.23 μL, 914.17 μmol) were sequentially added to a reaction flask. The mixture was left at 0°C, and then added to a solution of propionic anhydride (72 μL, 558.78 μmol) in dichloromethane (9 mL). The mixture was stirred at 0°C for 1 hour. 10 mL of water was added, the mixture was separated, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, and the organic phase was collected. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, with 1% triethylamine added) to obtain 048-5. ESI-LCMS: m / z = 269.1 [M+H] + .

[0396] Step 5: Synthesis of Compound 048 In a reaction flask, 048-5 (58 mg, 215.50 μmol), 1,4-dioxane (5 mL), 001-3 (155.08 mg, 431.01 μmol), potassium carbonate (119.14 mg, 862.01 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (13.27 mg, 32.33 μmol), and water (1 mL) were added sequentially. The flask was purged with nitrogen gas, and palladium acetate (2.42 mg, 10.78 μmol) and bis(triphenylphosphine)palladium(II) dichloride (7.56 mg, 10.78 μmol) were added. The mixture was heated to 75°C and stirred for 2 hours. 001-3 (155.08 mg, 431.01 μmol) was added, and the mixture was stirred at 75°C for 18 hours. The reaction solution was returned to 20°C, filtered with anhydrous sodium sulfate, and the cake was rinsed with 15 mL of ethyl acetate. The filtrate was collected and concentrated to obtain the crude product. The crude product was sequentially separated by thin-layer chromatography (dichloromethane:methanol = 20:1) and SFC chiral separation (column:DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm), mobile phase: [supercritical carbon dioxide - ethanol (0.1% aqueous ammonia)], isogradient elution: 40% ethanol (0.1% aqueous ammonia)) to obtain O48. 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (br s, 2H), 7.72 (d, J = 9.29 Hz, 1H), 7.60 - 7.68 (m, 2H), 7.48 (d, J = 8.53 Hz, 1H), 6.78 (d, J = 9.29 Hz, 1H), 5.78 (br d, J = 7.03 Hz, 1H), 5.69 (q, J = 7.70 Hz, 1H), 3.78 (s, 3H), 2.98 - 3.12 (m, 2H), 2.63 - 2.74 (m, 1H), 2.32 (q, J = 7.53 Hz, 2H), 1.82 - 1.92 (m, 1H), 1.22 - 1.26 (m, 3H); ESI-LCMS: m / z = 348.2 [M+H] + SFC analysis (column: Chiralpak AD-3, 50 × 4.6 mm ID., 3 μm, mobile phase: A: supercritical carbon dioxide, B: ethanol [0.05% diethylamine], gradient: 5%~40% B (1.5 min), 40% B (hold for 1.0 min), 5% B (hold for 0.5 min), flow rate: 4 mL / min, column temperature: 35°C, column pressure: 1500 psi) detected ee = 100% and retention time was 1.927 minutes.

[0397] Biological evaluation

[0398] Experimental Example 1: In vitro activity test of monoclonal cells overexpressing humanized CYP11B2 We used the human renal leiomyoma G402 cell line, which overexpresses humanized CYP11B2 cells, as a compound activity screening system. Details are as follows: 1) Information regarding cells, reagents, and equipment can be found in Tables 1 and 2.

[0399] [Table 1]

[0400] [Table 2]

[0401] 2) Compound information: The test compound was prepared to a working concentration of 10 μM using DMSO.

[0402] 3) Experimental Method

[0403] Day 1: Digested cells and extracted 1 × 10⁶ human renal leiomyoma G402 cells that overexpress humanized CYP11B2. 5 The cells were resuspended in a cell / mL solution, and 100 μL was taken and seeded into a 96-well plate.

[0404] Day 2: The culture medium was changed to DMEM / F12 containing 2.5% activated carbon-treated fetal bovine serum, and the test compound was added (5 μL of the test compound was added to the cell medium so that the final concentrations were 10000, 2500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, and 0 nM (DMSO content: 0.1%)). After 1 hour, the substrate was added: 30 mM 11-deoxycorticosterone was taken, diluted 1500-fold with culture medium, and then 5 μL was dispensed into each well to a final concentration of 1 μM, and incubated for 16 hours.

