Heterocyclic carboxylic acid derivative, preparation method therefor, and pharmaceutical application thereof

Abstract

Provided are a heterocyclic carboxylic acid derivative, a preparation method therefor, and a pharmaceutical application thereof. Specifically, provided are a heterocyclic carboxylic acid derivative as represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, and a use thereof as a therapeutic agent, in particular as an sGC (soluble guanylate cyclase) agonist and / or activator, and the use thereof in the preparation of a drug for treating and / or preventing diseases responsive to sGC agonists and / or activators.

Description

Heterocyclic carboxylic acid derivatives, their preparation methods and their pharmaceutical applications

[0001] This application claims priority to the following Chinese patent applications:

[0002] Chinese patent application 202510012565X, filed on January 3, 2025;

[0003] Chinese patent application 2025101150131, filed on January 23, 2025;

[0004] Chinese patent application 2025102428106, filed on February 28, 2025;

[0005] Chinese patent application 2025106315018, filed on May 15, 2025;

[0006] Chinese patent application 2025108645690, filed on June 25, 2025;

[0007] Chinese patent application 202511938161X, filed on December 19, 2025;

[0008] Chinese patent application 2025119743930, filed on December 24, 2025;

[0009] Chinese patent application 2025120068698, filed on December 27, 2025.

[0010] This application incorporates the full text of the aforementioned Chinese patent application. Technical Field

[0011] This disclosure pertains to the pharmaceutical field and relates to a heterocyclic carboxylic acid derivative, its preparation method, and its applications. Specifically, this disclosure relates to a heterocyclic carboxylic acid derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as an sGC (soluble guanylate cyclase) agonist and / or activator, and its use in the preparation of medicaments for treating and / or preventing sGC agonist and / or activator-mediated diseases. Background Technology

[0012] In recent years, the number of patients with chronic kidney disease (CKD) has increased dramatically due to the steadily rising prevalence of risk factors such as diabetes, obesity, and hypertension. Increasing scientific research in recent years aims to discover new pharmacological pathways for the treatment and / or prevention of CKD. Studies have found that the nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling cascade are involved in regulating various kidney functions. cGMP directly affects renal blood flow, renin secretion, glomerular function, and renal tubular exchange processes. Downregulation of the NO / sGC / cGMP signaling pathway can lead to serious kidney diseases such as CKD; therefore, the key catalytic enzyme in this pathway, soluble guanylate cyclase (sGC), has received widespread attention.

[0013] Soluble guanylate cyclase (sGC) catalyzes the conversion of GTP to cGMP in response to nitric oxide (NO) stimulation. sGC exists in two isoforms, α and β. Under normal conditions, sGC forms a reduced heterodimer composed of two isoforms bound to a heme atom, with heme being the primary NO-binding site. NO binds to the ferrous iron atom (Fe) of heme. 2+ The above significantly enhances the catalytic activity of sGC enzyme, while simultaneously removing Fe divalent atoms. 2+ Oxidized into trivalent iron atoms Fe 3+ Simultaneously, heme is lost and converted into oxidized sGC. NO cannot bind to sGC without heme. The resulting second messenger, cyclic guanosine monophosphate (cGMP), regulates downstream phosphodiesterase (PDE), ion channels, protein kinases, and other processes, participating in the regulation of various physiological functions, especially in the relaxation of vascular smooth muscle cells and the inhibition of their differentiation; inhibiting platelet aggregation and adhesion; and participating in the repair of various nerve functions in nerve signal transmission. Under pathological conditions, the inhibition of the NO / cGMP system leads to downregulation of signals, which may result in pathological processes such as hypertension, platelet aggregation, cell fibrosis, endothelial dysfunction, atherosclerosis, angina pectoris, and heart failure.

[0014] In the kidneys, sGC is mainly expressed in glomerular podocytes, renal tubular epithelial cells, and the glomerular matrix. It is responsible for regulating multiple renal physiological processes, including the contraction of afferent / efferent arterioles, podocyte function, cell differentiation and fibrosis, inflammatory cell infiltration and renal tubular contraction, and sodium excretion in the collecting ducts. It directly affects renal blood flow, renin secretion, glomerular function, and tubular exchange. However, in the kidneys of patients with chronic kidney disease (CKD), such as diabetic nephropathy (DKD), the NO / cGMP signaling pathway is severely impaired, leading to various renal pathological processes such as proteinuria and glomerulosclerosis.

[0015] Given the importance of the NO / sGC / cGMP signaling pathway in renal physiological processes, increasing sGC enzyme activity and cGMP production has become a novel treatment approach for CKD. Some NO-based drugs, such as early nitrates and YC-1, have been developed: these drugs do not depend on NO and bind to reduced sGC to stimulate greater cGMP production. However, YC-1 has been found to have multi-target effects, such as simultaneously inhibiting PDE activity. Therefore, sGC stimulators have been developed, such as Bayer's Riociguat and Vericiguat. These compounds are characterized by their NO-independent, selective stimulation of heme-binding sGC proteins, and synergistic effects with NO. However, in pathological conditions, the amount of heme-free sGC protein, i.e., oxidized sGC protein, is significantly increased, and these stimulators cannot act on oxidized sGC.

[0016] Therefore, new-generation sGC agonists such as BAY582667 and Runcaciguat (Bayer) have been developed. These drugs selectively act on heme-free sGC proteins without affecting the effect of NO on reduced sGCs. In a completed phase II clinical trial for CKD, Runcaciguat significantly reduced proteinuria by -47% in patients using and / or not using SGLT2 inhibitors. Avenciguat, an sGC agonist developed by Boehringer Ingelheim (BI), has also demonstrated clinical efficacy in a completed phase II clinical trial: significantly reducing proteinuria (-13.2%-23.4%) in both DKD and non-DKD patients using and / or not using SGLT2 inhibitors. Avenciguat is also undergoing phase II clinical trials for other diseases such as systemic sclerosis (SSc). These results show that sGC agonists have broad potential therapeutic applications. However, due to the poor safety and pharmacokinetic properties of existing compounds, there is an urgent need for a new generation of safe and effective sGC agonist compounds. Summary of the Invention

[0017] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0018] Ring A is selected from 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0019] Ring B is selected from 5 to 10-membered heteroaryl, 3 to 10-membered monocyclic heterocyclic, 5 to 14-membered spirocyclic, 5 to 14-membered bridged heterocyclic and 5 to 14-membered fused heterocyclic;

[0020] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups;

[0021] Ring D is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups;

[0022] Ring E is selected from 3- to 10-membered monocyclic heterocyclic groups, 5- to 14-membered spirocyclic heterocyclic groups, 5- to 14-membered bridged heterocyclic groups, and 5- to 14-membered fused heterocyclic groups;

[0023] R is selected from hydrogen atom, deuterium atom, deuterated C. 1-6 Alkyl, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0024] R a R b R c R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- The 6-alkoxy, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from the deuterium atom, deuterated C, etc. 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0025] Or two R atoms on adjacent ring atoms a Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. b Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. c Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. d Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. e Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 -SR s -C(O)R s -S(O) q R s -s(O)2NR n1 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0026] Or R a R b R c Rd and R e Any two atoms in the group and the atoms bonded to them together form a 3- to 20-membered heterocyclic group, a 3- to 20-membered cycloalkyl group, a 3- to 20-membered cycloalkenyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 3- to 20-membered heterocyclic group, the 3- to 20-membered cycloalkyl group, the 3- to 20-membered cycloalkenyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently and optionally selected from a deuterium atom, a deuterated C atom, or a deuterated C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0027] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0028] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1- 6-alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0029] n is 0, 1, 2, 3 or 4;

[0030] m can be 0, 1, 2, 3, or 4;

[0031] p is 0, 1, 2 or 3;

[0032] t can be 0, 1, 2, 3, or 4;

[0033] u is 0, 1, 2, 3, or 4; and

[0034] q can be 0, 1, or 2.

[0035] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0036] Ring A is selected from 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0037] Ring B is selected from 5 to 10-membered heteroaryl, 3 to 10-membered monocyclic heterocyclic, 5 to 14-membered spirocyclic, 5 to 14-membered bridged heterocyclic and 5 to 14-membered fused heterocyclic;

[0038] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups;

[0039] Ring D is selected from 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0040] Ring E is selected from 3- to 10-membered monocyclic heterocyclic groups, 5- to 14-membered spirocyclic heterocyclic groups, 5- to 14-membered bridged heterocyclic groups, and 5- to 14-membered fused heterocyclic groups;

[0041] R is selected from hydrogen atom, deuterium atom, deuterated C. 1-6 Alkyl, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0042] R a R b R c R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NRn1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- The 6-alkoxy, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl groups are each independently selected from the deuterium atom, deuterated C, etc. 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0043] Or two R atoms on adjacent ring atoms a Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. b Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. c Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. d Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. eTogether with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 -SR s -C(O)R s -S(O) q R s -S(O)2NR n1 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0044] Or R a R b R c R d and R e Any two atoms in the group and the atoms bonded to them together form a 3- to 20-membered heterocyclic group, a 3- to 20-membered cycloalkyl group, a 3- to 20-membered cycloalkenyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 3- to 20-membered heterocyclic group, the 3- to 20-membered cycloalkyl group, the 3- to 20-membered cycloalkenyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently and optionally selected from a deuterium atom, a deuterated C atom, or a deuterated C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) q R s -S(O)2NRn1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0045] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0046] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1- 6-alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0047] n is 0, 1, 2, 3 or 4;

[0048] m can be 0, 1, 2, 3, or 4;

[0049] p is 0, 1, 2 or 3;

[0050] t can be 0, 1, 2, 3, or 4;

[0051] u is 0, 1, 2, 3, or 4; and

[0052] q can be 0, 1, or 2.

[0053] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0054] Ring A is selected from 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0055] Ring B is selected from 5 to 10-membered heteroaryl, 3 to 10-membered monocyclic heterocyclic, 5 to 14-membered spirocyclic, 5 to 14-membered bridged heterocyclic and 5 to 14-membered fused heterocyclic;

[0056] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups;

[0057] Ring D is selected from 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0058] Ring E is selected from 3- to 10-membered monocyclic heterocyclic groups, 5- to 14-membered spirocyclic heterocyclic groups, 5- to 14-membered bridged heterocyclic groups, and 5- to 14-membered fused heterocyclic groups;

[0059] R is selected from hydrogen atom, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0060] R a R b R c R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-It is substituted by one or more substituents selected from 6-alkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0061] Or two R atoms on adjacent ring atoms a Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. b Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. c Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. d Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. e Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 -SR s -C(O)R s -S(O) q R s -S(O)2NR n1 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0062] Or R a R b R c R d and R eAny two atoms in the group and the atoms bonded to them together form a 3- to 20-membered heterocyclic group, a 3- to 20-membered cycloalkyl group, a 3- to 20-membered cycloalkenyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 3- to 20-membered heterocyclic group, the 3- to 20-membered cycloalkyl group, the 3- to 20-membered cycloalkenyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently and optionally selected from halogens, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0063] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0064] R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0065] n is 0, 1, 2, 3 or 4;

[0066] m can be 0, 1, 2, 3, or 4;

[0067] p is 0, 1, 2 or 3;

[0068] t can be 0, 1, 2, 3, or 4;

[0069] u is 0, 1, 2, 3, or 4; and

[0070] q can be 0, 1, or 2.

[0071] The purpose of this disclosure is to provide a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0072] Ring A is selected from 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups;

[0073] Ring B is selected from 5 to 10-membered heteroaryl, 3 to 10-membered monocyclic heterocyclic, 5 to 14-membered spirocyclic, 5 to 14-membered bridged heterocyclic and 5 to 14-membered fused heterocyclic;

[0074] The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups;

[0075] Ring D is selected from 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0076] Ring E is selected from 3- to 10-membered monocyclic heterocyclic groups, 5- to 14-membered spirocyclic heterocyclic groups, 5- to 14-membered bridged heterocyclic groups, and 5- to 14-membered fused heterocyclic groups;

[0077] R is selected from hydrogen atom, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0078] R a R b R c R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1- It is substituted by one or more substituents selected from 6-alkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl;

[0079] Or two R atoms on adjacent ring atoms a Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. b Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. c Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. d Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. e Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 -SRs -C(O)R s -S(O) q R s -S(O)2NR n1 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0080] Or R a R b R c R d and R e Any two atoms in the group and the atoms bonded to them together form a 3- to 20-membered heterocyclic group, a 3- to 20-membered cycloalkyl group, a 3- to 20-membered cycloalkenyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 3- to 20-membered heterocyclic group, the 3- to 20-membered cycloalkyl group, the 3- to 20-membered cycloalkenyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently and optionally selected from halogens, oxo groups, C-terminal groups, and C-terminal groups. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0081] R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0082] R sThey may be the same or different each time they appear, and each is independently selected from hydrogen atoms, C atoms, etc. 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0083] n is 0, 1, 2, 3 or 4;

[0084] m can be 0, 1, 2, 3, or 4;

[0085] p is 0, 1, 2 or 3;

[0086] t can be 0, 1, 2, 3, or 4;

[0087] u is 0, 1, 2, 3, or 4; and

[0088] q can be 0, 1, or 2.

[0089] In another embodiment of this disclosure, ring A is selected from 5- to 6-membered heteroaryl groups containing 1-3 N atoms or from 5- to 6-membered heterocyclic groups containing 1-3 N atoms.

[0090] In another embodiment of this disclosure, R a They may be the same or different each time they appear, and each is independently selected from a hydrogen atom or a halogenated carbon atom. 1-4 alkyl.

[0091] In another embodiment of this disclosure, m is 0 or 1.

[0092] In another embodiment of this disclosure, R is selected from hydrogen atoms and C. 1-4 Alkyl group, preferably with hydrogen atoms.

[0093] In another embodiment of this disclosure, wherein... Selected from

[0094] In another embodiment of this disclosure, wherein... for

[0095] In another embodiment of this disclosure, the ring C is selected from phenyl and 5- to 6-membered heteroaryl groups, preferably phenyl, pyridyl, or...

[0096] In another embodiment of this disclosure, R c The elements may be the same or different each time they appear, and each is independently selected from hydrogen atoms and halogens, preferably hydrogen atoms, F or Cl.

[0097] In another embodiment of this disclosure, two adjacent R c The atoms attached to it together form 3- to 6-membered heterocyclic groups or 3- to 6-membered cycloalkenyl groups that are optionally substituted with halogens.

[0098] In another embodiment of this disclosure, ring D is selected from phenyl or 5- to 6-membered heteroaryl, preferably phenyl, pyridyl, or...

[0099] In another embodiment of this disclosure, R d The atoms may be the same or different each time they appear, and each is independently selected from hydrogen atoms and halogens, preferably hydrogen atoms or F.

[0100] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomers, or its pharmaceutically acceptable salts are compounds of general formula (II), its stereoisomers, or their pharmaceutically acceptable salts:

[0101] in,

[0102] x 1 Selected from N or CR x1 ;

[0103] x 2 Selected from N or CR x2 ;

[0104] x 3 Selected from N or CR x3 ;

[0105] x 4 Selected from N or CR x4 ;

[0106] x 5 Selected from N or CR x5 ;

[0107] x 6 Selected from N or CR x6 ;

[0108] x 7 Selected from N or CR x7 ;

[0109] x 8 Selected from N or CR x8 ;

[0110] R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0111] R e1 R e2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0112] Or R x2 and R x3 R x2 and R x1 R x3 and R x4 They, together with the atoms attached to them, form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NRn3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0113] Or R x5 and R x4 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more of the following substituents: alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0114] Or R x6 And one of the R e2 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups and 5- to 10-membered heteroaryl groups are each independently selected independently from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 Rn4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0115] Or R x8 And one of the R b Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0116] Ring B, Ring E, R b R n1 R n2 R n3 R n4 R s , n, u, q are as defined in general formula (I).

[0117] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomers, or its pharmaceutically acceptable salts are compounds of general formula (II), its stereoisomers, or their pharmaceutically acceptable salts:

[0118] in:

[0119] in:

[0120] x 1 Selected from N or CR x1 ;

[0121] x 2 Selected from N or CR x2 ;

[0122] x 3 Selected from N or CR x3 ;

[0123] x 4 Selected from N or CR x4 ;

[0124] x 5 Selected from N or CR xs ;

[0125] x 6 Selected from N or CR x6 ;

[0126] x 7 Selected from N or CR x7 ;

[0127] x 8 Selected from N or CR x8 ;

[0128] R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1- 6-alkoxy, C 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)Rs Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0129] R e1 R e2 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy groups, C groups optionally substituted with 3 to 6-membered cycloalkyl groups 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0130] Or R x2 and R x3 R x2 and R x1 R x3 and R x4 These atoms, together with the atoms attached to them, form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NRn1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0131] Or R x5 and R x4 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more of the following substituents: alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0132] Or R x6 And one of the R e2 Together with the atoms bonded to them, they form a ring F; the ring F is arbitrarily bounded by z R atoms. f replace;

[0133] Ring F is selected from 5- to 10-membered heterocyclic groups and 5- to 10-membered heteroaryl groups;

[0134] R f Selected from deuterium atoms and deuterated C 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC1-6 alkyl, -SR s -C(O)NR n3 R n4-C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0135] Or R x8 And one of the R b Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)N Rn 3R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0136] z can be 0, 1, 2, 3, or 4;

[0137] Ring B, Ring E, R b R n1 R n2 R n3 R n4 R s , n, u, q are as defined in any scheme of this disclosure.

[0138] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomers, or its pharmaceutically acceptable salts are compounds of general formula (II), its stereoisomers, or their pharmaceutically acceptable salts:

[0139] in:

[0140] in:

[0141] x 1 Selected from N or CR x1 ;

[0142] x 2 Selected from N or CR x2 ;

[0143] x 3 Selected from N or CR x3 ;

[0144] x 4 Selected from N or CR x4 ;

[0145] x 5 Selected from N or CR x5 ;

[0146] x 6 Selected from N or CR x6 ;

[0147] x 7 Selected from N or CR x7 ;

[0148] x 8 Selected from N or CR x8 ;

[0149] Rx 1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1- 6-alkoxy, C 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0150] R e1 R e2 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups;

[0151] Or R x2 and R x3 R x2 and R x1 R x3 and R x4 These atoms, together with the atoms attached to them, form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0152] Or R x5 and R x4 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more of the following substituents: alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0153] Or R x6 And one of the R e2 Together with the atoms bonded to them, they form a ring F; the ring F is arbitrarily bounded by z R atoms. f replace;

[0154] Ring F is selected from 5- to 10-membered heterocyclic groups and 5- to 10-membered heteroaryl groups;

[0155] R f Selected from deuterium atoms and deuterated C 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O)u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0156] Or R x8 And one of the R b Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0157] z can be 0, 1, 2, 3, or 4;

[0158] Ring B, Ring E, R b R n1 R n2 R n3 R n4 R s , n, u, q are as defined in any scheme of this disclosure.

[0159] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomer, or its pharmaceutically acceptable salt is a compound of general formula (IIa), general formula (IIa-1), or general formula (IIa-2), its stereoisomer, or its pharmaceutically acceptable salt:

[0160] in:

[0161] Each group is defined as defined in any scheme of this disclosure.

[0162] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are compounds of general formula (II-1), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0163] in:

[0164] The groups in general formula (II-1) are defined as defined in any scheme of this disclosure.

[0165] In another embodiment of this disclosure, the compounds of general formula (I) and general formula (II), their stereoisomers or pharmaceutically acceptable salts thereof, are compounds of general formula (II-2), their stereoisomers or pharmaceutically acceptable salts thereof:

[0166] in:

[0167] The groups in general formula (II-2) are defined as defined in any scheme of this disclosure.

[0168] In another embodiment of this disclosure, the compound of general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are compounds of general formula (II), general formula (II-1), or general formula (II-2), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0169] in:

[0170] x 1 Selected from N or CR x1 ;

[0171] x 2 Selected from N or CR x2 ;

[0172] x 3 Selected from N or CR x3 ;

[0173] x 4 Selected from N or CR x4 ;

[0174] x 5 Selected from N or CR x5 ;

[0175] x 6 Selected from N or CR x6 ;

[0176] x 7 Selected from N or CR x7 ;

[0177] x 8 Selected from N or CRx 8 ;

[0178] R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0179] R e1 R e2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy;

[0180] Or R x2 and R x3 R x2 and R x1 R x3 and R x4They, together with the atoms attached to them, form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0181] Or R x5 and R x4 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -s(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more of the following substituents: alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0182] Or R x6And one of the R e2 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups and 5- to 10-membered heteroaryl groups are each independently selected independently from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0183] Or R x8 And one of the R b Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl;

[0184] Ring B, Ring E, R b Rn1 R n2 R n3 R n4 R s , n, u, q are as defined in general formula (I).

[0185] In another embodiment of this disclosure, ring B is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered fused heterocyclic, 5- to 8-membered spirocyclic and phenyl.

[0186] In another embodiment of this disclosure, ring B is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered fused heterocyclic and 5- to 8-membered spirocyclic.

[0187] In another embodiment of this disclosure, ring B is selected from 5- to 6-membered heterocyclic groups and 5- to 8-membered bridged heterocyclic groups.

[0188] In another embodiment of this disclosure, R b It is a hydrogen atom.

[0189] In another embodiment of this disclosure, wherein Selected from Where * indicates a connection to ring C or x 1 The rings they belong to are connected.

[0190] In another embodiment of this disclosure, wherein Selected from Where * indicates a connection to ring C or x 1 The rings are connected, preferably

[0191] In another embodiment of this disclosure, wherein Selected from Where * indicates a connection to ring C or x 1 The rings they belong to are connected.

[0192] In another embodiment of this disclosure, R b Selected from hydrogen atoms.

[0193] In another embodiment of this disclosure, R e R e1 and R e2 The same or different, and each independently selected from hydrogen atoms, optionally substituted with 3 to 6-membered cycloalkyl groups, are C atoms. 1-4 Alkyl, Halogenated C 1-4 Alkyl, 3- to 6-membered cycloalkyl, hydroxy C 1-4Alkyl, -C(O)R s and -C(O)NR n1 R n2 ;R s Selected from C 1-4 Alkyl, C 1-4 Alkoxy and 3- to 6-membered cycloalkyl; R n1 and R n2 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-4 alkyl.

[0194] In another embodiment of this disclosure, R e R e1 and R e2 The same or different, and each independently selected from -CH2CH(CH3)2, -CH2CHF2, cyclopropyl, hydrogen atom, methyl, ethyl, isopropyl, tert-butyl, -CHF2、 -CH2CF3、

[0195] In another embodiment of this disclosure, R e1 C 1-4 Alkyl; preferably, R e1 It is -CH2CH(CH3)2.

[0196] In another embodiment of this disclosure, R e2 It is a hydrogen atom.

[0197] In another embodiment of this disclosure, R e1 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and 3- to 6-membered cycloalkyl; preferably, R e1 Selected from -CH2CH(CH3)2, -CH2CHF2 and cyclopropyl.