[0405] Day 3: Cell supernatant was collected, and 200 μL of methanol solution containing an internal standard (internal standard: 35 ng / mL ketoprofen, or 7.5 ng / mL carbamazepine, or 5 ng / mL diphenhydramine, or 10 ng / mL tolbutamide) was added. The mixture was stirred with a vortex mixer, centrifuged (4000 × g, 4°C, 5 min), and 100 μL of supernatant was taken and 100 μL of pure water was added. The mixture was stirred with a vortex mixer, centrifuged (4000 g, 4°C, 15 min), and the supernatant was taken and detected by ESI-LCMS / MS.

[0406] 4) Data analysis: Ratio = Aldosterone peak area / Internal standard peak area Control activity%=Ratio test compound / Ratio DMSO×100% The ratio test compound is the ratio value of the test compound at various concentrations. The Ratio DMSO is the ratio value when the test compound is not added. X=Log(compound concentration) Y = Control preference IC of the test compound 50 The values ​​were obtained by nonlinear regression fitting using XLfit5.5.0. The test results are shown in Table 3.

[0407] [Table 3]

[0408] Experimental conclusion: The compounds of the present invention have a significant inhibitory effect on humanized CYP11B2 and can inhibit aldosterone production, and can be used clinically to treat primary aldosteronism, refractory hypertension, and other metabolic syndromes associated with aldosterone abnormalities.

[0409] Experimental Example 2: In vitro activity test of monoclonal cells overexpressing humanized CYP11B1 A human renal leiomyoma G402 cell line overexpressing humanized CYP11B1 cells was used as a compound-selective screening system. Details are as follows:

[0410] 1) The information on cells, reagents, and equipment is consistent with that of Experiment Example 1 (Activity of monoclonal cells overexpressing humanized CYP11B2).

[0411] 2) Compound information: The test compound was prepared to a working concentration of 50 μM using DMSO.

[0412] 3) Experimental Method

[0413] Day 1: Digested cells and extracted 1 × 10⁶ human renal leiomyoma G402 cells that overexpress CYP11B1. 5The cells were resuspended in a cell / mL solution, and 100 μL was taken and seeded into a 96-well plate.

[0414] Day 2: The culture medium was changed to DMEM / F12 containing 2.5% activated carbon-treated fetal bovine serum. The test compound was added: 5 μL of the test compound was added to the cell culture medium to achieve final concentrations of 50000, 12500, 3125, 1526, 781.25, 260.42, 86.81, 28.94, 9.65, and 0 nM (DMSO content: 0.5%). After 1 hour, the substrate was added: 30 mM 11-deoxycortisol was taken, diluted 1500-fold with culture medium, and then 5 μL was dispensed into each well to a final concentration of 1 μM, and incubated for 16 hours.

[0415] Day 3: Cell supernatant was collected, and 200 μL of methanol solution containing an internal standard (internal standard: 35 ng / mL ketoprofen, or 7.5 ng / mL carbamazepine, or 5 ng / mL diphenhydramine, or 10 ng / mL tolbutamide) was added. The mixture was stirred with a vortex mixer, centrifuged (4000 × g, 4°C, 5 min), and 100 μL of supernatant was taken and 100 μL of pure water was added. The mixture was stirred with a vortex mixer, centrifuged (4000 g, 4°C, 15 min), and the supernatant was taken and analyzed by ESI-LCMS / MS.

[0416] 4) Data analysis: Ratio = Cortisol peak area / Internal standard peak area Control activity%=Ratio test compound / Ratio DMSO×100% The ratio test compound is the ratio value of the test compound at various concentrations. The Ratio DMSO is the ratio value when the test compound is not added. X=Log(compound concentration) Y = Control preference

[0417] IC of the test compound 50The values ​​were obtained by nonlinear regression fitting using XLfit5.5.0. The test results are shown in Table 4.

[0418] [Table 4]

[0419] Experimental conclusions: The compounds of the present invention exhibit weak inhibitory effects on humanized CYP11B1, have little effect on cortisol synthesis, and have excellent clinical safety.

[0420] Experimental Example 3: In vitro pharmacokinetic studies in rats

[0421] Experimental Objective: Male SD rats were used as test animals, and the blood concentration of the compound was measured after a single administration to evaluate its pharmacokinetic behavior.

[0422] Experimental Procedure: Two healthy adult male SD rats were selected as the oral administration group. The solvent for the oral administration group was 20% PEG400 + 10% solutol + 70% water. After mixing the test compound with the solvent, a clear solution of 0.25 mg / mL was prepared by vortexing and sonication. After orally administering 2 mg / kg to the rats, whole blood was collected at a predetermined time to prepare plasma. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 5.

[0423] [Table 5]

[0424] Experimental conclusions: The compounds of the present invention exhibited a longer half-life, higher oral exposure, and better oral bioavailability in oral in vivo pharmacokinetic experiments in rats, demonstrating favorable pharmacokinetic properties as oral drugs.

[0425] Experimental Example 4: In vivo pharmacokinetic studies in cynomolgus monkeys

[0426] Experimental Objective: Male cynomolgus monkeys were used as test animals, and the blood concentration of the compound was measured after a single administration to evaluate its pharmacokinetic behavior.

[0427] Experimental Procedure: Two healthy adult male cynomolgus monkeys were selected as the oral administration group. The solvent for the oral administration group was 20% PEG400 + 10% solutol + 70% water. After mixing the test compound and solvent, a clear solution of 0.6 mg / mL was prepared by vortexing and sonication. Oral dose to the cynomolgus monkeys: 1 mg / kg or 3 mg / kg. Whole blood was collected at a predetermined time after oral administration, plasma was prepared, and drug concentrations were analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 6.

[0428] [Table 6]

[0429] Note: -- indicates that it has not been tested.

[0430] Experimental conclusions: The compounds of the present invention exhibited a longer half-life, higher oral exposure, and better oral bioavailability in oral in vivo pharmacokinetic experiments in cynomolgus monkeys, demonstrating favorable pharmacokinetic properties as oral drugs.

[0431] Experimental Example 5: Permeability Test

[0432] Experimental Objective: Using an MDR1-MDCKII monolayer cell model, the permeability and efflux ratio of the compound of the present invention were measured to determine the membrane permeability and P-gp transporter efflux capacity of the compound.

[0433] Experimental protocol: MDR1-MDCKII cells (from the Netherlands Cancer Institute) were placed in 96-well plates (Corning) in a 3.33 × 10⁶ arrangement.5 Cells were seeded at a cell density of cells / ml and cultured for 4-7 days to form a cell aggregate monolayer. Hanks equilibrium salt solution (pH 7.40) containing 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) was used as the transport buffer. Bidirectional transport of the test compound was tested at a concentration of 2 μM, and the DMSO concentration in the culture system was controlled to less than 1%. After adding the sample, the cell plates were cultured for 2.5 hours at 37±1°C, 5% CO2, and saturated humidity. All samples were quantitatively analyzed using LC-MS / MS. Apparent transmittance coefficient (P) app The apparent permeability coefficient (P) was calculated using the following formula: (P) (cm / s). app The calculation (in cm / s) was performed using the following formula: P app =(dC r / dt)×V r / (A × C0). Here, dC r / dt is the cumulative concentration of the compound at the receptor end per unit time (μM / s), V r is the volume of solution at the receiving end (the volumes of solution at the upper and lower ends are 0.075 mL and 0.250 mL, respectively), and A is the relative surface area of ​​the cell monolayer (0.143 cm²). 2 ) where C0 is the starting concentration (μM) of the test substance or the peak area ratio of the reference substance at the end of administration. The elimination ratio was calculated using the following formula: ER=P app (BA) / P app (AB). The experimental results are shown in Table 7.

[0434] [Table 7]

[0435] Experimental conclusion: The compound of the present invention has high permeability, a low excretion ratio, and excellent drug-forming properties.

[0436] Experimental Example 6: In vitro metabolic stability study of liver microsomes

[0437] Experimental objective: To evaluate the metabolic stability of the test compound in human liver microsomes.