[0198] In another embodiment of this disclosure, R e1 C atoms selected from hydrogen atoms, optionally substituted with 3 to 6-membered cycloalkyl groups 1-4 Alkyl, Halogenated C 1-4 Alkyl, 3- to 6-membered cycloalkyl, hydroxy C 1-4 Alkyl, -C(O)R s and -C(O)NR n1 R n2 ;R s Selected from C 1-4 Alkyl, C 1-4 Alkoxy, 3- to 6-membered cycloalkyl; R n1 and R n2 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms.1-4 alkyl.

[0199] In another embodiment of this disclosure, R e1 Selected from hydrogen atom, methyl, ethyl, isopropyl, tert-butyl, -CHF2、 -CH2CF3、

[0200] In another embodiment of this disclosure, R e1 Selected from

[0201] In another embodiment of this disclosure, ring E is selected from 6-membered monocyclic heterocyclic groups, 6- to 9-membered fused heterocyclic groups, and 6- to 9-membered bridged heterocyclic groups.

[0202] In another embodiment of this disclosure, wherein... Same or different, and each selected independently

[0203] In another embodiment of this disclosure, wherein... Selected from

[0204] In another embodiment of this disclosure, wherein... Selected from

[0205] In another embodiment of this disclosure, wherein... Selected from

[0206] In another embodiment of this disclosure, wherein... Selected from

[0207] In another embodiment of this disclosure, x 1 Selected from N, CH and CF; or x 2 Selected from CH, C-Cl and CF; or x 3 Selected from N, CH, CF, C-CH3, C-CN, C-CF3 and -C-CHF2; or x 4 Selected from N, CH and CF; or x 5 Selected from C-CN, C-OCH3, CH and CF; or x 6 Selected from N, C-OCH3, C-CN, CH and CF; or x 7 Selected from N and CH; or x 8 Selected from N, CH and CF.

[0208] In another embodiment of this disclosure, x 1 Selected from N, CH and CF.

[0209] In another embodiment of this disclosure, x 2 Selected from CH and C-Cl.

[0210] In another embodiment of this disclosure, x 2 For CF.

[0211] In another embodiment of this disclosure, x 3 Selected from N, CH and CF.

[0212] In another embodiment of this disclosure, x 3 Selected from C-CH3, C-CN, C-CF3 and -C-CHF2.

[0213] In another embodiment of this disclosure, x 4 Selected from N, CH and CF.

[0214] In another embodiment of this disclosure, x 5 Selected from CH and CF.

[0215] In another embodiment of this disclosure, x 5 Selected from C-CN and C-OCH3.

[0216] In another embodiment of this disclosure, x 6 Selected from CH and CF.

[0217] In another embodiment of this disclosure, x 6 Selected from N, C-OCH3 and C-CN.

[0218] In another embodiment of this disclosure, x 7 For CH.

[0219] In another embodiment of this disclosure, x 7 Let N be the number of elements in the array.

[0220] In another embodiment of this disclosure, x 8 Selected from N, CH and CF.

[0221] In another embodiment of this disclosure, R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8The same or different, and each independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl groups, cyano groups, hydrogen atoms, and halogens.

[0222] In another embodiment of this disclosure, R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-4 Alkyl groups and halogens, preferably hydrogen atoms or halogens.

[0223] In another embodiment of this disclosure, R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 The same or different, and each independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl and cyano groups.

[0224] In another embodiment of this disclosure, R x2 and R x3 The atoms attached to it together form 3- to 6-membered heterocyclic groups or 3- to 6-membered cycloalkenyl groups that are optionally substituted with halogens.

[0225] In another embodiment of this disclosure, wherein... Same or different, and each selected independently * indicates that it is connected to end B of the ring.

[0226] In another embodiment of this disclosure, wherein... Selected from * indicates that it is connected to end B of the ring.

[0227] In another embodiment of this disclosure, wherein... for * indicates that it is connected to end B of the ring.

[0228] In another embodiment of this disclosure, wherein... Selected from * indicates that it is connected to end B of the ring.

[0229] In another embodiment of this disclosure, wherein... Same or different, and each selected independently

[0230] In another embodiment of this disclosure, wherein... Selected from

[0231] In another embodiment of this disclosure, wherein... Selected from

[0232] In another embodiment of this disclosure, R x5 and R x4 The atoms attached to it together form 5 to 8-membered heterocyclic groups.

[0233] In another embodiment of this disclosure, wherein... Same or different, and each selected independently

[0234] In another embodiment of this disclosure, R d and R e The atoms bonded to it together form an optional C 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 3 to 8-membered heterocyclic groups substituted with alkyl-C(O)- or oxo-substituted groups.

[0235] In another embodiment of this disclosure, R d and R e The atoms attached to it together form 3 to 8-membered heterocyclic groups that may be optionally substituted with methyl, -CD3, CH3-C(O)- or oxo groups.

[0236] In another embodiment of this disclosure, ring F is a 3- to 8-membered heterocyclic group.

[0237] In another embodiment of this disclosure, ring F is a 3- to 8-membered heterocyclic group containing 1 to 3 identical or different heteroatoms.

[0238] In another embodiment of this disclosure, ring F is a 3- to 8-membered heterocyclic group containing 1 or 2 identical or different heteroatoms.

[0239] In another embodiment of this disclosure, ring F is a 3- to 8-membered heterocyclic group containing two identical or different heteroatoms.

[0240] In another embodiment of this disclosure, ring F is a 5- to 8-membered nitrogen-containing heterocyclic group, which, in addition to containing a N atom, further contains one heteroatom selected from N, O, and S.

[0241] In another embodiment of this disclosure, ring F is a 6-membered nitrogen-containing heterocyclic group, which, in addition to containing a N atom, further contains one heteroatom selected from N and O.

[0242] In another embodiment of this disclosure, R f Selected from hydrogen atoms, C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkyl-C(O)- and oxo groups.

[0243] In another embodiment of this disclosure, R f It is selected from hydrogen atom, methyl, -CD3, CH3-C(O)- and oxo group.

[0244] In another embodiment of this disclosure, ring F is selected from... The letters D and E indicate the positions of rings D and E.

[0245] In another embodiment of this disclosure, rings F and R f The structural units are selected from The letters D and E indicate the positions of rings D and E.

[0246] In another embodiment of this disclosure, R x6 And one of the R e2 The atoms attached to it together form 3 to 8-membered heterocyclic groups.

[0247] In another embodiment of this disclosure, wherein... Same or different, and each selected independently

[0248] In another embodiment of this disclosure, wherein... Selected from

[0249] In another embodiment of this disclosure, wherein... for

[0250] In another embodiment of this disclosure, wherein... Selected from

[0251] In another embodiment of this disclosure, wherein... Selected from

[0252] In another embodiment of this disclosure, wherein... Selected from

[0253] In another embodiment of this disclosure, wherein... Same or different, and each selected independently

[0254] In another embodiment of this disclosure, wherein... Selected from

[0255] In another embodiment of this disclosure, R x8 And one of the R b The atoms attached to it together form 5- to 10-membered heterocyclic groups.

[0256] In another embodiment of this disclosure, wherein... Selected from

[0257] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0258] Where, x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R el Ring F, R f As described in any of the embodiments disclosed herein.

[0259] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt comprises a compound, its stereoisomer, or its pharmaceutically acceptable salt having any of the following general formulas:

[0260] in,

[0261] X is selected from -(CR)f1 R f2 ) s -O-、-(CR f1 R f2 ) s NR f3 -、-O-(CR f1 R f2 ) s and -NR f3 -(CR f1 R f2 ) s ;

[0262] Y does not exist or is selected from -CR f1 R f2 -;

[0263] s is selected from 0, 1, 2, or 3;

[0264] R f1 and R f2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-4 Alkyl and halogen; preferably, R f1 and R f2 All are hydrogen atoms;

[0265] R f3 Selected from hydrogen atoms, C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkyl-C(O)- and oxo groups; preferably, R f3 Selected from hydrogen atoms, methyl groups, -CD3, CH3-C(O)-, and oxo groups;

[0266] x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e1 As described in any of the embodiments disclosed herein.

[0267] In another embodiment of this disclosure, wherein Selected from The letters D and E indicate the positions of rings D and E.

[0268] In another embodiment of this disclosure, wherein Selected from The letters D and E indicate the positions of rings D and E.

[0269] In another embodiment of this disclosure, wherein Selected from The letters D and E indicate the positions of rings D and E.

[0270] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0271] in:

[0272] Ring E, x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e1 R e2 u is as defined in any of the aforementioned schemes.

[0273] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0274] in:

[0275] x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e2 As defined by any of the aforementioned schemes.

[0276] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0277] in:

[0278] Ring E, x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8R e1 R e2 u is as defined in any of the aforementioned schemes.

[0279] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0280] in:

[0281] x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e2 As defined by any of the aforementioned schemes.

[0282] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0283] in:

[0284] Ring E, x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e1 R e2 u is as defined in any of the aforementioned schemes.

[0285] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt comprises a compound, its stereoisomer, or its pharmaceutically acceptable salt having any of the following general formulas:

[0286] in:

[0287] x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e2 As defined by any of the aforementioned schemes.

[0288] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0289] in:

[0290] The ring F is selected from 5-8 membered heterocyclic groups; preferably, the ring F is selected from 6-8 membered heterocyclic groups containing 1 to 3 O or N atoms;

[0291] R f Selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl group, CH3C(O)-, oxo group; preferably hydrogen atom, methyl group, -CD3, CH3C(O)-, oxo group;

[0292] Other groups are as defined in any of the schemes disclosed herein.

[0293] In another embodiment of this disclosure, the compound, its stereoisomer, or its pharmaceutically acceptable salt is a compound, its stereoisomer, or its pharmaceutically acceptable salt represented by any of the following general formulas:

[0294] in:

[0295] Ring F is a 5-8 membered heterocyclic group; preferably, ring F is a 6-8 membered heterocyclic group containing 1 to 3 O or N atoms;

[0296] R f Selected from hydrogen atoms, C 1-6 Alkyl, deuterated C 1-6 Alkyl group, CH3C(O)- and oxo group; preferably hydrogen atom, methyl group, -CD3, CH3C(O)- and oxo group;

[0297] Other groups are as defined in any of the schemes disclosed herein.

[0298] This disclosure also provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein typical compounds of this disclosure include, but are not limited to, any structure in scheme A below:

[0299] In another embodiment of this disclosure, the pharmaceutically usable salt of the compound is a hydrochloride or a formate. Preferably, the hydrochloride contains one, two, or three hydrochloric acid molecules, and the formate contains one, two, or three formic acid molecules.

[0300] In another embodiment of this disclosure, the pharmaceutically acceptable salt of the compound is any of the structures in scheme B below:

[0301] Another aspect of this disclosure relates to the crystal form of the compound shown below, wherein the crystal system is monoclinic, the space group is C2, and the unit cell parameters are: α=90°, β=105.432(3)°, γ=90°;

[0302] Another aspect of this disclosure relates to the crystal form of the compound shown below, wherein the crystal system is monoclinic, the space group is P21, and the cell parameters are: α=90°, β=115.517(5)°, γ=90°;

[0303] Another aspect of this disclosure relates to compounds of the following general formula, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0304] in:

[0305] R 3 Selected from deuterium atoms and deuterated C 1-6 Alkyl, C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0306] R 1 The same or different each time it appears, and each is independent of the hydrogen atom, the amino protecting group and the optionally substituted phenyl group, wherein the amino protecting group is preferably -Boc;

[0307] R 2The components may be the same or different each time they appear, and are each independently selected from halogens, boronic esters, and boric acids; preferably, R 2 They may be the same or different each time they appear, and each is independently selected from Br and

[0308] In another embodiment of this disclosure, "optionally substituted" refers to optional substitution by halogens, deuterium atoms, or deuterated C atoms. 1-6 Alkyl, C 1-6 Alkyl or halogenated C 1-6 Alkyl substitution.

[0309] In another embodiment of this disclosure, the compound is selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts:

[0310] Another aspect of this disclosure relates to a pharmaceutical composition comprising the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), (IIa), (IIa-1), (IIa-2), (II-3), (II-3a), (II-3b), (IIa-3), (IIa-3a), (IIa-3b), (I-1a), (I-1b), (I-2a), (I-2a'), and (I-2a”) of this disclosure. General formula (I-2b), General formula (I-2b'), General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula Compounds of the formula (I-2da), general formula (I-2da'), general formula (I-2da”), general formula (I-1cb), general formula (I-1db), general formula (I-2cb), general formula (I-2cb'), general formula (I-2cb”), general formula (I-2db), general formula (I-2db'), general formula (I-2db”) or Scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms described above, and one or more pharmaceutically acceptable carriers.

[0311] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), and (IV-c). -c), General formula (IIa), General formula (IIa-1), General formula (IIa-2), General formula (II-3), General formula (II-3a), General formula (II-3b), General formula (IIa-3), General formula (IIa-3a), General formula (IIa-3b), General formula (I-1a), General formula (I-1b), General formula (I-2a), General formula (I-2a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b') General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2da') Use of compounds of general formula (I-2da”), general formula (I-1cb), general formula (I-1db), general formula (I-2cb), general formula (I-2cb'), general formula (I-2cb”), general formula (I-2db), general formula (I-2db'), general formula (I-2db”) or scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms described above, or pharmaceutical compositions comprising them, in the preparation of medicaments for sGC agonists and / or activators.

[0312] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), and (IV-c). General formula (IIa), General formula (IIa-1), General formula (IIa-2), General formula (II-3), General formula (II-3a), General formula (II-3b), General formula (IIa-3), General formula (IIa-3a), General formula (IIa-3b), General formula (I-1a), General formula (I-1b), General formula (I-2a), General formula (I-2a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b'), General formula (I-2b) ”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2da'), General formula (I-2da”) Use of compounds of general formula (I-1cb), general formula (I-1db), general formula (I-2cb), general formula (I-2cb'), general formula (I-2cb”), general formula (I-2db), general formula (I-2db'), general formula (I-2db”) or scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms described above, or pharmaceutical compositions comprising them, in the preparation of a medicament for the treatment and / or prevention of diseases mediated by sGC agonists and / or activators.

[0313] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), (IIa), (IIa-1), and (IIa- 2) General formula (II-3), General formula (II-3a), General formula (II-3b), General formula (IIa-3), General formula (IIa-3a), General formula (IIa-3b), General formula (I-1a), General formula (I-1b), General formula (I-2a), General formula (I-2a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b'), General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2da'), General formula (I-2da”), General formula (I-1cb), General formula (I-1db), General formula (I-2cb), General formula (I-2cb'), General formula (I-2cb”), General formula (I-2db), General formula (I-2db'), General Use of the compound of formula (I-2db”) or scheme A, its stereoisomer or pharmaceutically acceptable salt thereof, or the crystal form thereof, or pharmaceutical composition comprising thereof in the preparation of a medicament for the treatment and / or prevention of heart failure (HFrEF, HFmrE and HFpEF), hypertension (HTN), chronic kidney disease and diabetic nephropathy (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases, nonproliferative diabetic retinopathy and dementia or diabetic foot ulcers.

[0314] This disclosure also relates to a method for agitating and / or activating sGCs, comprising administering to a patient the desired therapeutically effective amount of the following formulas: (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), (IIa), (IIa-1), (IIa-2), (II-3), (II-3a), (II-3b), (IIa-3), (IIa-3a), (IIa-3b), (I-1a), (I-1b), (I-2a), (I-2a'), (I-2a'). I-2a”), general formula (I-2b), general formula (I-2b'), general formula (I-2b”), general formula (I-1c), general formula (I-1d), general formula (I-2c), general formula (I-2c'), general formula (I-2c”), general formula (I-2d), general formula (I-2d'), general formula (I-2d”), general formula (I-1ca), general formula (I-1da), general formula (I-2ca), general formula (I-2ca'), general formula (I-2c Compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising the above formulas (I-2da), (I-2da'), (I-2da"), (I-1cb), (I-1db), (I-2cb), (I-2cb'), (I-2cb"), (I-2db"), (I-2db'), (I-2db"), or Scheme A, or pharmaceutical compositions comprising the above formulas (I-2db"), or Scheme A, thereof, or pharmaceutically acceptable salts thereof, or crystal forms thereof.

[0315] This disclosure also relates to a method for treating and / or preventing sGC agonist and / or activator-mediated diseases, comprising administering to a desired patient a therapeutically effective amount of general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (III-a), general formula (II-1), general formula (II-2), general formula (III-2), general formula (III-3), general formula (II-4), general formula (II-5), general formula (II-1), general formula (II-2), general formula (II ... I-b), General Formula (III-c), General Formula (IV-a), General Formula (IV-b), General Formula (IV-c), General Formula (IIa), General Formula (IIa-1), General Formula (IIa-2), General Formula (II-3), General Formula (II-3a), General Formula (II-3b), General Formula (IIa-3), General Formula (IIa-3a), General Formula (IIa-3b), General Formula (I-1a), General Formula (I-1b), General Formula (I-2a), General Formula (I-2) a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b'), General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I Compounds of the formula (I-2ca”), general formula (I-2da), general formula (I-2da'), general formula (I-2da”), general formula (I-1cb), general formula (I-1db), general formula (I-2cb), general formula (I-2cb'), general formula (I-2cb”), general formula (I-2db), general formula (I-2db'), general formula (I-2db”) or Scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising them.

[0316] This disclosure also relates to a method of treating and / or preventing disease, comprising administering to a patient a therapeutically effective amount of the following formulas: (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), and (IV-c). Formula (IIa), General Formula (IIa-1), General Formula (IIa-2), General Formula (II-3), General Formula (II-3a), General Formula (II-3b), General Formula (IIa-3), General Formula (IIa-3a), General Formula (IIa-3b), General Formula (I-1a), General Formula (I-1b), General Formula (I-2a), General Formula (I-2a'), General Formula (I-2a”), General Formula (I-2b), General Formula (I-2b'), General Formula (I-2b”), General Formula (I-1c), General Formula (I-1d), General Formula (I-2c) General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2da'), General formula (I-2da”), General formula (I-1cb), General formula (I-1db), General formula (I-2cb), General formula (I-2cb'), General formula (I-2cb”), General formula (I-2 The disease is selected from compounds of formula (I-2db'), formula (I-2db") or scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising them; the disease is selected from heart failure (HFrEF, HFmrE and HFpEF), hypertension (HTN), chronic kidney disease and diabetic nephropathy (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases, nonproliferative diabetic retinopathy and dementia or diabetic foot ulcers.

[0317] This disclosure further relates to a general formula (I), general formula (II), general formula (II-1), general formula (II-2), general formula (III), general formula (III-1), general formula (III-2), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (III-a), general formula (III-b), general formula (III-c), general formula (IV-a), general formula (IV-b), general formula (IV-c), general formula (IIa), general formula (IIa-1), general formula (IIa-2), general formula (II-3), general formula (II-3a), general formula (II-3b), general formula (IIa-3), general formula (IIa-3a), general formula (IIa-3b), general formula (I-1a), general formula (I-1b), general formula (I-2a), general formula (I-2a'), general formula (I-2a”), general formula (I-2b), general formula (I-2b), general formula (I-2a'), general formula (I-2a” ...'), general formula (I-2a''), general formula (I-2a''), general formula (I-2a''), general formula (I-2a''), general formula (I-2a''), general formula (I-2a''), general formula (I-2a Formula (I-2b'), General Formula (I-2b”), General Formula (I-1c), General Formula (I-1d), General Formula (I-2c), General Formula (I-2c'), General Formula (I-2c”), General Formula (I-2d), General Formula (I-2d'), General Formula (I-2d”), General Formula (I-1ca), General Formula (I-1da), General Formula (I-2ca), General Formula (I-2ca'), General Formula (I-2ca”), General Formula (I-2da) Compounds of formula (I-2da'), formula (I-2da”), formula (I-1cb), formula (I-1db), formula (I-2cb), formula (I-2cb'), formula (I-2cb”), formula (I-2db), formula (I-2db'), formula (I-2db”), or scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising thereof, used as pharmaceuticals.

[0318] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), and (I). V-c), General Formula (IIa), General Formula (IIa-1), General Formula (IIa-2), General Formula (II-3), General Formula (II-3a), General Formula (II-3b), General Formula (IIa-3), General Formula (IIa-3a), General Formula (IIa-3b), General Formula (I-1a), General Formula (I-1b), General Formula (I-2a), General Formula (I-2a'), General Formula (I-2a”), General Formula (I-2b), General Formula (I-2b) '), General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2 Compounds of formula (I-2da”), formula (I-1cb), formula (I-1db), formula (I-2cb), formula (I-2cb’), formula (I-2cb”), formula (I-2db), formula (I-2db’), formula (I-2db”), or Scheme A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising thereof, used as sGC agonists and / or activators.

[0319] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), and (IV-c). ), General formula (IIa), General formula (IIa-1), General formula (IIa-2), General formula (II-3), General formula (II-3a), General formula (II-3b), General formula (IIa-3), General formula (IIa-3a), General formula (IIa-3b), General formula (I-1a), General formula (I-1b), General formula (I-2a), General formula (I-2a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b'), General formula ( I-2b”), general formula (I-1c), general formula (I-1d), general formula (I-2c), general formula (I-2c'), general formula (I-2c”), general formula (I-2d), general formula (I-2d'), general formula (I-2d”), general formula (I-1ca), general formula (I-1da), general formula (I-2ca), general formula (I-2ca'), general formula (I-2ca”), general formula (I-2da), general formula (I-2da'), general formula (I The compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising the above, are used for the treatment and / or prevention of diseases mediated by sGC agonists and / or activators.

[0320] This disclosure further relates to general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), (IIa), (IIa-1), and (II-2). a-2), General formula (II-3), General formula (II-3a), General formula (II-3b), General formula (IIa-3), General formula (IIa-3a), General formula (IIa-3b), General formula (I-1a), General formula (I-1b), General formula (I-2a), General formula (I-2a'), General formula (I-2a”), General formula (I-2b), General formula (I-2b'), General formula (I-2b”), General formula (I-1c), General formula (I-1d), General formula (I-2c), General formula (I-2c'), General formula (I-2 c”), General formula (I-2d), General formula (I-2d'), General formula (I-2d”), General formula (I-1ca), General formula (I-1da), General formula (I-2ca), General formula (I-2ca'), General formula (I-2ca”), General formula (I-2da), General formula (I-2da'), General formula (I-2da”), General formula (I-1cb), General formula (I-1db), General formula (I-2cb), General formula (I-2cb'), General formula (I-2cb”), General formula (I-2db), General formula (I-2 Compounds of the formula (I-2db”) and those shown in Table A, their stereoisomers or pharmaceutically acceptable salts thereof, or the crystal forms thereof, or pharmaceutical compositions comprising them, for the treatment and / or prevention of heart failure (HFrEF, HFmrE and HFpEF), hypertension (HTN), chronic kidney disease and diabetic nephropathy (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases, nonproliferative diabetic retinopathy and dementia, or diabetic foot ulcers.