[0438] Experimental materials: Reduced nicotinamide adenine dinucleotide phosphate (NADPH), purchased from Corning or Xenotech and stored in a -80°C freezer; Supplier: Chem-impex international; Control compounds: testosterone, diclofenac, propafenone.

[0439] Experimental procedure:

[0440] 1. Preparation of the working solution Stock solution: 10 mM DMSO solution. Preparation of working solution concentration: The stock solution was diluted to 100 μM with 100% acetonitrile (organic phase content: 99% acetonitrile, 1% DMSO).

[0441] 2. Experimental Procedure Two 96-well culture plates, named T60 culture plates and NCF60 culture plates respectively, were prepared and preheated for 10 minutes.

[0442] Liver microsomes were diluted with 100 mM potassium phosphate buffer to a protein concentration of 0.56 mg / mL.

[0443] 445 μL of microsomal working solution (hepatic microsome protein concentration: 0.56 mg / mL) was transferred to preheated culture plates T60 and NCF60, respectively, and pre-cultured in a 37°C water bath for approximately 10 minutes.

[0444] After pre-culture, 5 μL of the test sample or control compound working solution was added to the T60 culture plate and the NCF60 culture plate, respectively, and mixed. 50 μL of potassium phosphate buffer was added to each well of the NCF60 culture plate and mixed uniformly to initiate the reaction.

[0445] 180 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) and 6 μL of NADPH regeneration system working solution were added to the T0 stop plate, and 54 μL of sample was transferred from the T60 culture plate to the T0 stop plate (T0 sample was generated). 44 μL of NADPH regeneration system working solution was added to each well of the T60 culture plate to initiate the reaction. Only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of stop solution were added to a blank plate. Consequently, in the test compound or control compound samples, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone were 1 μM, the liver microsome concentration was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0446] After culturing for the appropriate time (5, 15, 30, 45, 60 minutes), 180 μL of stop solution was added to each sample well of the stop plate, and then 60 μL of sample was removed from the T60 culture plate and placed in the stop plate to stop the reaction.

[0447] After uniformly shaking all sample plates, they were centrifuged at 4°C for 20 minutes (rotation speed: 4000 rpm). 80 μL of supernatant was taken from each well, diluted in 240 μL of pure water, and mixed uniformly for 10 minutes. LC-MS / MS analysis was performed. The experimental results are shown in Table 8.

[0448] [Table 8]

[0449] Experimental conclusion: The compounds of the present invention exhibited low clearance rates in human liver microsomes and good metabolic stability.

[0450] Experimental Example 7: Plasma Protein Binding Rate Test of Compounds

[0451] Experimental objective: To evaluate the protein binding rate of the compound of the present invention in the plasma of SD rats, cynomolgus monkeys, and humans using equilibrium dialysis.

[0452] Test protocol: 796 μL of blank plasma (purchased from Bioreclamation IVT) was collected from humans, SD rats, and cynomolgus monkeys, and either a test compound working solution or a warfarin working solution was added to achieve a final concentration of 2 μM of the test compound and warfarin in the plasma samples.

[0453] The samples were thoroughly mixed. The final concentration of DMSO in the organic phase was 0.5%. 50 μL of the test compound and warfarin plasma sample were transferred to a sample receiving plate, and the corresponding volume of blank plasma or buffer was added to bring the final volume of each sample well to 100 μL, with a plasma:dialysis buffer volume ratio of 1:1. Then, stop solution was added to these samples, and these samples were designated as T0 samples for recovery and stability testing.

[0454] The test compound and warfarin plasma sample were added to the administration end of each dialysis well, and blank dialysis buffer was added to the corresponding receptor end of each dialysis well. Next, the dialysis plate was sealed with a gas-permeable membrane and placed in a humidified 5% CO2 incubator, where it was incubated at 37°C and 100 rpm for 4 hours with shaking.

[0455] After dialysis was completed, 50 μL of dialysis buffer sample and post-dialysis plasma sample were pipetteed into a new sample receiving plate. Each sample well had a final volume of 100 μL, and the corresponding volume of blank plasma or buffer was added to the sample so that the plasma:dialysis buffer volume ratio was 1:1.

[0456] Data analysis:

[0457] After protein precipitation treatment of all samples, LC / MS / MS analysis was performed, and the ionization rate and plasma protein binding rate of the compounds were calculated using the following formulas: Ionization rate (%) = 100 × Fc / Tc, Plasma protein binding rate of the compound (%) = 100% - Ionization rate of the compound (%). Here, Fc is the concentration of the compound at the buffer end of the dialysis plate, Tc is the concentration of the compound at the plasma end of the dialysis plate, and T0 is the concentration of the compound in the plasma sample at zero time. The experimental results are shown in Table 9.

[0458] [Table 9]

[0459] Experimental conclusion: The compound of the present invention exhibits moderate binding affinity to different types of plasma proteins, an appropriate proportion of free drug in plasma, and good drug-forming ability.

[0460] Experiment Example 8: Human liver microsomal CYP inhibition experiment

[0461] Experimental Objective: To evaluate the inhibitory activity of a test substance against human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using a 5-in-1 probe substrate for CYP isozymes.

[0462] Mixed human liver microsomes (HLMs) were purchased from Corning Inc. (Steuben, New York, USA) and stored at -70°C or below until use.

[0463] Diluted test sample working solutions were added to a culture system containing human liver microsomes, probe substrates, and cardiovascular cofactors. A control solution containing only the solvent and no test sample was used as the enzyme activity control (100%). The concentrations of metabolites produced by the probe substrate in the samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Nonlinear regression analysis of the mean activity rate and concentration of the test samples was performed using SigmaPlot (V.11). 50 The values ​​were calculated using inverse logarithmic equations with three or four parameters. The experimental results are shown in Table 10.

[0464] [Table 10]

[0465] Experimental conclusion: The compounds of the present invention do not have inhibitory effects on the CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and the risk of drug interactions is extremely low.

Claims

1. A compound represented by formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, Ring A is Ring A １ and ring Ａ Selected from 2, Ring A １ teeth, 【Chemistry 2】 Selected from, Ring A ２ teeth, 【Transformation 3】 Selected from the above, 【Chemistry 4】 Each of these independently comprises 1, 2, or 3 R １ It is optionally replaced by, Ring B is Ring B １ and ring B ２ Selected from, Ring B １ is selected from phenyl, pyridyl and pyridazinyl, and the phenyl, pyridyl and pyridazinyl are each independently optionally substituted by one, two or three R ６ groups, Ring B ２ The 5-membered heteroaryl is selected from a 5-membered heteroaryl, and the 5-membered heteroaryl has 1, 2, or 3 R ６ It is optionally replaced by, T is a single bond, CH ２ Selected from NH and O, T １ is O and CR ４ R ５ Selected from, R １ H, =NR, C １－３ Alkyl and C １－３ Selected from haloalkyls, Each R ２ , R ３ , R ４ and R ５ These are H, F, Cl, Br, I, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl and C １－３ Selected from haloalkoxys, where R ２ , R ３ , R ４ and R ５ These four cannot be H at the same time. Or, R ２ and R ３ These, together with the carbon atoms linked to them, form a cyclopropyl group. Or, R ４ and R ５ These, together with the carbon atoms linked to them, form a cyclopropyl group. Or, R ３ and R ４ These, together with the carbon atoms linked to them, form a double bond or a cyclopropyl group. Each R ６ These are H, F, Cl, Br, I, and C, respectively, independently. １－３ Selected from alkyl groups, Structural unit 【Transformation 5】 teeth, 【Transformation 6】 Selected from, R ７１ The R is selected from a 4-6 member heterocycloalkyl group, where the 4-6 member heterocycloalkyl group has 1, 2, or 3 R groups. ａ It is optionally replaced by, R ８１ These are H, F, Cl, Br, I and C １－３ Selected from alkyl groups, Ring C is Ring C １ and ring C ２ Selected from, Ring C １ is one R ９ C replaced by ５－６ Selected from cycloalkyl, the R ９ Ha-NHC(=O)-C １－３ Alkyl, -NH-C(=O)-5-6 member heteroaryl, -NH-4-6 member heterocycloalkyl, 4-6 member heterocycloalkyl and 【Transformation 7】 Selected from, the -NHC(=O)-C １－３ Alkyl, -NH-C(=O)-5-6 member heteroaryl, -NH-4-6 member heterocycloalkyl, and 4-6 member heterocycloalkyl each independently have 1, 2, or 3 R ｂ It is optionally replaced by, Ring C ２ teeth, 【Transformation 8】 Selected from the above, 【Chemistry 9】 Each of these independently comprises 1, 2, or 3 R ｅ It is optionally replaced by, Each R ａ These are F, Cl, Br, I, and C, respectively, independently. １－３ Alkyl and -S (=O) ２ -C １－３ Selected from alkyl groups, Each R ｂ These are F, Cl, Br, I, and C, respectively, independently. １－３ Alkyl, -C(=O)-C １－３ Alkyl and -NH-C(=O)-C １－３ Selected from alkyl groups, R ｃ and R ｄ C ３－５ Forming a cycloalkyl or 5-6 member heterocycloalkyl, Each R ｅ These are F, Cl, Br, I, =O, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, -NHC(=O)-C １－３ Alkyl, -NHC(=O)-C １－３ Alkoxy, -NHC(=O)-C １－３ Selected from alkylamino and =NR, R is C １－３ Alkyl and C １－３ Selected from alkoxy, the C １－３ Alkyl and C １－３ Each alkoxy is independently and optionally substituted with one, two, or three halogens. n is either 0 or 1, 【Chemistry 10】 It is either a single bond or a double bond. In the aforementioned 5-membered heteroaryl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O, S, and N. The conditions are, 1) Ring A is A １ Selected from, ring B is B １ When not selected from, ring C is C ２ Selected from, or, 2) Ring A is A １ Selected from, ring B is B １ Selected from, ring C has one R ９ C replaced by ５－６ When selected from cycloalkyl, the R ９ teeth 【Chemistry 11】 (Selected from the above.)