[0321] The active compound can be formulated into a form suitable for administration via any appropriate route, preferably in a unit dose manner or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0322] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound; preferably, the composition may contain 1 to 95% by weight of the active compound.

[0323] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0324] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0325] Terminology Explanation

[0326] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0327] The term "therapeutic effective dose" refers to a sufficient amount of the compound of this disclosure, its pharmaceutically acceptable salts, or its stereoisomers to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dose of the compound of Formula I, or its pharmaceutically acceptable salts and compositions thereof, must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific therapeutic effective dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0328] The term "isomer" as used in this disclosure includes geometric isomers and stereoisomers, such as trans-restricted isomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which are within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a functional group isomer that has different hydrogen bonding sites through one or more double bond shifts; for example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to stereoisomers of molecules having two or more chiral centers and being non-mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations of a molecule where double bonds or single bonds of cyclic carbon atoms cannot rotate freely.

[0329] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction can be used, or the absolute configuration of a compound can be confirmed by the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Some compounds disclosed herein can be obtained through chiral resolution, or prepared from intermediates obtained through chiral resolution. For these compounds, given the confirmed number of chiral carbon atoms or chiral sites, those skilled in the art should clearly understand the number and structure of the compounds obtained through resolution, and can confirm the correspondence between the resolved compounds and the compound structures using conventional techniques in the art. Furthermore, this disclosure further tests the effects of the resolved compounds, or their effects can be inferred from the effects of other structurally similar compounds. Based on this, these compounds obtained through resolution or prepared from intermediates obtained through resolution should be considered fully disclosed.

[0330] Those skilled in the art know that when a cyclic compound has a coplanar delocalized system and the number of π electrons is 4n+2, the ring is aromatic. The aromatic structure in a compound can be represented by either dashed lines indicating electron delocalization or by alternating single and double bonds. For example, the structure of a benzene ring can be drawn as follows: It can also be

[0331] "Optionally" or "optionally" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally (optionally) alkyl group substituted with halogen or cyano" includes cases where the alkyl group is substituted with halogen or cyano and cases where the alkyl group is not substituted with halogen or cyano.

[0332] When the substituent structure contains... A truncated bond indicates that the bond is a linking bond to a substituent, for example... This indicates that the benzene ring is attached to a given group or a given structural formula via a carbon atom.

[0333] The presence of a dash "-" in a substituent structure indicates the connection point for the substituent. For example, -SCH3 is connected to a given group or given structural formula via a sulfur atom. The absolute configuration representing the center of a solid, i.e., the R or S configuration. It indicates cis or trans configuration. Double real or double dummy bonds both indicate cis configuration, and one real and one dummy bond indicates trans configuration.

[0334] When a substituent can be cross-bonded to a ring, it means that the substituent can bond with any atom on that ring. For example, structural units. This indicates that the substituent R can be substituted at any position on the benzene ring.

[0335] When a listed substituent does not specify which atom it is attached to a given group or given structural formula, the substituent may be attached by any of its bondable atoms.

[0336] When any variable (e.g., R) d When a compound appears more than once in its composition or structure, its definition is independent in each case. For example, This indicates that the cyclopentyl group is surrounded by 3 R groups. d Replaced, and each R d Each has its own independent options.

[0337] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0338] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1- 10 "Alkyl" refers to compounds including C1, C2, C3, C4, C5, C6, C7, C8, C9, C6, C7, C8, C9, C9, C1, C1, C1, C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ... 10 Alkyl, "C 1-6 Alkyl", C 1-4 Alkyl", C 1-3 Alkyl; specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0339] Unless otherwise specified, the term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Preferred halogenated C 1-6 Alkyl, more preferably halogenated C 1-4 Alkyl groups. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0340] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups, and "hydroxyalkyl" as used in this disclosure includes "hydroxyl C". 1-6 Alkyl group, hydroxyl group 1-4 Alkyl groups; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, and -CH2CH2CH2OH. wait.

[0341] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-4 "Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-4 Alkoxy, more preferably C 1-3 Alkyl group.

[0342] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-4Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0343] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups.

[0344] The term "hetero" refers to substituted or unsubstituted heteroatoms and their oxidized forms (also called heteroatomic groups). The heteroatoms are generally selected from N, O, S, and P, and the oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined in the text). The number of atoms on the ring is usually defined as the ring number. For example, "3-6 membered heterocyclic alkyl" refers to a ring consisting of 3-6 atoms arranged in a ring, each ring optionally containing 1 to 3 heteroatoms and / or heteroatomic groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR. Each ring is optionally substituted by an R group, R being a group defined in the text.

[0345] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, condensation, or other means. The carbon atom in the cycloalkyl group can be further oxidized, i.e., forming C(O). Unless otherwise specified, "membered cycloalkyl" as used herein includes both monocyclic cycloalkyl and polycyclic cycloalkyl such as spiro, condensed, or bridged cycloalkyl groups. The cycloalkyl group includes "3 to 20-membered cycloalkyl", "3 to 10-membered cycloalkyl", "5 to 10-membered cycloalkyl", "5 to 12-membered cycloalkyl", "3 to 8-membered cycloalkyl", "4 to 8-membered cycloalkyl", "3 to 6-membered cycloalkyl", and "3 to 5-membered cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0346] Unless otherwise specified, "cycloalkenyl" means one or more of the cyclic bonds in a "cycloalkyl" group that are double bonds and that the cycloalkenyl group is not aromatic. The carbon atom in the cycloalkenyl group may be further oxidized, forming a C(O) group. The cycloalkenyl group includes "3- to 20-membered cycloalkenyl", "3- to 10-membered cycloalkenyl", "5- to 10-membered cycloalkenyl", "5- to 12-membered cycloalkenyl", "3- to 8-membered cycloalkenyl", "3- to 6-membered cycloalkenyl", "3- to 5-membered cycloalkenyl", and "5- to 6-membered cycloalkenyl". Specific examples include, but are not limited to, those mentioned above.

[0347] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or unsaturated cyclic group derived by replacing one or more cyclic carbon atoms in a cycloalkyl group with heteroatoms and / or heterogroups. Unless otherwise specified, the heterocyclic group may contain one or more double bonds (heterocyclic groups include heterocyclic alkenyl groups). The heteroatoms and / or heterogroups are generally selected from N, O, S, NO, SO, S(O)₂, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1 to 3 N and / or O atoms. Unless otherwise specified, the term "membered heterocyclic group" as used herein includes both monocyclic heterocyclic groups and polycyclic heterocyclic groups such as spiro, fused, or bridged heterocyclic groups. The heterocyclic groups include "3 to 20-membered heterocyclic groups", "3 to 10-membered heterocyclic groups", "5 to 10-membered heterocyclic groups", "3 to 8-membered heterocyclic groups", "3 to 6-membered heterocyclic groups", "3 to 5-membered heterocyclic groups", "4 to 8-membered heterocyclic groups", "4 to 6-membered heterocyclic groups", "5 to 6-membered heterocyclic groups", and "5 to 12-membered heterocyclic groups". Specific examples include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc.

[0348] Unless otherwise specified, the term "heterocyclic alkenyl" refers to a "heterocyclic group" in which one or more cyclic bonds are double bonds and the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. The heterocyclic group includes "3- to 10-membered heterocyclic alkenyl", "5- to 10-membered heterocyclic alkenyl", "3- to 8-membered heterocyclic alkenyl", "3- to 6-membered heterocyclic alkenyl", "3- to 5-membered heterocyclic alkenyl", "4- to 8-membered heterocyclic alkenyl", "4- to 6-membered heterocyclic alkenyl", "5- to 6-membered heterocyclic alkenyl", and "5- to 12-membered heterocyclic alkenyl". Specific examples include, but are not limited to: wait.

[0349] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which may be a monocyclic or a plurality of rings fused together. Preferably, it is a 5- to 10-membered aryl group, more preferably a 5- to 8-membered aryl group, and most preferably a monocyclic 5- to 6-membered aryl group; examples of aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0350] The term "heteroaryl" as used in this disclosure refers to an aromatic monocyclic or polycyclic group comprising one or more heteroatoms and / or heterogroups, wherein the heteroatoms and / or heterogroups are generally selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any substituent that may exist, wherein the carbon atom in the heterocycle is optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms, and the N and S atoms may optionally be oxidized and the N atom may optionally be quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "fused heteroaryl," wherein a fused heteroaryl refers to an aromatic group comprising one or more heteroatoms formed by two or more cyclic structures sharing two adjacent atoms. The heteroaryl is preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl, and most preferably a monocyclic 5- to 6-membered heteroaryl. Unless otherwise specified, the term "heteroaryl" as used herein generally refers to a "monocyclic heteroaryl," such as the "5- to 6-membered heteroaryl" described herein, which does not possess the potential to form a fused-ring heteroaryl. When it is a "fused heteroaryl," it will be specifically indicated that it is a "fused" heteroaryl structure, such as an "8- to 10-membered fused heteroaryl." The heteroaryl described in this disclosure is preferably a "nitrogen-containing heteroaryl," more preferably a "5- to 6-membered nitrogen-containing heteroaryl." The heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, containing only 1, 2, or 3 nitrogen atoms, or containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., S and / or O atoms), or containing 2 nitrogen atoms and 1 or 2 other heteroatoms. Specific examples of the heteroaryl include, but are not limited to: furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazole, pyrazolyl, etc.

[0351] Unless otherwise specified, the term "bridged ring group" refers to a saturated or partially saturated ring structure formed by two or more carbon rings sharing two non-adjacent carbon atoms. Optionally, the carbon atoms in the ring structure may be substituted with oxygen. "Bridged ring group" includes, for example, "4- to 10-membered bridged ring group," "5- to 11-membered bridged ring group," "6- to 11-membered bridged ring group," "5- to 10-membered bridged ring group," "5- to 7-membered bridged ring group," "7- to 10-membered bridged ring group," "6- to 9-membered bridged ring group," "7- to 8-membered bridged ring group," "9- to 10-membered bridged ring group," etc. Specific examples include, but are not limited to:

[0352] Unless otherwise specified, the term "bridged heterocyclic group" refers to a saturated or partially saturated cyclic structure derived from the substitution of at least one carbon atom in the "bridged cyclic group" by a heteroatom / heteroatomic group selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any possible substituent group, and the "bridged cycloalkyl group" is as defined above. "Bridged heterocyclic groups" include, for example, "4- to 10-membered bridged heterocyclic groups," "5- to 14-membered bridged heterocyclic groups," "5- to 11-membered bridged heterocyclic groups," "5- to 8-membered bridged heterocyclic groups," "6- to 11-membered bridged heterocyclic groups," "5- to 10-membered bridged heterocyclic groups," "7- to 10-membered bridged heterocyclic groups," "6- to 9-membered bridged heterocyclic groups," "7- to 8-membered bridged heterocyclic groups," "9- to 10-membered bridged heterocyclic groups," "6- to 10-membered bridged heterocyclic alkenyl groups," "6- to 8-membered bridged heterocyclic alkenyl groups," and "7- to 8-membered nitrogen-containing bridged heterocyclic alkenyl groups," etc. Preferably, the heteroatom is independently selected from 1-3 N and / or O atoms. Preferably, the bridging heterocyclic group is a "nitrogen-containing bridging heterocyclic group," meaning that at least one ring atom is N, and optionally contains one or more other heteroatoms; preferably, the "nitrogen-containing bridging heterocyclic group" contains 1 N atom and 0-2 atoms selected from N and / or O and / or S. Preferably, the "nitrogen-containing bridging heterocyclic group" contains 1 N atom and 0-1 atoms selected from O and / or S. Preferably, the bridging heterocyclic group is an "oxygen-containing bridging heterocyclic group," meaning that at least one ring atom is O, and optionally contains one or more other heteroatoms; preferably, the "oxygen-containing heterocyclic group" contains 1 O atom and 0-2 atoms selected from N and / or O. Specific examples include, but are not limited to: wait.

[0353] Unless otherwise specified, the term "fused heterocyclic group" refers to a saturated or partially saturated non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent atoms, containing at least one heteroatom in the ring; the heteroatom is generally selected from N, O, and S; the cyclic carbon atom and heteroatom in the fused heterocycle can be further oxidized to form a cyclic group containing C(O), NO, SO, or S(O)2 groups, which are also included within the definition of heterocyclic group in this invention. "Fused heterocyclic group" includes, for example, "5 to 14-membered fused heterocyclic group", "5 to 11-membered fused heterocyclic group", "5 to 8-membered fused heterocyclic group", "6 to 11-membered fused heterocyclic group", "5 to 10-membered fused heterocyclic group", "7 to 10-membered fused heterocyclic group", "6 to 9-membered fused heterocyclic group", "7 to 8-membered fused heterocyclic group", "9 to 10-membered fused heterocyclic group", "6 to 10-membered fused heterocyclic alkenyl group", "6 to 8-membered fused heterocyclic alkenyl group", "7 to 8-membered nitrogen-containing fused heterocyclic alkenyl group", etc. The fusion method can be 5-6 membered heterocyclic fused with 5-6 membered heterocyclic, 5-6 membered heterocyclic fused with 5-6 membered cycloalkyl, benzo5-6 membered heterocyclic, benzo5-6 membered saturated heterocyclic, 5-6 membered heteroaryl fused with 5-6 membered heterocyclic, 5-6 membered heteroaryl fused with 5-6 membered saturated heterocyclic, benzo5-6 membered heterocyclic fused with 5-6 membered heterocyclic, 5-6 membered heteroaryl fused with 5-6 membered heterocyclic, benzo5-6 membered cycloalkyl fused with 5-6 membered heterocyclic, 5-6 membered heteroaryl fused with 5-6 membered cycloalkyl fused with 5-6 membered heterocyclic; specific examples of the fused heterocyclic group include, but are not limited to:

[0354] Unless otherwise specified, the term "spiroheterocyclic group" refers to a saturated or partially saturated cyclic structure derived from the substitution of at least one carbon atom in a "spirocyclic group" by a heteroatom / heteroatomic group selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any possible substituent group. The "spirocyclic group" is as defined above. It includes, but is not limited to, cyclic structures formed from heterocyclic spiroheterocycles and heterocyclic spirocyclic alkanes. The spirocyclic group preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably 1 NR and 0-1 NR or O heteroatoms. The spirocyclic group is preferably a "nitrogen-containing spirocyclic group," which refers to a spirocyclic ring with at least one NR ring atom. The term "spiroheterocyclic group" includes, for example, 5- to 14-membered spiroheterocyclic groups, 7- to 11-membered spiroheterocyclic groups, 7- to 9-membered spiroheterocyclic groups, 7- to 11-membered nitrogen-containing spiroheterocyclic groups, 7- to 9-membered nitrogen-containing spiroheterocyclic groups, "5- to 11-membered spiroheterocyclic groups," "5- to 8-membered spiroheterocyclic groups," "6- to 11-membered spiroheterocyclic groups," "5- to 10-membered spiroheterocyclic groups," "7- to 10-membered spiroheterocyclic groups," "6- to 9-membered spiroheterocyclic groups," "7- to 8-membered spiroheterocyclic groups," "9- to 10-membered spiroheterocyclic groups," "6- to 10-membered spiroheterocyclic alkenyl groups," "6- to 8-membered spiroheterocyclic alkenyl groups," and "7- to 8-membered nitrogen-containing spiroheterocyclic alkenyl groups," etc. Specific examples include, but are not limited to: wait.

[0355] When a substituent can be cross-bonded to a ring, it means that the substituent can bond with any atom on that ring. For example, structural units. Indicates substituent R b Substitution can occur at any position on ring B (including NH), and R b The number of atoms is n; when the ring contains NH, it means that NH, like other ring atoms, can be converted by R. b What it replaces, namely R b It can replace H, or it can choose not to replace H.

[0356] When any variable (e.g., R) b When a structural unit appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, structural units. This indicates that ring B is divided by n R's. b Replaced, and each R b Each has its own independent options.

[0357] When a listed substituent does not specify which atom it is attached to a given group or given structural formula, the substituent may be attached by any of its bondable atoms. For example, pyrimidine as a substituent means that any carbon or nitrogen atom on the pyrimidine ring is attached to the substituted group. Another example is ring B in this disclosure, selected from... The absence of a defined connection site in the structural unit means that any carbon atom on the tetrahydropyran ring can be attached to a given group or a given structural formula.

[0358] In particular, all combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0359] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0360] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0361] The term "medicinal salt" refers to the general formulas (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (III-a), (III-b), (III-c), (IV-a), (IV-b), (IV-c), (IIa), (IIa-1), (IIa-2), (II-3), (II-3a), (II-3b), (IIa-3), (IIa-3a), (IIa-3b), (I-1a), (I-1b), (I-2a), (I-2a'), (I-2a"), and (I-2a" of this disclosure. Formula (I-2b), General Formula (I-2b'), General Formula (I-2b”), General Formula (I-1c), General Formula (I-1d), General Formula (I-2c), General Formula (I-2c'), General Formula (I-2c”), General Formula (I-2d), General Formula (I-2d'), General Formula (I-2d”), General Formula (I-1ca), General Formula (I-1da), General Formula (I-2ca), General Formula (I-2ca'), General Formula (I-2ca) The compounds, or their stereoisomers, shown in Table A, and their derivatives prepared by reacting with relatively non-toxic acids or bases, are listed below. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified compounds alone with suitable acids or bases. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides, or organic amines to yield base addition salts, including alkali metal and alkaline earth metal cations, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also encompass amino acid salts. When the compounds contain relatively basic functional groups, they react with organic or inorganic acids to yield acid addition salts. In another embodiment of this disclosure, the "pharmaceutical salt" is selected from formate or hydrochloride; wherein the number of formates is preferably 0, 1, 2 or 3, more preferably 0 or 1; and the number of hydrochlorides is preferably 0, 1, 2 or 3, more preferably 0 or 1.

[0362] In the compounds described in Table B of this disclosure, as well as the synthetic intermediates and synthetic examples, any compound described as a salt of the corresponding base or acid is generally a salt with an unknown exact stoichiometric composition, obtained by its respective preparation and / or purification methods. Therefore, unless otherwise specified, additional terms in nouns and structural formulas, such as “hydrochloride,” “trifluoroacetate,” “sodium salt,” “xHCl,” “xCF3COOH,” or “xNa,” should not be interpreted in a stoichiometric sense in the case of such salts, but rather should be considered descriptively only for the salt-forming components present therein. The x values ​​of 0, 1, 2, or 3 listed in Table B of this disclosure are merely illustrative possible values ​​for x, but not limited to 0, 1, 2, or 3.

[0363] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0364] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0365] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0366] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0367] Technical effect

[0368] The disclosed compound exhibits significant agonistic and / or activating effects on sGC, and compared to the control compound (the compound in WO2022122910A1), the disclosed compound demonstrates significant advantages in in vitro, pharmacokinetic, and pharmacodynamic properties. The structure of the control compound is as follows: Attached Figure Description

[0369] Figure 1 shows the ellipsoidal diagram of the F08S molecular structure.

[0370] Figure 2 is an ellipsoidal diagram of the E21R molecular structure. Detailed Implementation

[0371] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0372] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants. The compounds of this disclosure can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this disclosure.

[0373] 1. Summary of Experimental Instruments

[0374] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS).

[0375] NMR measurements were performed using the following instruments: Bruker Avance III 400 MHz, Bruker Avance NEO 400 MHz, and Bruker Ascend Evo 400 MHz. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with heavy water (D2O) as the internal standard (DMSO). NMR chemical shifts (δ) are given in parts per million (ppm).

[0376] The determination was performed using liquid chromatography-mass spectrometry (LC-MS) with an Agilent 1260 & G6125B single quadrupole mass spectrometer, a Shimadzu LC-20ADXR & MS 2020 & MS 2010 single quadrupole mass spectrometer (ion source: electrospray ionization).

[0377] HPLC determinations were performed using a Shimadzu 20AD high-performance liquid chromatograph and an Agilent 1290 Infinity II.

[0378] Preparative HPLC was performed using a GILSON GX281 332 Pump and an Agilent 1260 Infinity II.

[0379] Chiral HPLC determination was performed using a Shimadzu LC-20AB with a PDA detector.

[0380] Supercritical fluid chromatography (SFC) was performed using waters UPCC with PDA Detector, QDa Detector, and SQ Detector 2.

[0381] Supercritical fluid chromatography (SFC) was performed using Waters SFC150 MGM.

[0382] The starting materials and intermediates directly used in this disclosure can be synthesized according to methods known in the art or are commercially available. Experimental methods not specifying specific conditions in the examples are generally performed under conventional conditions or according to the conditions recommended by the raw material or product manufacturer. Reagents not specifying their source are commercially available conventional reagents.

[0383] The reaction process in the examples can be monitored using conventional methods such as thin-layer chromatography (TLC) and LC-MS. The eluent system for purification column chromatography (which can be conventional column chromatography or rapid column chromatography) and the developing solvent system for TLC can be composed of one or more of the following solvents: dichloromethane, methanol, n-hexane, ethyl acetate, petroleum ether, ethyl acetate, acetone, dichloromethane, etc. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents, such as triethylamine, acetic acid, trifluoroformic acid, etc., can also be added for adjustment. Unless otherwise specified, the percentage content (%) mentioned in this disclosure refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0384] 2. Synthesis Examples

[0385] The preparation method of the compound disclosed herein is based on prior patent WO2022122910A1.

[0386] All compounds described in this disclosure were synthesized using methods described in prior patents or conventional techniques employed by those skilled in the art. The structures of the target compounds, obtained according to the referenced synthetic routes and the specific compound synthesis schemes described in this disclosure, were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Characterization data for some of the compounds are shown in Table 1.

[0387] Table 1

[0388] Synthesis of specific compounds:

[0389] Synthesis of intermediates:

[0390] Intermediate INT-1

[0391] Step 1: Synthesis of compound INT-1-2

[0392] Compound INT-1-1 (20 g, 82.94 mmol), diisopropylethylamine (22.26 g, 172.23 mmol), and 2-methylpropionaldehyde (6.32 g, 87.65 mmol) were added to a solution of dichloromethane (300 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was quenched with 150 mL of water, extracted with dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The solution was then passed through a rapid silica gel column (eluting with a 0-7% ethyl acetate / n-hexane gradient @ 100 mL / min) to give 17.2 g of compound INT-1-2.

[0393] MS(ESI)M / Z: 297.1 [M+H] + .

[0394] 1 H NMR(400MHz CHLOROFORM-d)δppm 7.36-7.31(m, 2H), 6.83-6.77(m, 2H), 3.20-3.14(m, 4H), 2.59-2.51(m, 4H) , 2.15 (d, J=7.4Hz, 2H), 1.82 (td, J=6.9, 13.6Hz, 1H), 0.93 (d, J=6.6Hz, 6H).