2. R is CH ３ ,CH ２ CH ３ CF ３ , OCH ３ and OCF ３ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

3. R ａ is selected from -S(=O) ２ -CH ２ CH ３ The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt selected therefrom.

4. Each R ｂ is independently selected from F, Cl, Br, I, CH ３ , -C(=O)-CH ２ CH ３ and -NHC(=O)-CH ２ CH ３ The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, selected from

5. R ｃ and R ｄ together with the carbon atoms linked to them 【Chemistry 12】 A compound according to claim 1 that forms a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. R ｅ is -NHC(=O)-CH ２ CH ３ , = NCH ３ and = N - OCH ３ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

7. R １ CH ３ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

8. Each R ２ , R ３ , R ４ and R ５ These are H, F, Cl, Br, and CH, respectively, independently. ３ CHF ２ CF ３ ,CH ２ CH ３ , OCH ３ , OCH ２ CH ３ Selected from, here, R ２ , R ３ , R ４ and R ５ The compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein the four elements cannot be H at the same time.

9. R ７１ teeth, 【Chemistry 13】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

10. R ９ is -NHC(=O)-CH ２ CH ３ -NH-C(=O)-pyridyl, -NH-C(=O)-isoxazolyl, -NH-piperidinyl, -NH-pyrrolidinyl, -NH-azetidinyl, piperidinyl and 【Chemistry 14】 Selected from the above, -NHC(=O)-CH ２ CH ３ -NH-C(=O)-pyridyl, -NH-C(=O)-isoxazolyl, -NH-piperidinyl, -NH-pyrrolidinyl, -NH-azetidinyl, and piperidinyl each independently contain 1, 2, or 3 R ｂ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted by the above.

11. R ９ teeth 【Chemistry 15】 Selected from the above, 【Chemistry 16】 Each of these independently comprises 1, 2, or 3 R ｂ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, substituted by.

12. R ９ teeth, 【Chemistry 17】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

13. Ring B １ teeth, [Chemistry 18] A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

14. Ring B ２ The compound is selected from thienyl, thiazolyl, imidazolyl, and pyrazolyl, and each of the thienyl, thiazolyl, imidazolyl, and pyrazolyl independently comprises 1, 2, or 3 R compounds. ａ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted by the above.