[0395] Step 2: Synthesis of compound INT-1

[0396] Compound INT-1-2 (17.2 g, 57.87 mmol), bis-pinacol borate (17.6 g, 69.31 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (4.2 g, 5.74 mmol), potassium acetate (17 g, 173.22 mmol), and dioxane (170 mL) were degassed and purged three times with nitrogen. The mixture was then stirred at 100 °C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure and passed through a rapid silica gel column (eluting buffer: 0-5% ethyl acetate / n-hexane gradient @ 100 mL / min) to give 12.4 g of compound INT-1.

[0397] MS(ESI)M / Z: 345.3 [M+H]+ .

[0398] 1 H NMR (400MHz CHLOROFORM-d) δppm 7.71 (d, J=8.8Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 3.29 (br s, 4H), 2.55 (br s, 4H), 2.16 (br d, J=4.0Hz, 2H), 1.91-1.77 (m, 1H), 1.33 (s, 12H), 0.94 (br d, J=6.5Hz, 6H).

[0399] intermediate INT-2

[0400] Step 1: Synthesis of compound INT-2-3

[0401] To a solution of INT-2-1 (28 g, 147.25 mmol) dissolved in toluene (400 mL), 2-(tributylphosphine)acetonitrile (88.85 g, 368.14 mmol) and INT-2-2 (69.29 g, 294.51 mmol) were added. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and passed through a rapid silica gel column (eluting with a 0–7.8% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give 32 g of compound INT-2-3.

[0402] MS(ESI)M / Z: 408.1 [M+H] + .

[0403] 1 H NMR (400MHz CHLOROFORM-d) δppm7.90 (s, 1H), 7.31-7.69 (m, 6H), 5.14 (s, 2H), 4.55 (br s, 1H), 4.33 (q, J=7.15Hz, 3H), 4.15-4.29 (m, 1H), 3.32 (br t, J=11.62Hz, 1H), 2.85 (br s, 1H), 2.18 (br s, 2H), 1.89 (br d, J=11.44Hz, 1H), 1.62-1.75 (m, 1H), 1.37 (t, J=7.15Hz, 3H).

[0404] Step 2: Synthesis of compound INT-2-4

[0405] A methanol solution (32 g, 78.54 mmol) of compound INT-2-3 was mixed with wet palladium on carbon (8.36 g, 7.85 mmol, 10% purity) in 400 mL of the solution. The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 21 g of compound INT-2-4.

[0406] MS(ESI) M / Z: 274.0 [M+H] + .

[0407] 1 H NMR(400MHz DMSO-d6)δppm 8.01 (s, 1H), 7.59 (t, J=52.0Hz, 1H), 4.37-4.51 (m, 1H), 4.26 (q, J=7.03Hz, 2H), 3.04 (dd, J=11. 80, 3.76Hz, 1H), 2.82-2.92(m, 2H), 2.42(td, J=12.36, 2.64Hz, 1H), 1.96-2.04(m, 2H), 1.73(br d, J=13.30Hz, 1H), 1.44-1.57 (m, 1H), 1.28 (t, J=7.03Hz, 3H).

[0408] Step 3: Synthesis of compound INT-2-6

[0409] INT-2-4 (5 g, 18.30 mmol), INT-2-5 (7.19 g, 21.96 mmol), tris(dibenzylacetone)palladium (3.35 g, 3.66 mmol), 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (2.28 g, 3.66 mmol), and cesium carbonate (11.92 g, 36.59 mmol) were degassed with dioxane (80 mL), purged three times with nitrogen, and then stirred at 100 °C under nitrogen for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product, which was then passed through a rapid silica gel column (eluting with a 0-50% dichloromethane / petroleum ether gradient @ 60 mL / min) to give 5.76 g of compound INT-2-6.

[0410] MS(ESI)M / Z: 520.3 [M+H] + .

[0411] 1H NMR(400MHz CHLOROFORM-d)δppm 7.92 (s, 1H), 7.53 (t, J=52.8Hz, 1H), 7.31 (d, J=8.70Hz, 2H), 6.85-6.94 (m, 4H), 6.78-6.83 (m, 1H) , 5.04 (s, 2H), 4.79-4.91 (m, 1H), 4.34 (q, J=7.15Hz, 2H), 3.82 (s, 3H), 3.68-3.75 (m, 1H), 3.57 (br d, J=11.21Hz, 1H), 3.19 (t, J=10.67Hz, 1H), 2.64 (td, J=11.24, 3.64Hz, 1H), 2.03-2.25 (m, 2H), 1.80-1.99 (m, 2H), 1.38 (t, J=7.15Hz, 3H).

[0412] Step 4: Synthesis of compound INT-2-7

[0413] A solution of compound INT-2-6 (6 g, 11.54 mmol) in dichloromethane (48 mL) was added to trifluoroacetic acid (73.68 g, 646.20 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with an aqueous sodium bicarbonate solution (400 mL), extracted with dichloromethane (300 mL × 3), dehydrated with anhydrous sodium sulfate in the organic phase, filtered, and concentrated under reduced pressure to give 4.5 g of compound INT-2-7.

[0414] MS(ESI)M / Z: 400.2[M+H] + .

[0415] Step 5: Synthesis of compound INT-2

[0416] At -50°C, triethylamine (2.66 g, 26.26 mmol) and trifluoromethanesulfonic anhydride (3.70 g, 13.13 mmol) were added to a solution of compound INT-2-7 (3.5 g, 8.75 mmol) in dichloromethane (35 mL). The mixture was stirred at -50°C for 1 hour. The mixture was quenched with an aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL × 3), dehydrated with anhydrous sodium sulfate in the organic phase, filtered, and concentrated under reduced pressure to give 5.2 g of crude compound INT-2.

[0417] MS(ESI)M / Z: 532.2 [M+H] + .

[0418] Step 6: Synthesis of compound INT-2-5

[0419] Potassium carbonate (39.97 g, 289.22 mmol) and potassium iodide (36.01 g, 216.92 mmol) were added to a solution of compound INT-2-8 (30 g, 144.61 mmol), 4-methoxybenzyl chloride (29.44 g, 188.00 mmol), and acetone (400 mL). The mixture was stirred at 75 °C for 12 h. The reaction mixture was concentrated under reduced pressure and passed through a rapid silica gel column (eluting with a 0-3% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 35 g of compound INT-2-5.

[0420] 1 H NMR(400MHz CHLOROFORM-d)δppm 7.55 (d, J=2.50Hz, 1H), 7.38 (d, J=8.70Hz, 2H), 7.20 (dd, J=8.82, 2.50Hz, 1H), 6.90-6.96 (m, 2H), 6.86 (d, J=8.70Hz, 1H), 5.07 (s, 2H), 3.83 (s, 3H).

[0421] intermediate INT-3

[0422] Step A: Synthesis of compound INT-3-2

[0423] To a solution of INT-3-1 (10 g, 46.2 mmol) and 3,4-difluoronitrobenzene (8.09 g, 50.9 mmol) in dimethyl sulfoxide (200 mL), diisopropylethylamine (17.9 g, 139 mmol) was added, and the mixture was stirred in an oil bath at 145 °C for 15 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was first washed with water (100 mL × 3), then with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-20% ethyl acetate / petroleum ether gradient) to obtain 13.7 g of compound INT-3-2.

[0424] 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J=12.0Hz, 2H), 7.16 (t, J=8.9Hz, 1H), 4.74 (t, J=5.2Hz, 1H), 4.00-3.84(m, 3H), 3.51(t, J=6.1Hz, 2H), 3.37-3.33(m, 2H), 3.23-2.97(m, 2H), 1.42(s, 9H).

[0425] Step B: Synthesis of compound INT-3-3

[0426] Under ice bath conditions, sodium hydride (1.9 g, 77.1 mmol) was added in portions to a solution of INT-3-2 (13.7 g, 38.6 mmol) in 100 mL of N,N-dimethylformamide. The mixture was stirred for 1 hour under ice bath conditions, then allowed to react at room temperature for another hour. The reaction mixture was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed first with water (100 mL × 3), then with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-25% ethyl acetate / petroleum ether gradient) to give 9.6 g of compound INT-3-3.

[0427] MS(ESI)M / Z: 280.2 [M+H-56] +

[0428] Step C: Synthesis of compound INT-3

[0429] Under ice bath conditions, tetrahydroxydiboron (2.41 g, 26.9 mmol) was added in portions to a solution of INT-3-3 (3.0 g, 8.95 mmol) and 4,4'-bipyridine (14.0 mg, 89 μmol) in 20 mL of N,N-dimethylformamide. The mixture was stirred under ice bath conditions for 0.5 h. The reaction mixture was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed first with water (100 mL × 3), then with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-35% ethyl acetate / petroleum ether gradient) to give 2.5 g of compound INT-3.

[0430] MS(ESI)M / Z: 306.2 [M+H] + .

[0431] intermediate INT-4

[0432] Step A: Synthesis of compound INT-4-2

[0433] To a solution of INT-4-1 (10 g, 46.2 mmol) and 3,4-difluoronitrobenzene (8.09 g, 50.9 mmol) in dimethyl sulfoxide (200 mL), diisopropylethylamine (17.9 g, 139 mmol) was added, and the mixture was stirred in an oil bath at 145 °C for 15 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was first washed with water (100 mL × 3), then with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-20% ethyl acetate / petroleum ether gradient) to give 13 g of compound INT-4-2.

[0434] MS(ESI)M / Z: 300.1 [M+H-56] + .

[0435] Step B: Synthesis of compound INT-4-3

[0436] Under ice bath conditions, sodium hydride (1.76 g, 73.2 mmol) was added in portions to a solution of INT-4-2 (13.0 g, 36.6 mmol) in N,N-dimethylformamide (100 mL). The mixture was stirred for 1 hour under ice bath conditions, then allowed to react at room temperature for 1 hour. The reaction mixture was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed with water (100 mL × 3) and then with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-25% ethyl acetate / petroleum ether gradient) to obtain 8.5 g of compound INT-4-3.

[0437] MS(ESI)M / Z: 280.2 [M+H-56] +

[0438] Step C: Synthesis of compound INT-4

[0439] Under ice bath conditions, tetrahydroxydiboron (2.99 g, 33.4 mmol) was added in portions to a solution of INT-4-3 (2.8 g, 8.35 mmol) and 4,4'-bipyridine (13.0 mg, 84 μmol) in N,N-dimethylformamide (40 mL). The mixture was stirred under ice bath conditions for 0.5 hours. The reaction mixture was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed with water (100 mL × 3) and then with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-35% ethyl acetate / petroleum ether gradient) to give 2.1 g of compound INT-4.

[0440] MS(ESI)M / Z: 306.2 [M+H] + .

[0441] 1 H NMR (400MHz, DMSO-d6) δ6.59 (d, J=8.6Hz, 1H), 6.08 (dd, J=8.5, 2.5Hz, 1H), 6.02 (d, J=2.5Hz, 1H), 4.49 (s, 2H), 4.19 (dd , J=10.6, 2.6Hz, 1H), 3.91 (dd, J=24.2, 12.8Hz, 2H), 3.80 (dd, J=10.7, 9.0Hz, 1H), 3.58 (dt, J=11.8, 2.9Hz, 1H), 2.94 (br s, 1H), 2.72 (ddt, J=11.8, 8.9, 2.9Hz, 1H), 2.62-2.50 (m, 1H), 2.34 (td, J=11.9, 3.4Hz, 1H), 1.41 (s, 9H).

[0442] Intermediate INT-5

[0443] Step 1: Synthesis of compound INT-5-2

[0444] The toluene (40 mL) solution of compounds INT-5-1 (2.0 g, 7.07 mmol), INT-5-1a (1.4 g, 7.07 mmol), tris(dibenzylacetone)palladium (0.32 g, 0.35 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.41 g, 0.71 mmol), and sodium tert-butoxide (1.02 g, 10.6 mmol) was degassed, purged three times with nitrogen, and then stirred at 80 °C under nitrogen for 3 hours. Extraction was performed with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-20% ethyl acetate / petroleum ether gradient) to give 2.1 g of compound INT-5-2.

[0445] 1H NMR (400MHz, Chloroform-d) δ7.31 (d, J=8.4Hz, 2H), 6.47 (d, J=8.5Hz, 2H), 4.56 (d, J=55.3Hz, 1H), 4.34 (s, 1H), 3.56 (d, J=8.8Hz , 1H), 3.41 (d, J=30.1Hz, 2H), 3.14 (dd, J=37.9, 8.9Hz, 1H), 2.02 (d, J=9.6Hz, 1H), 1.93 (t, J=12.3Hz, 1H), 1.43 (d, J=17.2Hz, 9H).

[0446] Step 2: Synthesis of compound INT-5-3

[0447] Add 10 mL of trifluoroacetic acid to a solution of INT-5-2 (2.1 g, 5.94 mmol) in dichloromethane (30 mL) and continue stirring at room temperature for 3 hours. Concentrate the reaction solution, quench with saturated sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (40 mL × 3), wash the organic phase with saturated brine (10 mL), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.53 g of crude compound INT-5-3, which can be used directly in the next step.

[0448] MS(ESI)M / Z: 253.0 [M+H] + .

[0449] Step 3: Synthesis of compound INT-5-4

[0450] To a solution of INT-5-3 (1.5 g, 5.93 mmol) and isobutyraldehyde (1.28 g, 17.8 mmol) in dichloromethane (50 mL), N,N-diisopropylethylamine (2.3 g, 17.8 mmol) was added. After stirring at room temperature for 10 minutes, sodium borohydride acetate (5.03 g, 23.7 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 hours. A saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (elution buffer: 0-20% ethyl acetate / petroleum ether gradient) to obtain 1.4 g of compound INT-5-4.

[0451] MS(ESI)M / Z: 309.2 [M+H] + .

[0452] 1H NMR (400MHz, Chloroform-d) δ7.30-7.21(m, 2H), 6.45-6.38(m, 2H), 4.12(br s, 1H), 3.50(br s, 1H), 3.32 (dd, J=8.9, 2.2Hz, 1H), 3.22 (dd, J=8.9, 1.5Hz, 1H), 2.96 (dd, J=9.4, 2.1Hz, 1H), 2.51 (dd, J=9.4, 1.5Hz, 1H), 2.31-2.15 (m, 2H), 1.95 (d, J=8.6Hz, 1H), 1.84 (d, J=9.4Hz, 1H), 1.63-1.45 (m, 1H), 0.86 (dd, J=6.6, 4.6Hz, 6H).

[0453] Step 4: Synthesis of compound INT-5

[0454] At -78°C, n-butyllithium (1.46 mL, 1.75 mmol, 2.5 M) was added dropwise to a tetrahydrofuran (10 mL) solution of INT-5-4 (0.45 g, 1.46 mmol), and the mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (2 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography (eluting with a 0-25% ethyl acetate / petroleum ether gradient) to give 0.48 g of compound INT-5.

[0455] MS(ESI)M / Z: 357.2 [M+H] + .

[0456] 1 H NMR (400MHz, Chloroform-d) δ7.66 (d, J=8.5Hz, 2H), 6.53 (d, J=8.7Hz, 2H), 4.24 (s, 1H), 3.55 (s, 1H), 3.41-3.29 (m, 2H), 3.04 (d, J=12.9Hz, 1H), 2.52 (d, J=9.3Hz, 1H), 2.30-2.16 (m, 2H), 1.94-2.03 (m, 1H), 1.86 (d, J=9 .3Hz, 1H), 1.66-1.51 (m, 1H), 1.32 (s, 12H), 0.86 (dd, J=6.7, 4.4Hz, 6H).

[0457] Example A01

[0458] Step 1: Synthesis of compound A01-3

[0459] Add A01-1 (1.6 g, 9.63 mmol) and A01-2 (1.40 g, 11.56 mmol) to an ethanol solution (20 mL) of sodium ethoxide (786.50 mg, 11.56 mmol). Stir the mixture at 85 °C for 12 h (two parallel batches). After TLC monitoring showed complete reaction of the starting materials, filter the reaction mixture and concentrate the filtrate under reduced pressure to obtain a residue. Purify the residue by rapid silica gel chromatography (elution gradient of 0–15% ethyl acetate / hexane). 1.57 g of product A01-3 was obtained.

[0460] 1 H NMR (400MHz, CHLOROFORM-d) δ = 6.06-5.68 (m, 2H), 5.20-5.03 (m, 2H), 4.24 (q, J = 7.1Hz, 2H), 3.96 (t, J = 7.1Hz, 1H), 2.80-2.68 (m, 2H), 1.32-1.25 (m, 3H).

[0461] Step 2: Synthesis of compound A01-4

[0462] Sudan III (1 mg, 2.84 μmol) was added to a solution of A01-3 (1.37 g, 6.64 mmol) in dichloromethane (60 mL) and methanol (30 mL). The solution was cooled to -78 °C, and ozone was bubbled into the reaction mixture at -78 °C until the red color disappeared. After adding dimethyl sulfide (4.01 g, 64.54 mmol), the reaction mixture was heated to 20 °C and stirred at 20 °C for 2 h. After TLC monitoring showed that the starting materials had reacted completely, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–25% ethyl acetate / hexane). 1.03 g of product A01-4 was obtained.

[0463] Step 3: Synthesis of compound A01-6

[0464] Add A01-5 (1.15 g, 5.76 mmol) and p-toluenesulfonic acid (82.73 mg, 480.40 μmol) to a 12 mL solution of A01-4 (1 g, 4.80 mmol). Stir the mixture at 50 °C for 12 h. After LCMS monitoring showed complete reaction of the starting materials, concentrate the reaction mixture under reduced pressure to obtain the residue. Purify the residue by rapid silica gel chromatography (elution gradient of 0–10% ethyl acetate / hexane, flow rate 35 mL / min). 470 mg of product A01-6 was obtained.

[0465] MS(ESI) M / Z: 395.3 [M+Na]+ .

[0466] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.83-7.46 (m, 1H), 6.81 (br s, 1H), 6.61 (d, J=3.0Hz, 1H), 4.50-4.25 (m, 4H), 4.18-4.06 (m, 1H), 2.88 (dd, J=10.8, 12.5Hz, 1H), 2.79-2.65(m, 1H), 2.32-2.15(m, 1H), 1.91-1.59(m, 3H), 1.46-1.42(m, 9H), 1.35(t, J=7.0Hz, 3H).

[0467] Step 4: Synthesis of compound A01-7

[0468] A hydrochloric acid / dioxane solution (2M, 18.00 mL) of A01-6 (450 mg, 1.21 mmol) was stirred at 20 °C for 4 h. After LCMS monitoring showed that the starting material had reacted completely, the reaction solution was concentrated under reduced pressure to obtain 350 mg of product A01-7.

[0469] MS(ESI)M / Z: 273.2 [M+H] + .

[0470] 1 H NMR (400MHz, METHANOL-d4) δ = 7.93-7.52 (m, 1H), 7.21 (br s, 1H), 6.68 (d, J=3.0Hz, 1H), 4.31 (q, J=7.0Hz, 2H), 3.65-3.54 (m, 1H), 3.51-3.35 (m, 2H), 3.3 2-3.27 (m, 2H), 3.13-3.00 (m, 1H), 2.33-2.10 (m, 3H), 2.04-1.82 (m, 1H), 1.36 (t, J=7.2Hz, 3H).

[0471] Step 5: Synthesis of compound A01-9

[0472] To a solution of A01-7 (100 mg, 367.26 μmol) in acetonitrile (4 mL), diisopropylethylamine (142.39 mg, 1.10 mmol) and A01-8 (90.26 mg, 514.16 μmol) were added. The mixture was stirred at 60 °C for 2 h. After LCMS monitoring showed complete reaction of the starting materials, the reaction solution was concentrated under reduced pressure to produce a residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–25% ethyl acetate / hexane, flow rate 20 mL / min). 110 mg of product A01-9 was obtained.

[0473] MS(ESI)M / Z: 428.2 [M+H] + .

[0474] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.89-7.50 (m, 2H), 7.10 (d, J = 2.0Hz, 1H), 7.03-6.96 (m, 2H), 6.63 (d, J=3.1Hz, 1H), 4.86-4.71 (m, 1H), 4.29 (q, J=7.1Hz, 2H), 3.66-3.52 (m, 1H), 3.20 (br d, J=12.6Hz, 1H), 3.12 (dd, J=9.8, 11.5Hz, 1H), 3.02-2.89 (m, 1H), 2.27 (br dd, J=3.7, 8.1Hz, 1H), 2.02-1.80 (m, 3H), 1.35 (t, J=7.1Hz, 3H).

[0475] Step 6: Synthesis of compound A01-10

[0476] To a solution of A01-9 (110 mg, 257.11 μmol) in N,N-dimethylformamide (1 mL), tetrahydroxydiboron (92.20 mg, 1.03 mmol) and 4-(4-pyridyl)pyridine (6.02 mg, 38.57 μmol) were added. The mixture was stirred at 0–20 °C for 0.5 h. After LCMS monitoring showed that the starting material had reacted completely, the reaction mixture was diluted with water (15 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–25% ethyl acetate / hexane, flow rate 20 mL / min) to obtain 80 mg of product A01-10.

[0477] MS(ESI)M / Z: 398.1 [M+H] + .

[0478] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.95 (s, 1H), 7.55 (t, J = 53.2Hz, 1H), 6.98-6.7 4(m, 3H), 6.54(d, J=3.0Hz, 1H), 4.83-4.66(m, 1H), 4.28-4.12(m, 2H), 3.37(br dd, J=2.5, 11.6Hz, 1H), 3.16(br d, J=11.6Hz, 1H), 2.77-2.56 (m, 2H), 2.26-2.15 (m, 1H), 2.04-1.86 (m, 2H), 1.73 (dt, J=4.7, 11.8Hz, 1H), 1.30-1.22 (m, 3H).

[0479] Step 7: Synthesis of compound A01-11

[0480] At 0°C, tert-butyl nitrite (41.47 mg, 402.17 μmol) and copper bromide (31.44 mg, 140.76 μmol) were added to a solution of A01-10 (80 mg, 201.08 μmol) in acetonitrile (0.2 mL). The reaction mixture was heated to 20°C and stirred at 20°C for 1 h. After LCMS monitoring showed that the starting material had reacted completely, the reaction mixture was diluted with water (15 mL) and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–10% ethyl acetate / hexane, flow rate 18 mL / min) to obtain 47 mg of product A01-11.

[0481] MS(ESI)M / Z: 461.1 / 463.1 [M+H] + .

[0482] 1H NMR (400MHz, CHLOROFORM-d) δ = 7.66 (t, J = 52.8Hz, 1H), 7.47 (d, J = 8.5Hz, 1H), 7.00 (d, J = 2.4Hz, 2H), 6.91 (dd, J=2.4, 8.4Hz, 1H), 6.61 (d, J=3.1Hz, 1H), 4.93-4.74 (m, 1H), 4.29 (q, J=7.1Hz, 2H), 3.68-3.56 (m, 1H), 3.29 (br d, J=11.6Hz, 1H), 2.93-2.76 (m, 2H), 2.31-2.21 (m, 1H), 2.02-1.89 (m, 2H), 1.86-1.72 (m, 1H), 1.35 (t, J=7.2Hz, 3H).

[0483] Step 8: Synthesis of compound A01-13

[0484] A01-11 (47 mg, 101.79 μmol), INT-1 (45.56 mg, 132.33 μmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (8.31 mg, 10.18 μmol), and potassium carbonate (42.20 mg, 305.38 μmol) were added sequentially to dioxane (2 mL) and water (0.5 mL), and the mixture was purged with nitrogen three times. The mixture was then stirred at 100 °C under a nitrogen atmosphere for 1 h. After LCMS monitoring showed that the reactants had reacted completely, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (elution gradient of 0–15% ethyl acetate / hexane, flow rate 18 mL / min) to obtain 48 mg of product A01-13.

[0485] MS(ESI)M / Z: 599.5 [M+H] + .

[0486] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.46-7.59 (m, 3H), 7.16-6.86 (m, 6H), 6.58 (d , J=3.1Hz, 1H), 4.62-4.45(m, 1H), 4.28(q, J=7.1Hz, 2H), 3.76-3.56(m, 2H), 3.52-3.35(m, 2H), 3.31-3.04(m, 4H), 2.83-2.54(m, 4H), 2.50-2.42(m, 1H), 2.20-2.07(m, 2H), 1.94-1.77(m, 1H), 1.73-1.58(m, 3H), 1.48-1.29(m, 9H).

[0487] Step 9: Synthesis of compound A01

[0488] To a solution of A01-13 (45 mg, 75.11 μmol) in tetrahydrofuran (2 mL) and methanol (0.2 mL), an aqueous solution of lithium hydroxide hydrate (31.51 mg, 751.06 μmol) (0.2 mL) was added. The mixture was stirred at 50 °C for 12 h. After LCMS monitoring showed that the reaction was complete, the reaction mixture was diluted with water (10 mL), the pH was adjusted to 2–3, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The obtained residue was preparatively separated to yield 12.06 mg of product A01.

[0489] MS(ESI)M / Z: 571.4 [M+H] + .

[0490] 1 H NMR (400MHz, METHANOL-d4) δ = 7.73-7.40 (m, 3H), 7.22-6.96 (m, 6H), 6.53 (d, J = 2.8Hz, 1H), 4.51-4.36 (m, 1H), 3.90 (br t, J = 11.8Hz, 2H), 3.71 (br d, J=11.8Hz, 2H), 3.27-3.20 (m, 4H), 3.17-3.07 (m, 4H), 2.84 (t, J=10.5Hz, 1H), 2.74-2.6 0 (m, 1H), 2.32-2.16 (m, 1H), 2.13-2.01 (m, 1H), 1.86-1.51 (m, 3H), 1.11 (d, J=6.5Hz, 6H).

[0491] Example B01

[0492] Step 1: Synthesis of compound B01-2

[0493] Under nitrogen protection, n-butyllithium (2.5M, 1.47mL) was slowly added dropwise to an anhydrous tetrahydrofuran (15mL) solution of INT-2-5 (1g, 3.05mmol) at -78°C. After the addition was complete, the mixture was stirred at -78°C for half an hour. Then, a solution of BO1-1 (503.90mg, 3.66mmol) dissolved in anhydrous tetrahydrofuran (2mL) was added dropwise. The reaction mixture was slowly raised to room temperature and the reaction was continued for 12 hours. The reaction mixture was quenched by pouring it into an aqueous solution of ammonium chloride (20mL) under a weak nitrogen stream. The mixture was then extracted twice with ethyl acetate (40mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (elution buffer: 0–10% ethyl acetate: n-hexane) to obtain 540mg of compound BO1-2.

[0494] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.83 (d, J=2.74Hz, 1H), 7.46 (dd, J=8.82, 2.74Hz, 1H), 7.33-7.37 (m, 2H), 7.0 2(d, J=8.94Hz, 1H), 6.93-6.97(m, 2H), 5.10(s, 2H), 4.65(s, 2H), 3.85(s, 3H)

[0495] Step 2: Synthesis of compound B01-3

[0496] Add BO1-2a (33.63 mg, 369.02 μmol) to a solution of BO1-2 (0.1 g, 307.52 μmol) in anhydrous ethanol (4 mL). Stir the mixture at 80°C for 1 hour. After cooling to room temperature, concentrate under reduced pressure to obtain 120 mg of crude compound BO1-3, which was used directly in the next step.

[0497] MS(ESI)M / Z: 362.1 [M+H] + .

[0498] Step 3: Synthesis of compound B01-4

[0499] Compound B01-3a (88.42 mg, 397.96 μmol) was added to an anhydrous ethanol solution (4 mL) of compound B01-3 (0.12 g, 331.63 μmol). The mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient: 0–5% ethyl acetate: n-hexane) to obtain 26 mg of compound B01-4.

[0500] MS(ESI)M / Z: 400.0 [M+H] + .

[0501] 1 H NMR (400MHz, CHLOROFORM-d) δppm 10.44 (s, 1H), 8.14 (s, 1H), 7.69-7.97 (t, J=52.8Hz, 1H), 7.58 (d, J=2.50Hz, 1H), 7.50 (s, 1H), 7 .23 (dd, J=8.82, 2.50Hz, 1H), 7.00 (d, J=8.82Hz, 1H), 4.42 (q, J=7.11Hz, 2H), 1.41-1.45 (m, 3H)

[0502] Step 4: Synthesis of compound B01-5

[0503] At -50°C, trifluoromethanesulfonic anhydride (27.52 mg, 97.55 μmol) was added to a solution of compound B01-4 (26 mg, 65.03 μmol) and triethylamine (19.74 mg, 195.10 μmol) in dichloromethane (1 mL). The reaction mixture was stirred at -50°C for 1 hour. After returning to room temperature, the reaction mixture was diluted with dichloromethane (10 mL), then washed once with saturated sodium bicarbonate (10 mL) to separate the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 35 mg of compound B01-5, which was directly used in the next reaction step.

[0504] MS(ESI)M / Z: 532.0 [M+H] + .

[0505] Step 5: Synthesis of compound B01-6

[0506] A solution of compound B01-5 (35 mg, 65.81 μmol), INT-1 (27.19 mg, 78.97 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (4.82 mg, 6.58 μmol), anhydrous potassium phosphate (41.91 mg, 197.42 μmol), dioxane (0.5 mL), and water (0.1 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 80°C under nitrogen for 2 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 25 mg of compound B01-6.

[0507] MS(ESI)M / Z: 600.2 [M+H] + .

[0508] Step 6: Synthesis of compound B01

[0509] An aqueous solution of lithium hydroxide monohydrate (1M, 0.5mL) was added to a solution of compound B01-6 (25mg, 41.66μmol) in tetrahydrofuran (1mL) and methanol (0.5mL). The reaction solution was stirred at 20°C for 3 hours. The reaction solution was diluted with water (2mL), and the pH of the reaction solution was adjusted to 2 with 2M dilute hydrochloric acid. The solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC to obtain 9.5mg of compound B01.

[0510] MS(ESI)M / Z: 572.1 [M+H] + .

[0511] 1 H NMR (400MHz, METHANOL-d4) δppm 8.12 (s, 1H), 7.77 (d, J = 2.15Hz, 1H), 7.48 (dd, J = 8.23, 2.27Hz, 1H), 7.37 (d, J =8.34Hz, 1H), 7.34(s, 1H), 7.18(d, J=8.70Hz, 2H), 6.81-7.09(m, 3H), 3.88(br d, J=13.35Hz, 2H), 3.66(br d, J=11.92Hz, 2H), 3.12-3..26 (m, 4H), 3.07 (d, J=7.39Hz, 2H), 2.16-2.27 (m, 1H), 1.09 (d, J=6.68Hz, 6H)

[0512] Examples B04A and B04B

[0513] Step F: Synthesis of compound B04-7

[0514] Add BO4-6 (400 mg, 1.89 mmol) and ethanol (8 mL) to a 50 mL round-bottom flask, cool to 0 °C in an ice / salt bath, then add sodium borohydride (214.90 mg, 5.68 mmol) and stir at 0 °C for 1 hour. Dilute the reaction mixture with ethyl acetate (10 mL) and quench with saturated ammonium chloride aqueous solution (10 mL). Extract with ethyl acetate (10 mL × 2) and wash the combined organic phases with brine (10 mL). Dry with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give a buttery substance. Then purify the oily substance by silica gel chromatography (0-10%, methanol / dichloromethane) to give 400 mg of compound BO4-7.

[0515] 1H NMR (400MHz, CD3CN) δ4.47-4.29 (m, 1H), 4.25-4.14 (m, 1H), 3.93 (dd, J=7.2, 13.6Hz, 1H), 3.34-3.20 (m, 1H), 3.1 0(d, J=4.8Hz, 1H), 2.47-2.38(m, 1H), 2.32-2.22(m, 1H), 2.14-2.06(m, 1H), 1.91-1.83(m, 1H), 1.42-1.38(m, 9H)

[0516] Step G: Synthesis of compound B04-8

[0517] Add BO4-7 (400 mg, 1.88 mmol), ethyl 5-(difluoromethyl)-1H-pyrazole-4-carboxylate (499.28 mg, 2.63 mmol), tributyl cyanomethylene phosphate (905.32 mg, 3.75 mmol), and toluene (20 mL) to a 50 mL round-bottom flask, and stir the mixture at 100 °C for 16 hours. Concentrate the reaction mixture under vacuum until dry to give a black oil. Elute the oil by silica gel chromatography (0-25%, ethyl acetate / n-hexane) to give 150 mg of compound BO4-8.

[0518] MS(ESI)M / Z: 386.1 [M+H] + .

[0519] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.55 (t, J=52.8Hz, 1H), 5.15 (t, J=8.0Hz, 1H), 4.70-4.44 (m, 1H), 4.42-4.17 (m, 3H), 3.92 (br s, 1H), 2.69 (q, J=5.2Hz, 1H), 2.60-2.40 (m, 2H), 2.39-2.27 (m, 1H), 1.57-1.43 (m, 10H), 1.35 (t, J=7.2Hz, 3H)

[0520] Step H: Synthesis of compound B04-9

[0521] Add BO4-8 (150 mg, 389.20 μmol) and hydrogen chloride / 1,4-dioxane (3 mL) to a 10 mL round-bottom flask and stir at 25 °C for 4 hours. Concentrate the reaction solution directly to obtain 125 mg of compound BO4-9.

[0522] MS(ESI)M / Z: 286.1 [M+H] + .

[0523] 1 H NMR (400MHz, CD3CN) δ7.99 (s, 1H), 7.50 (t, J=52.0Hz, 1H), 5.42-5.32 (m, 1H), 4.27 (q, J=6.8Hz, 2H), 3.98 (q, J=4.4Hz, 1H), 3.93- 3.84 (m, 2H), 2.85-2.76 (m, 1H), 2.61-2.51 (m, 1H), 2.37-2.24 (m, 2H), 1.97-1.95 (m, 1H), 1.93-1.90 (m, 1H), 1.29 (t, J=7.2Hz, 3H)

[0524] Step I: Synthesis of compound B04-10

[0525] 4-Chloro-2-fluoro-1-nitrobenzene (81.84 mg, 466.20 μmol), BO4-9 (125 mg, 388.50 μmol), diisopropylethylamine (150.63 mg, 1.17 mmol), and acetonitrile (3 mL) were added to a dried 10 mL round-bottom flask, and the mixture was stirred at 60 °C for 4 hours. The reaction mixture was concentrated to dryness under vacuum to give a yellow oil. The oil was then purified by silica gel chromatography (0-20%, ethyl acetate / n-hexane) to give 150 mg of compound BO4-10.

[0526] MS(ESI)M / Z: 441.1 [M+H] + .

[0527] 1 H NMR (400MHz, CDCl3) δ7.90 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.53 (t, J=53.2Hz, 1H), 6.88-6. 78 (m, 2H), 5.20 (t, J=7.2Hz, 1H), 4.33 (q, J=7.2Hz, 2H), 4.08 (dd, J=8.0, 12.8Hz, 1H), 4.0 0 (q, J=5.2Hz, 1H), 3.48 (dd, J=7.6, 12.4Hz, 1H), 2.80 (q, J=5.2Hz, 1H), 2.73 (dd, J=9.2, 1 0.8Hz, 1H), 2.66-2.59 (m, 1H), 2.49-2.40 (m, 1H), 1.91-1.83 (m, 1H), 1.36 (t, J=7.2Hz, 3H)

[0528] Step J: Synthesis of compound B04-11

[0529] Add BO4-10 (150.00 mg, 340.27 μmol), a stir bar, 4,4-bipyridine (7.97 mg, 51.04 μmol), and N,N-dimethylformamide (3 mL) to a 10 mL round-bottom flask. Cool to 0 °C in an ice / salt bath, then slowly add tetrahydroxydiboron (91.52 mg, 1.02 mmol). Stir the final mixture at 25 °C for 0.5 h. Dilute the reaction mixture with water (10 mL) and ethyl acetate (10 mL), extract with ethyl acetate (5 mL × 2), and wash the combined organic phases with water (7 mL × 2) and brine (10 mL), respectively. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give a pale yellow oil. Elute the oil by silica gel chromatography (0–20%, ethyl acetate / n-hexane) to give 110 mg of compound BO4-11.

[0530] MS(ESI)M / Z: 411.1[M+H] + .

[0531] 1 H NMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.55 (t, J=53.2Hz, 1H), 7.12-7.05 (m, 1H), 6.97 (br d, J=9.2Hz, 1H), 6.76 (br d, J=8.4Hz, 1H), 5.33 (br t, J=7.6Hz, 1H), 4.33 (q, J=6.8Hz, 2H), 4.03-3.83 (m, 3H), 2.87-2.73 (m, 2H), 2.55-2.45(m, 1H), 2.44-2.35(m, 1H), 2.10-2.05(m, 1H), 1.37(t, J=7.2Hz, 3H)

[0532] Step K: Synthesis of compound B04-12

[0533] Add BO4-11 (80.00 mg, 194.72 μmol), p-toluenesulfonic acid monohydrate (148.16 mg, 778.88 μmol), and acetonitrile (1.6 mL) to a 10 mL round-bottom flask. Cool to 0 °C in an ice / salt bath. Then, add dropwise a mixed solution of potassium iodide (129.29 mg, 778.88 μmol), sodium nitrite (53.74 mg, 778.88 μmol), and water (0.8 mL). Stir the final mixture at 25 °C for 2 hours. Dilute the reaction mixture with water (10 mL) and ethyl acetate (10 mL), extract with ethyl acetate (5 mL x 2), and wash the combined organic phases with water (7 mL x 2) and brine (10 mL), respectively. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give a pale yellow oil. The oily substance was then eluted by silica gel chromatography (0-10%, ethyl acetate / n-hexane) to give 90 mg of compound B04-12.

[0534] MS(ESI)M / Z: 522.1[M+H] + .

[0535] 1 H NMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.76-7.41 (m, 2H), 6.94 (d, J=2.4Hz, 1H), 6.73 (dd, J=2.4, 8.4Hz, 1H), 5.22 (t, J=8.0Hz, 1H), 4.33 (q, J=7.2Hz, 2H), 4.10-3.96 (m, 2H), 3.75 (dd, J=7.2, 11.6Hz, 1H), 2.83-2.70 (m, 2H), 2.58-2 .49 (m, 1H), 2.41-2.32 (m, 1H), 1.87 (t, J = 9.6Hz, 1H), 1.37 (t, J = 7.2Hz, 3H)

[0536] Step L: Synthesis of compound B04-14

[0537] Add BO4-12 (80 mg, 153.34 μmol), INT-1 (105.59 mg, 306.67 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (11.22 mg, 15.33 μmol), potassium carbonate (42.39 mg, 306.67 μmol), water (800 μL), and 1,4-dioxane (1.6 mL) to a dried, nitrogen-filled 10 mL sealed vial. Stir at 100 °C for 2 hours. Then dilute the reaction mixture with water (10 mL) and ethyl acetate (10 mL), extract with ethyl acetate (5 mL × 2), and wash the combined organic phases with water (7 mL × 2) and brine (10 mL), respectively. Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give a pale yellow oil. The oily substance was then eluted by silica gel chromatography (0-30%, ethyl acetate / n-hexane) to obtain 80 mg of compound B04-14 after purification.

[0538] MS(ESI)M / Z: 612.2 [M+H] + .

[0539] Step M: Synthesis of compounds B04-A and B04-B

[0540] Add BO4-14 (70 mg, 114.35 μmol), tetrahydrofuran (2.8 mL), and ethanol (280 μL) to a 10 mL round-bottom flask. Then add a mixture of water (280 μL) and lithium hydroxide monohydrate (47.99 mg, 1.14 mmol) to the reaction mixture. Stir the final mixture at 50 °C for 2 hours. Dilute the reaction mixture with water (4 mL) and ethyl acetate (4 mL), then adjust the pH of the aqueous phase to <3. Extract with ethyl acetate (3 mL × 3), wash the combined organic phases with brine (3 mL), dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under vacuum to give a white solid. The solid was separated by SFC (column: 101-DAICEL CHIRALPAKIM 250×30 mm, 10 μm; mobile phase: [carbon dioxide-methanol (0.1% ammonia)]; B%: 45%, isocratic elution mode) to obtain P1 (retention time: 1.680 min) and P2 (retention time: 1.849 min). P1 was then subjected to HPLC (column: 20-Welch Xtimate C18 250×50 mm, 5 μm; mobile phase: [water (0.05% hydrogen chloride aqueous solution)-acetonitrile]; gradient: 48%-78% B, 7.0 min) to obtain 11.3 mg of compound B04A. P2 was subjected to HPLC chromatography (column: 20-Welch Xtimate C18 250×50mm, 5μm; mobile phase: [water (0.05% aqueous hydrogen chloride solution)-acetonitrile]; gradient: 45%-75% B, 7.0 min) to obtain 13.9 mg of compound B04B.

[0541] B04A:

[0542] MS(ESI)M / Z: 584.3 [M+H] + .

[0543] 1 H NMR (400MHz, CD3OD) δ7.81 (s, 1H), 7.68-7.36 (m, 3H), 7.24-7.03 (m, 5H), 5.12 (brt, J=5.6Hz, 1H), 4.17-4.01 (m, 1H), 3.99-3.82 (m, 2H), 3.79-3.57 (m, 4H), 3 .29-3.18(m, 4H), 3.10(d, J=7.2Hz, 2H), 2.76-2.67(m, 1H), 2.55-2.42(m, 2H), 2.41-2.32(m, 1H), 2.30-2.18(m, 1H), 1.97-1.80(m, 1H), 1.10(d, J=6.8Hz, 6H)

[0544] B04B:

[0545] MS(ESI)M / Z: 584.3 [M+H] + .

[0546] 1 H NMR (400MHz, CD3OD) δ7.82 (s, 1H), 7.67-7.37 (m, 3H), 7.24-7.03 (m, 5H), 5.11 (t, J=5.2Hz, 1H), 4.13-4.03 (m, 1H), 3.96-3.83 (m, 2H), 3.79-3.57 (m, 4H), 3. 29-3.19(m, 4H), 3.10(d, J=7.2Hz, 2H), 2.74-2.68(m, 1H), 2.55-2.44(m, 2H), 2.41-2.32(m, 1H), 2.29-2.19(m, 1H), 1.93-1.79(m, 1H), 1.10(d, J=6.8Hz, 6H)

[0547] Example B06

[0548] Step 1: Synthesis of compound B06-2

[0549] Compound B06-1 (3.2 g, 22.83 mmol) was dissolved in 1,4-dioxane (40 mL), followed by B06-1a (5.98 g, 22.83 mmol), potassium carbonate (9.47 g, 68.49 mmol), cuprous iodide (0.43 g, 2.28 mmol), and N,N′-dimethylethylenediamine (0.30 g, 3.42 mmol). The mixture was purged three times with nitrogen. The reaction solution was reacted at 100 °C for 8 hours under nitrogen protection. After the reaction was complete, the reaction solution was extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by column chromatography (petroleum ether / ethyl acetate = 0–1 / 3) yielded B06-2 (6.6 g).

[0550] MS(ESI)M / Z: 322.2[M+H] + .

[0551] 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 7.99 (s, 1H), 6.40 (td, J=4.3, 2.1Hz, 1H), 4.36 (q, J=2.3Hz, 2H), 4.2 4 (q, J=7.1Hz, 2H), 3.46 (t, J=5.7Hz, 2H), 2.25 (dq, J=8.1, 2.9Hz, 2H), 1.42 (s, 9H), 1.27 (t, J=7.1Hz, 3H).

[0552] Step 2: Synthesis of compound B06-3

[0553] Tetrahydrofuran (60 mL) was added to a three-necked flask, and then the flask was completely purged with nitrogen. Diisopropylaminolithium (30.34 mL, 60.69 mmol, 2 mol / L) was added, and the mixture was cooled to -78 °C in a dry ice-ethanol bath. Then, BO6-2 (6.5 g, 20.23 mmol) dissolved in tetrahydrofuran (30 mL) was slowly added dropwise to the reaction mixture. The reaction was continued at -78 °C for 1 hour. Then, N,N-dimethylformamide (7.02 mL, 91.03 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and the reaction was continued for 1 hour. After the reaction was complete, a saturated ammonium chloride aqueous solution was slowly added dropwise to the reaction mixture in an ice bath to adjust the pH to 7. The mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness. The product was purified by column chromatography (petroleum ether / ethyl acetate = 0–1 / 5) to obtain B06-3 (1.8 g).

[0554] MS(ESI)M / Z: 350.2 [M+H] + .

[0555] 1 H NMR (400MHz, DMSO-d6) δ10.27 (s, 1H), 8.08 (s, 1H), 7.08-7.00 (m, 1H), 4.31 (q, J=7.1Hz, 2H), 3.55 ( t, J=5.5Hz, 2H), 2.32 (td, J=6.2, 1.5Hz, 2H), 1.97-1.89 (m, 2H), 1.42 (s, 9H), 1.31 (t, J=7.1Hz, 3H).

[0556] Step 3: Synthesis of compound B06-4

[0557] B06-3 (1.8 g, 5.15 mmol) was dissolved in dichloromethane (20 mL), completely purged with nitrogen, and cooled to -78 °C in a dry ice-ethanol bath. Then, bis(2-methoxyethyl)aminosulfur trifluoride (5.7 g, 25.75 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was extracted with dichloromethane (150 mL × 3) and saturated sodium bicarbonate (100 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. B06-4 (1.6 g) was purified by column chromatography (petroleum ether / ethyl acetate = 0–1 / 3).