15. Ring B ２ teeth, 【Chemistry 19】 A compound according to claim 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

16. Ring A ２ teeth, 【Chemistry 20】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

17. Ring C １ teeth, 【Chemistry 21】 A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

18. Ring C ２ teeth, 【Chemistry 22】 Selected from the above, 【Chemistry 23】 Each of these independently comprises 1, 2, or 3 R ｅ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted by the above.

19. Ring C ２ teeth, 【Chemistry 24】 A compound according to claim 18, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

20. The compound described in claim 1, its stereoisomer, or its pharmaceutically acceptable salt, wherein the compound is selected from the following. 【Chemistry 25】 (however, 【Chemistry 26】 It is selected from single bonds and double bonds, T ２ It is selected from CH and N, T ４ It is selected from CH and N, T ３ is selected from C and N, Ring E is, 【Chemistry 27】 Selected from, m is selected from 0, 1, 2, and 3. p is selected from 0, 1, and 2. Ring B is Ring B １ and ring B ２ Selected from, Ring B １ It is selected from phenyl, pyridyl, and pyridazinyl. Ring B ２ It is selected from five-membered heteroaryl compounds. T, T １ , R １ , R ２ , R ３ , R ６ , L, R ７ and R ８ (This is as defined in claim 1.)

21. The compound described above is selected from the following: the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 28】 (however, Ring B is selected from phenyl, pyridyl, pyridazinyl, and 5-membered heteroaryl. T １ is O and CR ４ R ５ Selected from, Each R ２ , R ３ , R ４ and R ５ These are H, F, Cl, Br, I, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl and C １－３ Selected from haloalkoxys, Or, R ２ and R ３ These, together with the carbon atoms linked to them, form a cyclopropyl group. Or, R ４ and R ５ These, together with the carbon atoms linked to them, form a cyclopropyl group. Or, R ３ and R ４ These, together with the carbon atoms linked to them, form a double bond or a cyclopropyl group. Each R ６ These are H, F, Cl, Br, I, and C, respectively, independently. １－３ Selected from alkyl groups, R ９ Ha-NHC(=O)-C １－３ Alkyl, -NH-C(=O)-5-6 member heteroaryl, -NH-4-6 member heterocycloalkyl, 4-6 member heterocycloalkyl, and 【Chemistry 29】 Selected from, the -NHC(=O)-C １－３ Alkyl, -NH-C(=O)-5-6 member heteroaryl, -NH-4-6 member heterocycloalkyl, and 4-6 member heterocycloalkyl each independently have 1, 2, or 3 R ｂ It is optionally replaced by, Each R ｂ These are F, Cl, Br, I, and C, respectively, independently. １－３ Alkyl, -C(=O)-C １－３ Alkyl and -NH-C(=O)-C １－３ Selected from alkyl groups, Each R ｅ These are F, Cl, Br, I, =O, and C, respectively, independently. １－３ Alkyl, C １－３ Alkoxy, C １－３ Alkylamino, -NHC(=O)-C １－３ Alkyl, -NHC(=O)-C １－３ Alkoxy, -NHC(=O)-C １－３ Selected from alkylamino and =NR, R is C １－３ Alkyl and C １－３ Selected from alkoxy, the C １－３ Alkyl and C １－３ Each alkoxy is independently and optionally substituted with one, two, or three halogens. m is selected from 0, 1, 2, and 3. 【Transformation 30】 It is either a single bond or a double bond. In the aforementioned five-membered heteroaryl, five- to six-membered heteroaryl, and four- to six-membered heterocycloalkyl, "hetero" represents one, two, three, or four heteroatoms or heteroatomic groups independently selected from O and N.

22. A compound represented by the following formula, its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】

23. A compound according to claim 21, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following formulas. 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】

24. Use of a compound according to any one of claims 1 to 23, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating aldosterone synthase inhibitor-related diseases.

25. Use of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt according to any one of claims 1 to 23 in the manufacture of a pharmaceutical product for treating refractory hypertension.

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