[0558] MS(ESI)M / Z: 372.2 [M+H] + .

[0559] 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 1H), 7.44 (t, J = 52.1Hz, 1H), 7.10 (s, 1H), 4.27 (q, J = 7.1Hz, 2H), 3.60-3.52 (m, 2H), 2.41 (t, J=6.2Hz, 2H), 1.97-1.89 (m, 2H), 1.43 (s, 9H), 1.29 (t, J=7.1Hz, 3H).

[0560] Step 4: Synthesis of compound B06-5

[0561] BO6-4 (1.2 g, 3.23 mmol) was dissolved in dichloromethane (20 mL), then trifluoroacetic acid (2 mL) was added, and the mixture was completely purged with nitrogen. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was extracted with dichloromethane (150 mL × 3) and saturated sodium bicarbonate (50 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain BO6-5 (890 mg).

[0562] MS(ESI)M / Z: 272.2 [M+H] + .

[0563] Step 5: Synthesis of compound B06-6

[0564] B06-5 (890 mg, 3.28 mmol) and 1-bromo-4-chloro-2-iodobenzene (1.04 g, 3.28 mmol) were dissolved in 1,4-dioxane (15 mL), followed by the addition of cesium carbonate (3.21 g, 9.84 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.38 g, 0.66 mmol), and tris(dibenzylideneacetone)dipalladium (0.3 g, 0.33 mmol). The mixture was thoroughly purged with nitrogen, and stirred at 100 °C for 8 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 5) to give B06-6 (150 mg).

[0565] MS(ESI)M / Z: 460.0 [M+H] + .

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 7.46 (t, J=52.2Hz, 1H), 7.23 (d, J=2.5Hz, 1H), 7.19 (dd, J=8.5, 2.5 Hz, 1H), 6.67 (s, 1H), 4.27 (q, J=7.1Hz, 2H), 3.55-3.44 (m, 2H), 2.49-2.42 (m, 2H), 2.02 (p, J=6.2Hz, 2H), 1.29 (t, J=7.1Hz, 3H).

[0567] Step 6: Synthesis of compound B06-7

[0568] B06-6 (150 mg, 0.33 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of INT-1 (110 mg, 0.33 mmol), sodium carbonate (100 mg, 0.99 mmol), and tetrakis(triphenylphosphine)palladium (57 mg, 0.05 mmol). The mixture was purged with nitrogen, and stirred at 90 °C for 4 hours. LC-MS showed complete conversion of the starting material, with the target product detected by MS. The reaction mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was washed with saturated brine (70 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 5) yielded B06-7 (120 mg).

[0569] MS(ESI)M / Z: 598.3 [M+H] + .

[0570] 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.45-7.17 (m, 5H), 7.12 (d, J=2.1Hz, 1H), 7. 00 (d, J=8.9Hz, 2H), 6.66 (s, 1H), 4.27 (q, J=7.1Hz, 2H), 3.18 (t, J=5.0Hz, 4H), 3.0 1 (dd, J=7.1, 3.8Hz, 2H), 2.47 (d, J=5.8Hz, 4H), 2.37-2.32 (m, 2H), 2.09 (d, J=7.4H z, 2H), 1.80 (dt, J=20.2, 6.6Hz, 3H), 1.29 (t, J=7.1Hz, 3H), 0.88 (d, J=6.5Hz, 6H).

[0571] Step 7: Synthesis of compound B06

[0572] B06-7 (120 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL) and water (0.5 mL), and then lithium hydroxide (43 mg, 1.80 mmol) was added. The mixture was purged with nitrogen and stirred at room temperature for 16 hours.

[0573] LC-MS showed complete conversion of the starting material, with the target product detected by MS. The reaction solution was adjusted to pH 2-3 using 4M hydrochloric acid, stirred at room temperature for 30 minutes, and extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Pre-HPLC purification yielded B06 (68 mg).

[0574] MS(ESI)M / Z: 570.3 [M+H] + .

[0575] 1H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 7.99 (s, 1H), 7.41 (t, J = 52.4Hz, 1H), 7.36 (d, J = 8.8Hz, 2H), 7.28 (d, J=8.3Hz, 1H), 7.23 (dd, J=8.3, 2.0Hz, 1H), 7.12 (d, J=2.1Hz, 1H), 7.08 (d, J=8.9Hz, 2H), 3. 83 (d, J=13.0Hz, 2H), 3.56 (d, J=12.0Hz, 2H), 3.47-3.31 (m, 2H), 3.20-3.05 (m, 2H), 3.03-2.92 (m, 4H), 2.34 (t, J=6.3Hz, 2H), 2.15 (hept, J=6.7Hz, 1H), 1.75 (p, J=5.3Hz, 2H), 1.02 (d, J=6.6Hz, 6H).

[0576] Example B15

[0577] Step 1: Synthesis of compound B15-2

[0578] Sodium borohydride (5.11 g, 142.58 mmol) was added in portions to a methanol solution (200 mL) of B15-1 (6 g, 63.09 mmol) and sodium bicarbonate (3.92 g, 46.69 mmol) at -78 °C, and the mixture was stirred for 20 min. Then, benzyl chloroformate (16.14 g, 94.64 mmol) was added dropwise, and the mixture was stirred at the same temperature for 2 h after the addition was complete. After the reaction was complete, the reaction mixture was quenched with 1 N NaOH aqueous solution (100 mL), and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (eluting buffer: 0–40% ethyl acetate / petroleum ether, flow rate: 80 mL / min) to give 3.8 g of product B15-2.

[0579] 1H NMR (400MHz, DMSO-d6) δ7.60-7.14 (m, 5H), 6.72 (t, J=8.4Hz, 1H), 5.14 (s, 2H), 5.03 (d, J=4.1Hz, 1H), 4.83 (ddt, J=34.8, 8.1, 3.8Hz, 1 H), 3.95-3.79 (m, 1H), 3.66 (ddd, J=14.9, 12.0, 3.4Hz, 1H), 3.23 (ddd, J=16.2, 12.1, 7.5Hz, 1H), 2.26-2.19 (m, 1H), 1.96-1.76 (m, 1H).

[0580] Step 2: Synthesis of compound B15-3

[0581] At -78°C under nitrogen atmosphere, diethylzinc (18 mL, 18 mmol, 1 M in hexane) was added dropwise to a 1,2-dichloroethane solution (50 mL) of B15-2 (2.8 g, 12 mmol) and stirred for 10 min. Then, chloroiodoform (3.17 g, 18 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution (30 mL), followed by extraction with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to produce a residue. The crude product was purified by rapid silica gel chromatography (elution gradient of 0–30% ethyl acetate / petroleum ether, flow rate 60 mL / min) to give 2.13 g of compound B15-3.

[0582] 1 H NMR (400MHz, DMSO-d6) δ7.50-7.23 (m, 5H), 5.25-5.05 (m, 2H), 4.70 (dd, J=19.2, 3.5Hz, 1H), 3.85-3.77 (m, 1H), 3.48 (ddd, J=38.7, 12.7, 5.2Hz, 1H), 3.08-2.70 (m, 2H), 2.03-1.85 (m, 1H), 1.67-1.58 (m, 1H), 1.12-0.97 (m, 1H), 0.79-0.51 (m, 2H).

[0583] Step 3: Synthesis of compound B15-5

[0584] To a toluene solution (40 mL) of INT-2-1 (1 g, 5.25 mmol), 2-(tributylphosphine)acetonitrile (2.54 g, 10.52 mmol) and B15-3 (1.95 g, 7.89 mmol) were added. The mixture was stirred at 120 °C for 8 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (80 g silica gel column, eluent gradient of 0–10% ethyl acetate / petroleum ether, flow rate 80 mL / min) to obtain 800 mg of product B15-5.

[0585] 1 H NMR (400MHz, DMSO-d6) δ8.06 (d, J=7.9Hz, 1H), 7.58 (td, J=52.0, 2.2Hz, 1H), 7.44-7.24 (m, 5 H), 5.13 (d, J=30.2Hz, 2H), 4.44-4.35 (m, 1H), 4.30-4.24 (m, 2H), 4.02-3.85 (m, 1H), 3.26-3 .11 (m, 1H), 3.01-2.86 (m, 1H), 2.44 (ddd, J=13.1, 11.0, 6.4Hz, 1H), 2.28 (dd, J=13.3, 5.2Hz , 1H), 1.51-1.41 (m, 1H), 1.29 (td, J=7.2, 3.0Hz, 3H), 0.95-0.90 (m, 1H), 0.50-0.34 (m, 1H).

[0586] Step 4: Synthesis of compound B15-6

[0587] Under nitrogen atmosphere, palladium / carbon (200 mg) was added to a 20 mL ethanol solution of B15-5 (800 mg, 1.91 mmol). The mixture was then purged with hydrogen and stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 530 mg of product B15-6.

[0588] MS(ESI)M / Z: 286.2 [M+H] + .

[0589] 1H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 7.57 (t, J=52.2Hz, 1H), 4.51-4.08 (m, 3H), 2.83-2.77 (m, 1H), 2.68-2.64 (m, 1H), 2.46-2.30 (m, 2H), 2.29-2.20 (m, 1H), 1.28 (t, J=7.1Hz, 3H), 1.18-1.07 (m, 1H), 1.14-1.10 (m, 1H), 0.72-0.67 (m, 1H).

[0590] Step 5: Synthesis of compound B15-8

[0591] N,N-diisopropylethylamine was added to a solution of B15-6 (500 mg, 1.75 mmol) and B15-7 (368.63 mg, 2.1 mmol) in dimethyl sulfoxide (20 mL), and the mixture was stirred at 80 °C for 8 h. After the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was purified by rapid silica gel chromatography (elution gradient of 0–10% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain 710 mg of product B15-8.

[0592] MS(ESI)M / Z: 441.2 [M+H] + .

[0593] Step 6: Synthesis of compound B15-9

[0594] At 0 °C and under nitrogen atmosphere, a solution of B15-8 (710 mg, 1.61 mmol) in N,N-dimethylformamide (10 mL) was mixed with 4,4′-bipyridine (12.57 mg, 81 μmol) and tetrahydroxydiboron (577.35 mg, 6.44 mmol), and the mixture was stirred for 0.5 h. After the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and then water (50 mL) was added. The solution was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography (elution gradient of 0–10% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain 500 mg of product B15-9.

[0595] 1H NMR (400MHz, DMSO-d6) δ8.08 (s, 1H), 7.61 (t, J=52.1Hz, 1H), 6.94 (d, J=2.4Hz, 1H), 6.80 (dd, J=8.4, 2.4Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 4.88 (s, 2H), 4.77-4.70 (m, 1H), 4.28 (q, J=7.1Hz, 2H ), 3.31-3.21 (m, 1H), 3.11 (dd, J=11.5, 3.8Hz, 1H), 2.62-2.57 (m, 1H), 2.49-2.41 (m, 1H), 2.34 -2.24(m, 1H), 1.49-1.40(m, 1H), 1.29(t, J=7.1Hz, 3H), 0.81-0.76(m, 1H), 0.51-0.48(m, 1H).

[0596] Step 7: Synthesis of compound B15-10

[0597] To a solution of B15-9 (250 mg, 0.61 mmol), p-toluenesulfonic acid (126 mg, 0.73 mmol), tetrabutylammonium bromide (393 mg, 1.22 mmol) in acetonitrile (10 mL), tert-butyl nitrite (75.5 mg, 0.73 mmol) and cuprous bromide (8.75 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 5 h. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (elution gradient of 0–5% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain 53 mg of product B15-10.

[0598] 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 7.81-7.45 (m, 2H), 7.23 (d, J=2.5Hz, 1H), 6.95 (dd, J=8.5, 2.4Hz, 1H), 4.78-4.71 (m, 1H), 4.28 (q, J=7.1Hz, 2H), 3.75-3.40 (m, 2H), 3.07-3.03 (m, 1H), 2.48-2.41 (m, 1H), 2.21 (ddd, J=13.5, 5.9, 2.3Hz, 1H), 1.68-1.48 (m, 1H), 1.29 (t, J=7.1Hz, 4H), 0.89-0.81 (m, 1H), 0.36 (ddd, J=6.7, 5.4, 3.5Hz, 1H).

[0599] Step 8: Synthesis of compound B15-12

[0600] To a solution of B15-10 (40 mg, 84 μmol) in 1,4-dioxane (1.5 mL) and water (0.4 mL), INT-1 (34.71 mg, 100 μmol), potassium carbonate (29.02 mg, 210 μmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (6.86 mg, 8.4 μmol) were added, followed by nitrogen purging three times. The mixture was stirred at 100 °C for 3 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (12 g silica gel column, eluent gradient of 0–15% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain 30 mg of product B15-12.

[0601] MS(ESI)M / Z: 612.2 [M+H] +

[0602] Step 9: Synthesis of compound B15

[0603] Lithium hydroxide hydrate (20.56 mg, 0.49 mmol) was added to a solution of B15-12 (30 mg, 49 μmol) in tetrahydrofuran (2 mL), water (0.2 mL), and methanol (0.2 mL). The mixture was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water (5 mL), the pH was adjusted to 2–3 with hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to yield 1.32 mg of compound B15.

[0604] MS(ESI)M / Z: 584.86 [M+H] + .

[0605] 1H NMR (400MHz, DMSO-d6) δ7.98 (s, 1H), 7.53 (t, J = 52.3Hz, 1H), 7.28 (d, J = 8.5Hz, 2H), 7.19 (d, J = 2.1Hz, 1H) , 7.10 (d, J=8.1Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 6.98 (dd, J=8.1, 2.0Hz, 1H), 4.46-4.39 (m, 1H), 3.85-3.79 ( m, 2H), 3.28 (dd, J=12.8, 4.5Hz, 1H), 3.22-2.98 (m, 8H), 2.46-2.42 (m, 1H), 2.40-2.28 (m, 1H), 2.19-2.10 ( m, 1H), 2.09-1.89 (m, 2H), 1.44-1.38 (m, 1H), 1.01 (d, J=6.6Hz, 6H), 0.61-0.56 (m, 1H), 0.28-0.11 (m, 1H).

[0606] Examples C04A and C04B

[0607] Step A: Synthesis of compound C04-2

[0608] Potassium carbonate (150 mg, 1.09 mmol) and CO4-1A (100 mg, 365.93 μmol) were added to a 2 mL solution of CO4-1 (80 mg, 413.36 μmol) in N,N-dimethylformamide. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 1), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0-7% ethyl acetate / hexane, @25 mL / min) to give 140 mg of compound CO4-2.

[0609] MS(ESI)M / Z: 447.1 [M+H] + .

[0610] 1H NMR (400MHz, CHLOROFORM-d) δppm 7.92(s, 1H), 7.56(t, J=52.8Hz, 1H), 6.98-6.87(m, 2H), 4.79-4.70(m, 1 H), 4.34(q, J=7.2Hz, 2H), 3.51-3.45(m, 1H), 3.41-3.34(m, 1H), 3.30(br d, J=11.6Hz, 1H), 2.91-2.83 (m, 1H), 2.23-2.10 (m, 2H), 1.97-1.79 (m, 2H), 1.38 (t, J=7.2Hz, 3H).

[0611] Step B: Synthesis of compound C04-3

[0612] Tetrahydroxydiboron (85 mg, 948.12 μmol) was added to a solution of CO4-2 (140 mg, 313.33 μmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at 0 °C for 5 min. 4,4-Bipyridine (8 mg, 51.22 μmol) was added in two portions at 0 °C. The mixture was slowly heated to 20 °C and stirred for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 1), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-7% ethyl acetate / hexane, @25 mL / min) to obtain 100 mg of compound CO4-3.

[0613] MS(ESI)M / Z: 417.2 [M+H] + .

[0614] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.92 (s, 1H), 7.58 (t, J = 52.8Hz, 1H), 6.84 (dd, J = 2.0, 10.4Hz, 1H), 6.78 (t, J = 2.0Hz, 1H), 4.92-4.74(m, 1H), 4.34(q, J=7.2Hz, 2H), 3.38(dd, J=3.6, 10.8Hz, 1H), 3.25(br d, J=11.2Hz, 1H), 3.17 (t, J=10.6Hz, 1H), 2.66 (dt, J=2.8, 11.8Hz, 1H), 2.20 (dt , J=4.0, 9.2Hz, 2H), 2.05-1.98 (m, 1H), 1.97-1.86 (m, 1H), 1.38 (t, J=7.2Hz, 3H).

[0615] Step C: Synthesis of compound CO4-4

[0616] To a 2 mL acetonitrile solution of CO4-3 (100 mg, 239.91 μmol), tert-butyl nitrite (52.02 mg, 504.46 μmol) and copper bromide (100 mg, 447.72 μmol) were added, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was diluted with 5 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-7% ethyl acetate / hexane, @25 mL / min) to give 80 mg of compound CO4-4.

[0617] MS(ESI)M / Z: 480.0 / 482.0 [M+H] + .

[0618] 1 H NMR (400MHz, CHLOROFORM-d) δppm7.92 (s, 1H), 7.58 (t, J=52.8Hz, 1H), 6.88 (dd, J=2.4, 8.0Hz, 1 H), 6.83 (t, J=2..0Hz, 1H), 4.94-4.85 (m, 1H), 4.34 (q, J=7.2Hz, 2H), 3.60-3.52 (m, 1H), 3.40 (br d, J=12.4Hz, 1H), 3.22 (t, J=10.8Hz, 1H), 2.79-2.69 (m, 1H), 2.25-2.10 (m, 2H), 2.02-1.93 (m, 2H), 1.38 (t, J=7.2Hz, 3H).

[0619] Step D: Synthesis of compound C04-5

[0620] To a mixed solution of CO4-4 (70 mg, 145.62 μmol) in dioxane (0.8 mL) and water (0.2 mL), INT-1 (60 mg, 174.27 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 15.03 μmol), and cesium carbonate (105 mg, 322.26 μmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-20% ethyl acetate / hexane, @25 mL / min) to give 70 mg of compound CO4-5.

[0621] MS(ESI)M / Z: 618.2 [M+H] + .

[0622] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.88 (s, 1H), 7.62 (t, J=52.8Hz, 1H), 7.35 (d, J=7.2Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 6.84 (dd, J=2.0, 9.2Hz, 1H), 6.79 (s, 1H), 4.57-4.45 (m, 1H), 4.33 (q, J=7.2Hz, 2H), 3.35 (br dd, J=3.2, 10.4Hz, 1H), 3.27 (br s, 4H), 3.15 (t, J=10.8Hz, 1H), 3.08 (br d, J=12.0Hz, 1H), 2.59 (br d, J=1.6Hz, 4H), 2.51-2.43(m, 1H), 2.17(br d, J=4.4Hz, 2H), 2.05-1.92 (m, 2H), 1.91-1.79 (m, 1H), 1.67-1.60 (m, 1H), 1.49-1.41 (m, 1H), 1.37 (t, J=7.2Hz, 3H), 0.95 (br d, J=6.4Hz, 6H).

[0623] Step E: Synthesis of compounds CO4A and CO4B

[0624] Lithium hydroxide monohydrate (1M, 1mL) was added to a mixed solution of CO4-5 (60.00 mg, 97.07 μmol) in tetrahydrofuran (1 mL) and methanol (0.1 mL), and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The mixture was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 35%, isocratic elution mode). The fraction was concentrated under reduced pressure, stirred with 2M hydrochloric acid / dioxane (3 mL) at 20 °C for 1 hour, concentrated under reduced pressure, and lyophilized. 23.2 mg of compound CO4A (retention time: 1.289 min) and 20.9 mg of compound CO4B (retention time: 1.570 min) were obtained.

[0625] C04A:

[0626] MS(ESI)M / Z: 590.3 [M+H] + .

[0627] 1H NMR (400MHz, METHANOL-d4) δppm 7.86 (s, 1H), 7.64-7.33 (m, 3H), 7.10 (d, J=8.8Hz, 2H), 6.96-6.90 (m, 2H), 4.45-4.31 (m, 1H), 3.91 (br d, J=5.2Hz, 2H), 3.75-3.66(m, 2H), 3.29-3.15(m, 5H), 3.14-3.02(m, 4H), 2.72-2.61(m, 1H), 2. 30-2.18 (m, 1H), 2.03-1.87 (m, 2H), 1.82-1.72 (m, 1H), 1.64-1.46 (m, 1H), 1.11 (d, J=6.4Hz, 6H).

[0628] C04B:

[0629] MS(ESI)M / Z: 590.3 [M+H] + .

[0630] 1 H NMR (400MHz, METHANOL-d4) δppm 7.86 (s, 1H), 7.63-7.34 (m, 3H), 7.10 (d, J=8.8Hz, 2H), 6.97-6.89 (m, 2H), 4.48-4.30 (m, 1H), 3.99-3.85 (m, 2H), 3.71 (br d, J=11.2Hz, 2H), 3.29-3.15(m, 5H), 3.15-3.02(m, 4H), 2.67(br t, J=10.8Hz, 1H), 2.32-2.17(m, 1H), 2.04-1.89(m, 2H), 1.78(br d, J=13.2Hz, 1H), 1.60-1.46 (m, 1H), 1.11 (d, J=6.4Hz, 6H).

[0631] Example C11

[0632] Step A: Synthesis of compound C11-2

[0633] 1-Chloro-2,5-difluoro-4-nitrobenzene (155.80 mg, 805.04 μmol), INT-2-4 (200 mg, 731.85 μmol), diisopropylethylamine (189.17 mg, 1.46 mmol), and acetonitrile (4 mL) were added to a dried 10 mL round-bottom flask. The mixture was stirred at 60 °C for 4 hours. After the reaction was monitored by LCMS until complete, the reaction solution was concentrated to obtain a yellow oil. The oil was then purified by silica gel column chromatography (0-20%, ethyl acetate / hexane) to give 300 mg of compound C11-2.

[0634] MS(ESI)M / Z: 447.0 [M+H] + .

[0635] 1 H NMR (400MHz, CDCl3) δ=7.91 (s, 1H), 7.74-7.41 (m, 2H), 7.24 (d, J=6.4Hz, 1H), 4.90-4.78 (m, 1H), 4.33 (q, J=7.2Hz, 2H), 3 .46-3.33 (m, 2H), 3.22 (d, J=12.0Hz, 1H), 2.91-2.82 (m, 1H), 2.27-2.07 (m, 2H), 1.99-1.88 (m, 2H), 1.36 (t, J=7.2Hz, 3H)

[0636] Step B: Synthesis of compound C11-3

[0637] C11-2 (300 mg, 671.43 μmol), 4-(4-pyridyl)pyridine (15.73 mg, 100.71 μmol), and N,N-dimethylformamide (3 mL) were added to a 10 mL round-bottom flask. The mixture was cooled to 0 °C in an ice / salt bath, and then tetrahydroxydiboron (180.58 mg, 2.01 mmol) was slowly added. The final mixture was stirred at 25 °C for 0.5 h. After the reaction was monitored by LCMS until complete, the reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL), extracted with ethyl acetate (5 mL × 2), and washed with water (7 mL × 2) and brine (10 mL), respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under vacuum to give a pale yellow oil. The oil was then purified by silica gel column chromatography (0–20% ethyl acetate / hexane) to give 115 mg of compound C11-3.

[0638] MS(ESI)M / Z: 417.2 [M+H] +

[0639] 1H NMR (400MHz, CDCl3) δ=7.91 (s, 1H), 7.56 (t, J=52.8Hz, 1H), 6.97 (d, J=7.6Hz, 1H), 6.49 (d, J=10.4Hz, 1H), 4.82-4.72 (m, 1H), 4.32 (q, J=7.2Hz, 2H), 4.17 (br s, 2H), 3.28-3.21 (m, 1H), 3.17-3.05 (m, 2H), 2.69-2.57 (m, 1H), 2.22-2 .12(m, 2H), 2.06-1.96(m, 1H), 1.91-1.78(m, 1H), 1.36(t, J=7.2Hz, 3H).

[0640] Step C: Synthesis of compound C11-4

[0641] Copper bromide (36.97 mg, 165.54 μmol) was added to a mixture of C11-3 (115 mg, 275.90 μmol), tert-butyl nitrite (56.90 mg, 551.79 μmol), and acetonitrile (3 mL). The mixture was then degassed, purged three times with nitrogen, and stirred at 25 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and then water (10 mL) was added. Extraction was performed with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-10% ethyl acetate / hexane, @35 mL / min) to obtain 400 mg of compound C11-4.

[0642] MS(ESI)M / Z: 482.1 [M+H] + .

[0643] Step D: Synthesis of compound C11-6

[0644] Potassium carbonate (28.75 mg, 208.03 μmol), INT-1 (46.56 mg, 135.22 μmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (7.61 mg, 10.40 μmol) were added to a solution of C11-4 (50 mg, 104.01 μmol) in 1 mL of dioxane and 0.2 mL of water for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and then water (10 mL) was added. The solution was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-50% ethyl acetate / hexane, @35 mL / min) to obtain 48 mg of compound C11-6.

[0645] MS(ESI)M / Z: 618.3 [M+H] + .

[0646] Step E: Synthesis of compound C11

[0647] Lithium hydroxide monohydrate (32.59 mg, 776.53 μmol) was added to a mixture of C11-6 (48 mg, 77.65 μmol), tetrahydrofuran (1 mL), methanol (0.2 mL), and water (0.2 mL). The mixture was then stirred at room temperature for 12 hours. The pH of the reaction solution was adjusted to acidic with 1 M hydrochloric acid, and then 21.9 mg of C11 was obtained by preparative HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [water (0.05% hydrochloric acid)-ACN]; gradient: 38%-68% B, 7.0 min).

[0648] MS(ESI)M / Z: 590.3 [M+H] + .

[0649] 1H NMR (400MHz, DMSO-d6) δ 10.08 (br s, 1H), 7.96 (s, 1H), 7.69-7.38 (m, 3H), 7.28-7.19 (m, 2H), 7.06 (br d, J=7.2Hz, 2H), 4.55-4.40 (m, 1H), 3.86 (br t, J=14.0Hz, 2H), 3.60(br s, 2H), 3.28(br t, J=12.0Hz, 2H), 3.16(br s, 2H), 3.07-2.95 (m, 4H), 2.63-2.56 (m, 2H), 2.21-2.12 (m, 1H), 2.04-1.85 (m, 2H), 1.76 (br d, J=12.0Hz, 1H), 1.58-1.45 (m, 1H), 1.10-0.97 (m, 6H).

[0650] Example D01

[0651] Step 1: Synthesis of compound D01-2

[0652] To a mixture of D01-1 (20 g, 66.47 mmol), D01-1a (14.18 g, 99.70 mmol) and N'N-dimethylformamide (200 mL), cesium carbonate (43.31 g, 132.94 mmol), R-naphthol (7.61 g, 26.59 mmol), and cuprous iodide (2.53 g, 13.29 mmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 16 hours. The reaction solution was filtered, concentrated under reduced pressure, and then water (200 mL) was added. The solution was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-10% ethyl acetate / hexane, @100mL / min) to give 10.5g of compound D01-2.

[0653] MS(ESI)M / Z: 317.1 [M+H] + .

[0654] Step 2: Synthesis of compound D01-3

[0655] A solution of D01-2 (10.5 g, 33.31 mmol) in dioxane (100 mL) was degassed with bis(diphenylphosphine) borate (10.15 g, 39.97 mmol), potassium acetate (9.81 g, 99.93 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (2.53 g, 13.29 mmol). The mixture was purged with nitrogen three times, and then stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (elution buffer: 0-10% ethyl acetate / hexane, @80 mL / min) to obtain 6.1 g of compound D01-3.

[0656] MS(ESI)M / Z: 363.2 [M+H] + .

[0657] 1 H NMR (400MHz, CHLOROFORM-d) δ7.60 (t, J=8.0Hz, 1H), 6.65 (dd, J=2.0, 8.4Hz, 1H), 6.54-6.49 (m, 1H), 3.33-3 .22 (m, 4H), 2.57-2.49 (m, 4H), 2.14 (d, J = 7.6Hz, 2H), 1.89-1.76 (m, 1H), 1.36 (s, 12H), 0.94 (d, J = 6.4Hz, 6H)

[0658] Step 3: Synthesis of compound D01-4

[0659] To a mixture of dioxane (8 mL) and water (1.6 mL) containing D01-3 (490.43 mg, 1.35 mmol) and INT-2 (600 mg, 1.13 mmol), potassium phosphate (718.37 mg, 3.38 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (82.54 mg, 112.81 μmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 80 °C for 10 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-10% ethyl acetate / hexane, @20 mL / min) to obtain 440 mg of compound D01-4.

[0660] MS(ESI)M / Z: 618.2 [M+H] + .

[0661] Step 4: Synthesis of compound D01

[0662] Lithium hydroxide monohydrate (298.71 mg, 7.12 mmol) was added to a mixed solution of tetrahydrofuran (5 mL), water (1 mL), and methanol (0.5 mL) containing DO1-4 (440 mg, 711.82 μmol), and the reaction mixture was stirred at 50 °C for 12 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (column: 20-Welch Ultimate C18 250 × 50 mm, 5 μm; mobile phase: [O1-water (0.05% HCl)-ACN]; gradient: 38%-68% B, 7.0 min) to obtain 305 mg DO1.

[0663] MS(ESI)M / Z: 590.4 [M+H] + .

[0664] 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.55 (t, J=52.8Hz, 1H), 7.38-7.26 (m, 1H), 7.20-7.10 (m , 3H), 6.97-6.86(m, 2H), 4.43-4.34(m, 1H), 3.90-3.87(m, 2H), 3.57(d, J=11.6Hz, 2H), 3.35( d, J=9.6Hz, 2H), 3.22-3.06 (m, 4H), 3.04-2.92 (m, 3H), 2.61 (t, J=11.6Hz, 1H), 2.16 (q, J=6.8 , 13.2Hz, 1H), 2.01-1.84 (m, 2H), 1.76-1.65 (m, 1H), 1.42-1.28 (m, 1H), 1.02 (d, J=6.4Hz, 6H)

[0665] Example E04A

[0666] Step A: Synthesis of compound E04A-2

[0667] Potassium hydroxide (3.89 g, 69.36 mmol) was added to a dimethyl sulfoxide (DMSO) solution of E04A-1 (5 g, 23.12 mmol) and E04A-1a (4.05 g, 25.43 mmol) in 50 mL of water. The mixture was stirred overnight at room temperature, and then stirred in an oil bath at 70 °C for 8 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (35 mL × 3). The organic phase was washed with saturated brine (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give 6.7 g of compound E04A-2.

[0668] MS(ESI)M / Z: 336.2 [M+H] + .

[0669] Step B: Synthesis of compound E04A-3

[0670] Iron powder (9.99 g, 178.9 mmol) was added to a 100 mL solution of acetic acid containing 6 g (17.89 mmol), and the reaction mixture was stirred at 25 °C for 5 hours. The reaction mixture was then extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (40 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting buffer: 0-40% ethyl acetate / petroleum ether) to obtain 4.6 g of compound E04A-3.

[0671] MS(ESI)M / Z: 306.2 [M+H] + .

[0672] Step C: Synthesis of compound E04A-4

[0673] Under ice bath conditions, 10 mL of 3N hydrochloric acid (1.2 mL, 3.54 mmol) was added to a methanol (10 mL) solution containing E04A-3 (0.36 g, 1.18 mmol), followed by dropwise addition of a water (5 mL) solution containing sodium nitrite (81 mg, 1.18 mmol). The reaction was allowed to proceed under ice bath conditions for 20 minutes, after which pinacol diboron (0.90 g, 3.54 mmol) was added, and the reaction was continued under ice bath conditions for 1 hour. The reaction solution was quenched to alkalinity with saturated sodium bicarbonate, and then extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to obtain 0.27 g of compound E04A-4.

[0674] MS(ESI)M / Z: 317.2 [M+H-100] + .

[0675] Step D: Synthesis of compound E04A-5

[0676] To a mixture of dioxane (9 mL) and water (3 mL) containing E04A-4 (0.13 g, 0.32 mmol), INT-2 (0.11 g, 0.20 mmol), potassium phosphate (0.13 g, 0.63 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (15.37 mg, 21.0 μmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 85 °C for 8 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (eluting with 0-10% ethyl acetate / petroleum ether) to obtain 72 mg of compound E04A-5.

[0677] MS(ESI)M / Z: 672.2 [M+H] + .

[0678] Step E: Synthesis of compound E04A-6

[0679] Add 1 mL of trifluoroacetic acid to a 5 mL solution of E04A-5 (72 mg, 0.11 mmol) in DCM, and stir at room temperature for 3 hours. Concentrate the reaction solution, neutralize the remaining TFA with an aqueous sodium bicarbonate solution, and then extract the reaction solution with ethyl acetate (20 mL × 3). Wash the organic phase with saturated brine (10 mL), combine the organic phases, dry them over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 66 mg of crude product E04A-6. Use directly for the next step.

[0680] MS(ESI)M / Z: 572.2 [M+H] + .

[0681] Step F: Synthesis of compound E04A-7

[0682] To a solution of E04A-6 (66 mg, 0.12 mmol) and isobutyraldehyde (26 mg, 0.36 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (47 mg, 0.36 mmol) was added. After stirring at room temperature for 10 minutes, sodium borohydride acetate (0.10 g, 0.48 mmol) was added at 0 °C, and the reaction mixture was stirred and mixed at 25 °C for 2 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 60 mg of crude yellow liquid product E04A-7. This was used directly in the next step.

[0683] MS(ESI)M / Z: 628.2 [M+H] + .

[0684] Step G: Synthesis of compound E04A

[0685] Lithium hydroxide monohydrate (60 mg, 1.44 mmol) was added to a mixed solution of E04B-4 (60 mg, 96 μmol) in tetrahydrofuran (2 mL), water (0.4 mL), and methanol (0.2 mL), and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (acidic conditions, 0.1% HCl, column: YMC-Actus Triart C18 ExRS) to give 23.1 mg of compound E04A.

[0686] MS(ESI)M / Z: 600.2 [M+H] + .

[0687] 1 H NMR: (400MHz, DMSO-d6) δ11.21 (s, 1H), 7.92 (s, 1H), 7.54 (t, J=52.5Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 7.13-7.05 (m, 3H), 7. 04-6.88 (m, 2H), 4.49 (tt, J=9.9, 4.4Hz, 1H), 4.35 (dd, J=10.8, 2.7Hz, 1H), 4.12-3.92 (m, 2H), 3.92-3.77 (m, 1H), 3.61 (d, J=11.9Hz, 2H), 3.42(t, J=12.9Hz, 1H), 3.25(dd, J=11.4, 4.0Hz, 1H), 3.17-2.91(m, 5H), 2.88-2.76(m, 1H), 2.71-2.56(m , 1H), 2.19 (dq, J=13.4, 6.7Hz, 1H), 2.07-1.87 (m, 2H), 1.83-1.74 (m, 1H), 1.65-1.41 (m, 1H), 1.05 (dd, J=8.6, 6.6Hz, 6H).

[0688] Examples E14A and E14B

[0689] Step 1: Synthesis of compounds E14-1A and E14-1B

[0690] Compound INT-2 (200 mg, 376.02 μmol), compound INT-5 (160.78 mg, 451.23 μmol), methanesulfonic acid (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (31.83 mg, 37.60 μmol), cesium carbonate (245.03 mg, 752.05 μmol), and water (0.6 mL) were degassed in a dioxane (3 mL) solution, purged three times with nitrogen, and then stirred at 60 °C under nitrogen for 15 min. Extraction was performed with ethyl acetate (3 mL × 3). The reaction mixture was concentrated under reduced pressure by filtration and purified by passing through a rapid silica gel column (eluting buffer: 0-20% ethyl acetate / n-hexane, @18 mL / min) to obtain 200 mg of crude compound E14-1. 54 mg of E14-1A or E14-1B (retention time: 1.295 min) and 30 mg of E14-1B or E14-1A (retention time: 1.533 min) were purified by prep-SFC (column: DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3.H2O)]; B%: 35%, isocratic elution mode).

[0691] MS(ESI)M / Z: 612.5 [M+H] + .

[0692] Step 2: Synthesis of E14A or E14B

[0693] Compound E14-1A or E14-1B (retention time: 1.295 min) (54 mg, 88.21 μmol) was added to a mixture of 0.16 mL of methanol and 1.5 mL of tetrahydrofuran, along with lithium hydroxide (1 M, 882.14 μL). The mixture was stirred at 25 °C for 3 hours. The pH was adjusted to 3 with HCl (0.5 M), and the mixture was extracted with dichloromethane:methanol = 10:1 (3 mL × 3). The organic phase was dehydrated with anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure by filtration to obtain a crude product. This crude product was purified by HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [H2O (0.05% HCl aqueous solution) - ACN]; gradient: 40%-70% B, 7.0 min) to obtain 25 mg of compound E14A or E14B (retention time: 1.580 min).

[0694] MS(ESI)M / Z: 584.5 [M+H] + .

[0695] 1H NMR (400MHz DMSO-d6) δppm 11.13 (br s, 1H), 9.44 (br d, J=1.31Hz, 1H), 7.94-8.02 (m, 1H), 7.39-7.73 (m, 3H), 7.01-7.18 (m, 3H), 6.73 (dd, J=8.70, 1.91Hz, 2H), 4.65 (br d, J=8.34Hz, 1H), 4.55-4.60(m, 1H), 4.46(br s, 1H), 3.54-3.68 (m, 2H), 3.21-3.38 (m, 2H), 3.11-3.20 (m, 1H), 2.97-3.07 (m, 2H), 2.80-2.93 (m, 1H), 2 .54(s, 2H), 2.35-2.44(m, 1H), 1.89-2.16(m, 4H), 1.61-1.76(m, 1H), 141-1.58(m, 1H), 0.94-1.02(m, 6H)

[0696] Step 3: Synthesis of E14B or E14A

[0697] Lithium hydroxide (1M, 490.08μL) was added to a mixture of compound E14-1B or E14-1A (retention time: 1.533 min) (30 mg, 49.01 μmol), methanol (0.16 mL), and tetrahydrofuran (1.5 mL). The mixture was stirred at 25 °C for 3 hours. The pH was adjusted to 3 with HCl (0.5 M), and the mixture was extracted with dichloromethane:methanol = 10:1 (3 mL × 3). The organic phase was dehydrated with anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure by filtration to obtain a crude product. The crude product was purified by HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [H2O (0.05% HCl aqueous solution) - ACN]; gradient: 40%-70% B, 7.0 min) to obtain 20 mg of compound E14B or E14A (retention time: 1.718 min).

[0698] MS(ESI)M / Z: 584.5 [M+H] + .

[0699] 1H NMR (400MHz DMSO-d6) δppm 11.14 (br s, 1H), 9.55 (br s, 1H), 7.93-8.01 (m, 1H), 7.38-7.74 (m, 3H), 7.02-7.18 (m, 3H), 6.67-6.79 (m, 2H), 4.65-4.72 (m, 1H), 4.44-4.60 (m, 2H), 3.71 (br s, 1H), 3.58(br d, J=9.30Hz, 1H), 3.21-3.35(m, 2H), 3.13-3.21(m, 1H), 3.01-3.11(m, 2H), 2 .86-2.98(m, 1H), 2.54(s, 2H), 2.34-2.45(m, 1H), 1.88-2.16(m, 4H), 1.70(br d, J=10.85Hz, 1H), 1.43-1.58(m, 1H), 0.92-1.02(m, 6H)

[0700] Example E16

[0701] Step 1: Synthesis of compound E16-3

[0702] At 0 °C, sodium nitrite (49.66 mg, 719.73 μmol) and potassium iodide (477.90 mg, 2.88 mmol) aqueous solution (0.5 mL) were added to a solution of C11-3 (150 mg, 359.86 μmol), p-toluenesulfonic acid (247.88 mg, 1.44 mmol), water (1.5 mL), and acetonitrile (3 mL). The mixture was then stirred at 25 °C for 12 hours. The mixture was quenched with saturated sodium thiosulfate aqueous solution (3 mL) and extracted with ethyl acetate (3 mL × 3). The reaction mixture was concentrated under reduced pressure and passed through a rapid silica gel column (eluting buffer: 0–6% ethyl acetate / n-hexane, @18 mL / min) to give 130 mg of compound E16-3.

[0703] MS(ESI)M / Z: 528.2 [M+H] + .

[0704] 1H NMR(400MHz CHLOROFORM-d)δppm 7.91 (s, 1H), 7.43-7.73 (m, 2H), 7.08 (d, J=6.79Hz, 1H), 4.86-4.99 (m, 1H), 4.34 (q, J=7.15Hz, 2H), 3.29-3.4 2(m, 1H), 3.13-3.25(m, 2H), 2.63-2.76(m, 1H), 2.07-2.25(m, 2H), 1.93-2.05(m, 2H), 1.37(t, J=7.09Hz, 3H)

[0705] Step 2: Synthesis of compound E16-5

[0706] Compound E16-3 (130 mg, 246.35 μmol), compound E04A-4 (112.82 mg, 270.98 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (18.03 mg, 24.63 μmol), potassium phosphate (156.87 mg, 739.05 μmol), and water (0.5 mL) were degassed in a dioxane (2 mL) solution, purged three times with nitrogen, and then stirred at 85 °C under nitrogen for 2 hours. Extraction was performed with ethyl acetate (3 mL × 3). The reaction mixture was filtered, concentrated under reduced pressure, and purified by passing through a rapid silica gel column (eluting buffer: 0-20% ethyl acetate / n-hexane, @18 mL / min) to give 130 mg of compound E16-5.

[0707] MS(ESI)M / Z: 690.3 [M+H] + .

[0708] 1 H NMR (400MHz CHLOROFORM-d) δppm 7.86 (s, 1H), 7.48 (t, J=52.4Hz, 1H), 7.13 (dd, J=8.28, 1.76Hz, 1H), 6.99-7.06 (m, 3H), 6.84 (br d, J=8.28Hz, 1H), 4.50-4.61(m, 1H), 4.22-4.36(m, 4H), 4.04(br dd, J=10.29, 9.03Hz, 1H), 3.69-3.79(m, 1H), 3.26(br d, J=8.03Hz, 1H), 2.96-3.18(m, 5H), 2.73-2.81(m, 1H), 2.53-2.69(m, 2H) , 1.93-2.05 (m, 2H), 1.64-1.83 (m, 2H), 1.51 (s, 9H), 1.36 (t, J=7.15Hz, 3H)

[0709] Step 3: Synthesis of compound E16-6

[0710] A solution of E16-5 (130 mg, 188.36 μmol) in 2 mL of dichloromethane was added to trifluoroacetic acid (399.10 mg, 3.50 mmol, 260.00 μL). The mixture was stirred at 25 °C for 1 hour. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with dichloromethane (3 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 45 mg of compound E16-6.

[0711] MS(ESI)M / Z: 590.1 [M+H] + .

[0712] Step 4: Synthesis of compound E16-8

[0713] Diisopropylethylamine (65.71 mg, 508.44 μmol) was added to a solution of compound E16-6 (100 mg, 169.48 μmol) and isobutyraldehyde (24.44 mg, 338.96 μmol) in dichloromethane (2 mL). The mixture was stirred at 20 °C for 30 min. Sodium triacetoxyborohydride (107.76 mg, 508.44 μmol) was added to the reaction mixture, and the mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched with an aqueous sodium bicarbonate solution (1 mL), extracted with dichloromethane (3 mL × 3), dehydrated with anhydrous sodium sulfate in the organic phase, filtered, concentrated under reduced pressure, and passed through a rapid silica gel column chromatography column (…). A 4g silica gel column was used as the eluent, with an elution buffer of 0-15% ethyl acetate / n-hexane gradient at 18 mL / min, to yield 100 mg of compound E16-8.

[0714] MS(ESI)M / Z: 646.3 [M+H] +

[0715] Step 5: Synthesis of compound E16

[0716] Compound E16-8 (100 mg, 154.76 μmol), methanol (0.22 mL), and tetrahydrofuran (2 mL) were added to lithium hydroxide LiOH (1 M, 1.55 mL). The mixture was stirred at 25 °C for 3 hours. The pH was adjusted to 3 with HCl (0.5 M), and the mixture was extracted with dichloromethane:methanol = 10:1 (3 mL × 3). The organic phase was dehydrated with anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure by filtration to obtain a crude product. The crude product was purified by HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [H2O (0.05% HCl aqueous solution) - ACN]; gradient: 35%-65% B, 7.0 min) to obtain 40 mg of compound E16.

[0717] MS(ESI)M / Z: 618.0 [M+H] + .

[0718] 1 H NMR(400MHz DMSO-d6)δppm 10.82(br d, J=1.91Hz, 1H), 7.95 (s, 1H), 7.41-7.70 (m, 1H), 7.18-7.24 (m, 2H), 7.15 (dd, J=8.34, 1.55Hz, 1 H), 7.09 (d, J=1.67Hz, 1H), 7.02 (d, J=8.58Hz, 1H), 4.41-4.49 (m, 1H), 4.34-4.38 (m, 1H), 4.06 (br d, J=12.64Hz, 1H), 3.94-3.98(m, 1H), 3.72-3.79(m, 1H), 3.63(br d, J=11.32Hz, 2H), 3.33(br t, J=12.52Hz, 1H), 3.08--3.18(m, 2H), 2.92-3.04(m, 4H), 2.81(q, J=1121Hz, 1H), 2.61(br t, J=10.91Hz, 1H), 2.16 (dt, J=13.35, 6.56Hz, 1H), 1.86-2.01 (m, 2H), 1.78 (br d, J=12.99Hz, 1H), 1.46-1.60 (m, 1H), 1.03 (dd, J=11.50, 6.62Hz, 6H)

[0719] Example E17R

[0720] Step A: Synthesis of compound E17R-2

[0721] At 0 °C, hydrochloric acid (3 M, 660.00 μL) and sodium nitrite (46 mg, 666.71 μmol) in water (2 mL) were slowly added dropwise to a methanol (4 mL) solution of INT-3 (200 mg, 654.94 μmol). The mixture was stirred at 0 °C for 0.3 h. Then, a methanol (4 mL) solution of pinacol diborate (500.00 mg, 1.97 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was slowly poured into a saturated sodium bicarbonate aqueous solution (15 mL) at 0 °C and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting with a 0-10% ethyl acetate / hexane gradient @ 25 mL / min) to give 140 mg of compound E17R-2.

[0722] MS(ESI)M / Z: 417.2 [M+H] + .

[0723] 1H NMR (400MHz, CHLOROFORM-d) δppm 7.34-7.31 (m, 1H), 7.24 (d, J=1.2Hz, 1H), 6.81 (d, J=8.4Hz, 1H), 4.23 (dd, J=2.8, 10.8Hz, 1H), 4.18-3.91 (m, 3H), 3.79-3.7 0 (m, 1H), 3.22-3.11 (m, 1H), 3.07-2.94 (m, 1H), 2.78 (dt, J=2.8, 12.4Hz, 1H), 2.69-2.56 (m, 1H), 1.49 (s, 9H), 1.32 (s, 12H).

[0724] Step B: Synthesis of compound E17R-3

[0725] To a mixed solution of E17R-2 (70 mg, 168.14 μmol) in dioxane (1 mL) and water (0.2 mL), INT-2 (90 mg, 169.21 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 17.77 μmol), and potassium phosphate (107 mg, 504.08 μmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-15% ethyl acetate / hexane, @25 mL / min) to give 100 mg of compound E17R-3.

[0726] MS(ESI)M / Z: 672.3 [M+H] + .

[0727] 1H NMR (400MHz, CHLOROFORM-d) δppm 7.87(s, 1H), 7.63-7.40(m, 1H), 7.16-7.10(m, 2H), 7.06-6.98(m, 3H), 6. 85(d, J=8.4Hz, 1H), 4.63-4.52(m, 1H), 4.35-4.28(m, 2H), 4.28-4.19(m, 2H), 4.10-3.97(m, 2H), 3.78-3.70(m, 1H), 3.38-3.31(m, 1H), 3.20-3.12 (m, 2H), 3.12-3.05 (m, 2H), 2.83-2.74 (m, 1H), 2.71-2.56 (m, 2H), 2.09 (br d, J=3.2Hz, 1H), 2.00 (br dd, J=3.6, 12.8Hz, 1H), 1.81-1.74 (m, 1H), 1.71-1.62 (m, 1H), 1.51 (s, 9H), 1.36 (t, J=7.2Hz, 3H).

[0728] Step C: Synthesis of compound E17R-4

[0729] Trifluoroacetic acid (230.25 mg, 2.02 mmol) was added to a solution of E17R-3 (100 mg, 148.77 μmol) in 1 mL of dichloromethane. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (8 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 85 mg of compound E17R-4.

[0730] MS(ESI)M / Z: 572.3 [M+H] + .

[0731] Step D: Synthesis of compound E17R-5

[0732] Isobutyraldehyde (22.12 mg, 306.77 μmol) and N,N-diisopropylethylamine (57.88 mg, 447.81 μmol) were added to a 2 mL solution of E17R-4 (85 mg, 148.59 μmol) in dichloromethane. The mixture was stirred at 20 °C for 30 minutes. Then, sodium borohydride acetate (95 mg, 448.24 μmol) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with dichloromethane (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-20% ethyl acetate / hexane, @25 mL / min) to give 90 mg of compound E17R-5.

[0733] MS(ESI)M / Z: 628.4 [M+H] + .

[0734] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.87 (s, 1H), 7.64-7.48 (m, 1H), 7.16-7.10 (m, 2H), 7.04-6.96 (m, 3H), 6.82 (d, J=8.4Hz, 1H) , 4.65-4.55 (m, 1H), 4.32 (q, J=7.2Hz, 2H), 4.23-4.17 (m, 1H), 4.05 (t, J=9.6Hz, 1H), 3.68 (br d, J=12.0Hz, 1H), 3.37(br dd, J=2.8, 10.0Hz, 1H), 3.27-3.07(m, 3H), 2.98(br d, J=12.0Hz, 1H), 2.90-2.79(m, 2H), 2.61-2.51(m, 1H), 2.28-2.21(m, 1H), 2.16(br d, J=7.6Hz, 2H), 2.02-1.94 (m, 1H), 1.88-1.72 (m, 3H), 1.70-1.61 (m, 1H), 1.37 (t, J=7.2Hz, 3H), 0.95 (br d, J=6.4Hz, 6H), 0.88-0.81 (m, 1H).

[0735] Step E: Synthesis of compound E17R

[0736] A solution of lithium hydroxide monohydrate (60 mg, 1.43 mmol) in water (0.2 mL) was added to a mixed solution of E17R-5 (90 mg, 143.28 μmol) in tetrahydrofuran (1 mL) and methanol (0.1 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 2 M hydrochloric acid / dioxane solution (3 mL) was added at 25 °C and stirred for 1 hour, followed by concentration under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [H2O (0.05% HCl)-ACN]; gradient: 40%-70% B, 7.0 min) to obtain 24.8 mg of E17R.

[0737] MS(ESI)M / Z: 600.1 [M+H] + .

[0738] 1H NMR (400MHz, METHANOL-d4) δppm8.12-7.33 (m, 5H), 7.22 (br s, 1H), 7.10 (br d, J=7.2Hz, 1H), 6.97 (br s, 1H), 5.36-5.07 (m, 1H), 4.54-4.19 (m, 3H), 4.14-3.98 (m, 2H), 3.93-3.70 (m, 4H), 3.50-3.33 (m, 2H), 3.30-3.21 (m, 1H), 3.14 (br d, J=7.2Hz, 2H), 3.03-2.89 (m, 1H), 2.28 (dt, J=6.4, 13.2Hz, 2H), 2.14-1.84 (m, 3H), 1.13 (dd, J=3.2, 6.4Hz, 6H).

[0739] Example E17S

[0740] Step A: Synthesis of compound E17S-2

[0741] At 0 °C, hydrochloric acid (3 M, 2 mL) and sodium nitrite (138.00 mg, 2.00 mmol) in water (5 mL) were slowly added dropwise to a methanol (10 mL) solution of INT-4 (600 mg, 1.96 mmol). The mixture was stirred at 0 °C for 0.3 h. Then, a methanol (10 mL) solution of pinacol diborate (1.50 g, 5.91 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction mixture was slowly poured into a saturated sodium bicarbonate aqueous solution (30 mL) at 0 °C and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-10% ethyl acetate / hexane, @40 mL / min) to give 520 mg of compound E17S-2.

[0742] MS(ESI)M / Z: 417.3 [M+H] + .

[0743] 1H NMR (400MHz, CHLOROFORM-d) δppm7.32 (dd, J=1.2, 8.0Hz, 1H), 7.24 (d, J=1.2Hz, 1H), 6.80 (d, J=8 .4Hz, 1H), 4.23 (dd, J=2.8, 10.4Hz, 1H), 4.14-4.06 (m, 2H), 3.96 (dd, J=8.4, 10.8Hz, 1H), 3.75 (br d, J=11.6Hz, 1H), 3.20-3.10 (m, 1H), 3.09-2.93 (m, 1H), 2.78 (dt, J=3.2, 12.4Hz, 1H), 2.71-2.51 (m, 1H), 1.49 (s, 9H), 1.32 (s, 12H)

[0744] Step B: Synthesis of compound E17S-3

[0745] To a mixed solution of E17S-2 (80 mg, 192.16 μmol) in dioxane (1 mL) and water (0.2 mL), INT-2 (100 mg, 188.01 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (14 mg, 19.13 μmol), and potassium phosphate (120 mg, 565.32 μmol) were added for degassing. The mixture was purged with nitrogen three times, and then stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-15% ethyl acetate / hexane, @25 mL / min) to give 95 mg of compound E17S-3.

[0746] MS(ESI)M / Z: 672.3 [M+H] + .

[0747] Step C: Synthesis of compound E17S-4

[0748] Trifluoroacetic acid (230.25 mg, 2.02 mmol) was added to a solution of E17S-3 (95.00 mg, 141.34 μmol) in 1 mL of dichloromethane. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (8 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 65 mg of compound E17S-4.

[0749] MS(ESI)M / Z: 572.3 [M+H] + .

[0750] Step D: Synthesis of compound E17S-5

[0751] Isobutyraldehyde (16.59 mg, 230.08 μmol) and N,N-diisopropylethylamine (44.52 mg, 344.48 μmol) were added to a solution of E17S-4 (65 mg, 113.63 μmol, 1 eq) in dichloromethane (1 mL). The mixture was stirred at 20 °C for 30 minutes. Then sodium borohydride acetate (72 mg, 339.72 μmol) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with dichloromethane (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was passed through a rapid silica gel column (eluting buffer: 0-20% ethyl acetate / hexane, @25 mL / min) to give 65 mg of compound E17S-5.

[0752] MS(ESI)M / Z: 628.3 [M+H] + .

[0753] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.88(s, 1H), 7.63-7.35(m, 1H), 7.14(d, J=8.4Hz, 1H), 7.08(d, J=1.6Hz, 1H), 7.05-7.00(m , 2H), 6.97 (s, 1H), 6.81 (d, J=8.4Hz, 1H), 4.65-4.56 (m, 1H), 4.32 (q, J=7.2Hz, 2H), 4.22 (br d, J=9.2Hz, 1H), 4.05-3.99 (m, 1H), 3.73-3.64 (m, 1H), 3.41-3.32 (m, 1H), 3.3 1-3.21 (m, 1H), 3.19-3.05 (m, 2H), 3.01-2.93 (m, 1H), 2.88-2.78 (m, 2H), 2.62 -2.45(m, 1H), 2.30-2.20(m, 1H), 2.19-2.12(m, 2H), 2.07-1.94(m, 2H), 1.89- 1.60 (m, 3H), 1.37 (t, J=7.2Hz, 3H), 1.23-1.12 (m, 1H), 0.95 (d, J=6.4Hz, 6H).

[0754] Step E: Synthesis of compound E17S

[0755] A solution of lithium hydroxide monohydrate (45 mg, 1.07 mmol) in water (0.2 mL) was added to a mixed solution of E17S-5 (65.00 mg, 103.48 μmol) in tetrahydrofuran (1 mL) and methanol (0.1 mL). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and 2 M hydrochloric acid / dioxane solution (3 mL) was added at 25 °C and stirred for 1 hour, followed by concentration under reduced pressure to obtain the crude product. The crude product was subjected to preparative-grade HPLC (column: 20-Welch Xtimate C18 250 × 50 mm, 5 μm; mobile phase: [H2O (0.05% HCl)-ACN]; gradient: 40%-70% B, 7.0 min) to obtain 20.2 mg of E17S.

[0756] MS(ESI)M / Z: 600.4 [M+H] + .

[0757] 1 H NMR (400MHz, METHANOL-d4) δppm 8.42-7.27 (m, 5H), 7.18 (br d, J=2.4Hz, 1H), 7.09-6.99 (m, 2H), 5.44-4.96 (m, 1H), 4.45 (br d, J=10.0Hz, 1H), 4.40-4.07 (m, 3H), 4.06-3.64 (m, 5H), 3.39 (br s, 2H), 3.30-3.22 (m, 1H), 3.12 (br d, J=7.2Hz, 2H), 3.02 (br t, J=11.6Hz, 1H), 2.28 (td, J=6.8, 13.6Hz, 2H), 2.14-2.04 (m, 1H), 1.96 (br s, 2H), 1.12 (dd, J=4.0, 6.4Hz, 6H).

[0758] Example F01R

[0759] Step A: Synthesis of compound F01-1

[0760] 220 mg of B04-12 was eluted by SFC (column: DAICEL CHIRALPAK IF (250 mm * 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3·H2O)]; B%: 15%, isocratic elution mode) to yield 104 mg of compound F01-1 (retention time: 0.692 min).

[0761] MS(ESI)M / Z: 522.3 [M+H] + .

[0762] Step B: Synthesis of compound F01-3

[0763] Add F01-1 (80.00 mg, 153.34 μmol), E04A-4 (89.37 mg, 214.67 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (11.22 mg, 15.33 μmol), potassium carbonate (42.39 mg, 306.67 μmol), water (40 μL), and 1,4-dioxane (200 μL) to a pre-dried and nitrogen-filled 10 mL sealed vial. Stir the final mixture at 100 °C for 2 hours. Then dilute the reaction mixture with water (10 mL) and ethyl acetate (10 mL), extract with ethyl acetate (10 mL × 2), and wash the combined organic phases with brine (10 mL). Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give a pale yellow oil. The oily substance was then eluted by silica gel chromatography (0-5% methanol / dichloromethane) to obtain 100 mg of compound F01-3.

[0764] MS(ESI)M / Z: 684.2 [M+H] + .

[0765] Step C: Synthesis of compound F01-4

[0766] Add F01-3 (100 mg, 146.16 μmol) and hydrogen chloride / 1,4-dioxane (2 mL) to a 10 mL round-bottom flask, and stir the mixture at 25 °C for 6 hours. Concentrate the mixture to obtain 90 mg of compound F01-4, which is used directly in the next step.

[0767] MS(ESI)M / Z: 584.1 [M+H] + .

[0768] Step D: Synthesis of compound F01-5

[0769] Add F01-4 (60 mg, 102.73 μmol), isobutyraldehyde (11.11 mg, 154.09 μmol), diisopropylethylamine (26.55 mg, 205.46 μmol), and dichloromethane (1.2 mL) to a 10 mL round-bottom flask, and stir at 25 °C for 30 min. Then add sodium triacetoxyborohydride (65.32 mg, 308.19 μmol), and stir the final mixture at 25 °C for 3.5 h. Quench the reaction mixture with saturated ammonium chloride aqueous solution (3 mL), extract with ethyl acetate (3 mL × 2), and wash the combined organic phases with brine (5 mL). Dry the organic phases with anhydrous sodium sulfate, filter, and concentrate to dryness under vacuum to give 60 mg of compound F01-5, which was used directly in the next reaction.

[0770] MS(ESI)M / Z: 640.2 [M+H] + .

[0771] Step E: Synthesis of compound F01R

[0772] 80 mg (124.97 μmol) of F01-5, 1.6 mL of tetrahydrofuran, and 160 μL of ethanol were added to a 2 mL sealed vial. Then, an aqueous solution of lithium hydroxide monohydrate (52.44 mg, 1.25 mmol) dissolved in water (160 μL) was added to the reaction mixture. The mixture was stirred at 50 °C for 4 hours. The reaction mixture was diluted with 4 mL of water and 4 mL of ethyl acetate, and the pH of the aqueous phase was adjusted to 6. Extraction was performed with ethyl acetate (3 mL × 3). The combined organic phases were washed with brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a white solid. The product was obtained by solid-state HPLC chromatography (column: 20-Welch Xtimate C18 250×50mm, 5μm; mobile phase: [water (0.05% aqueous hydrogen chloride solution)-acetonitrile]; gradient: 40%-70%B, 7.0 min), followed by HPLC chromatography (column: 57-Phenomenex Gemini NX C18 150×30mm, 5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%B, 8.0 min) to obtain 10.8 mg of compound F01R.

[0773] MS(ESI)M / Z: 612.4 [M+H] + .

[0774] 1H NMR (400MHz, CD3OD) δ7.82 (s, 1H), 7.61 (t, J=53.2Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.97 (dd, J=2.0, 8.4Hz, 1H), 6.9 3-6.88 (m, 3H), 6.83 (d, J=2.0Hz, 1H), 4.99 (t, J=7.6Hz, 1H), 4.27 (dd, J=2.4, 10.8Hz, 1H), 4.03-3.86 (m, 3H), 3.6 0 (dd, J=8.8, 12.4Hz, 1H), 3.42 (dd, J=7.6, 12.4Hz, 1H), 3.37-3.33 (m, 1H), 3.30-3.23 (m, 2H), 2.93 (dt, J=2.4, 12 .8Hz, 1H), 2.74-2.56(m, 5H), 2.44-2.28(m, 3H), 2.11-1.99(m, 1H), 1.64(t, J=9.6Hz, 1H), 1.02(d, J=6.4Hz, 6H).

[0775] Example B14 Hydrochloride

[0776] Step 1: Add benzyl hydrazide (3.9 g, 23.44 mmol) to a tetrahydrofuran solution (50 mL) of B14-1 (5 g, 23.44 mmol). Purge the reaction mixture three times with nitrogen and stir at room temperature for 60 hours. After the reaction is complete, extract the reaction mixture with ethyl acetate (200 mL × 3) and water (150 mL). Wash the organic phase with saturated sodium chloride (150 mL) and dry the organic phase with anhydrous sodium sulfate. Filter and concentrate the filtrate under vacuum to obtain the crude product. Purify by rapid silica gel chromatography to obtain 5.6 g of product B14-2.

[0777] MS(ESI)M / Z: 362.2 [M+H] + .

[0778] Step 2: Add sodium borohydride (1.17 g, 30.98 mmol) to a tetrahydrofuran solution (50 mL) of B14-2 (5.6 g, 15.49 mmol), purge with nitrogen three times, and stir the reaction solution at room temperature for 16 hours. After the reaction is complete, quench the reaction solution with methanol, concentrate under vacuum to remove the solvent, and obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 4.6 g of product B14-3.

[0779] MS(ESI)M / Z: 364.3 [M+H] + .

[0780] 1H NMR (400MHz, DMSO-d6) δ8.61 (d, J=19.6Hz, 1H), 7.41-7.27 (m, 5H), 5.09-4.97 (m, 2H), 4.44 (s, 1H), 3.72 (ddd, J=14.0, 6.8, 4.5Hz, 1H), 3 .65-3.25 (m, 1H), 3.15-2.89 (m, 2H), 2.69 (ddd, J=55.3, 13.9, 9.2Hz, 1H), 1.77-1.46 (m, 4H), 1.37 (d, J=16.5Hz, 9H), 1.31-1.18 (m, 2H).

[0781] Step 3: To a solution of B14-3 (4.6 g, 12.66 mmol) in ethanol (30 mL), 10% palladium on carbon (0.67 g, 0.63 mmol) was added under nitrogen protection. The mixture was purged three times with hydrogen, and stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethanol (80 mL × 3), and the filtrate was concentrated under reduced pressure to obtain 3.6 g of product B14-4.

[0782] MS(ESI)M / Z: 230.3 [M+H] + .

[0783] Step 4: Add B14-4A (6.98 g, 31.40 mmol) to an ethanol solution (40 mL) of B14-4 (3.6 g, 15.70 mmol), and purge with nitrogen three times. Stir the reaction mixture at room temperature for 16 hours. After the reaction is complete, extract with ethyl acetate (150 mL × 3) and water (100 mL). Wash the organic phase with saturated sodium chloride (100 mL) and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the residue by rapid silica gel chromatography to obtain 2.6 g of product B14-5.

[0784] MS(ESI)M / Z: 332.2 [M-56+H] + .

[0785] Step 5: The solution of B14-5 (2.6 g, 11.36 mol) in hydrochloric acid / ethyl acetate (2 M, 10 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain 2 g of crude product. 1 g of the crude product was purified by pre-HPLC to obtain 660 mg of product B14-6.

[0786] MS(ESI)M / Z: 288.2 [M+H] + .

[0787] 1H NMR (400MHz, DMSO-d6) δ8.48 (d, J=1.2Hz, 1H), 7.18 (t, J=53.7Hz, 1H), 4.50-4.42 (m, 1H), 4.23 (q, J=7.1Hz, 2H), 3.61-3.46 (m, 1H), 3.10-2.99 (m, 2H), 2.87 (dt, J=13.2, 5.3Hz, 1H), 2.71 (dddd, J=13.2, 8.1, 5.1Hz, 1H), 2.07 (dddd, J=13.4, 7.8, 5.7, 2.6Hz, 1H), 2.01-1.90 (m , 1H), 1.70 (dddd, J=21.1, 10.7, 5.5, 2.7Hz, 2H), 1.62-1.45 (m, 2H), 1.27 (t, J=7.1Hz, 3H).

[0788] Step 6: Add 4-chloro-2-fluoronitrobenzene (240 mg, 1.39 mmol) and N,N-diisopropylethylamine (540 mg, 4.17 mmol) to a solution of B14-6 (400 mg, 1.39 mmol) in sulfoxide (5 mL), purge three times with nitrogen, and then stir at 90 °C for 4 hours. After the reaction is complete, cool the reaction solution to room temperature and extract with ethyl acetate (100 mL × 3) and water (100 mL). Wash the organic phase with saturated sodium chloride (100 mL) and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 550 mg of product B14-7.

[0789] MS(ESI)M / Z: 443.1 [M+H] + .

[0790] Step 7: To a solution of B14-7 (550 mg, 1.24 mmol) in N,N-dimethylformamide (10 mL), 4,4′-bipyridine (1.9 mg, 1.39 mmol) and tetrahydroxydiboron (440 mg, 4.96 mmol) were added under ice bath conditions, and the mixture was purged three times with nitrogen. The mixture was then stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was extracted with ethyl acetate (100 mL × 3) and water (100 mL). The organic phase was washed with saturated sodium chloride (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 470 mg of product B14-8.

[0791] MS(ESI)M / Z: 413.2 [M+H] + .

[0792] 11H NMR (400MHz, DMSO-d6) δ8.48 (d, J=1.3Hz, 1H), 7.16 (t, J=53.6Hz, 1H), 6.94 (d, J=2.4Hz, 1 H), 6.81 (dd, J=8.5, 2.3Hz, 1H), 6.66 (d, J=8.6Hz, 1H), 4.98 (s, 2H), 4.70 (qd, J=7.5, 4.1Hz , 1H), 4.22 (q, J=7.1Hz, 2H), 3.42 (dd, J=13.7, 7.7Hz, 1H), 3.32 (dd, J=13.6, 4.3Hz, 1H), 2. 94 (q, J=5.9Hz, 2H), 2.18 (td, J=8.1, 3.7Hz, 2H), 1.91-1.73 (m, 4H), 1.26 (t, J=7.1Hz, 3H).

[0793] Step 8: To a solution of B14-8 (470 mg, 1.14 mmol) in acetonitrile (10 mL), add tert-butyl nitrite (140 mg, 1.37 mmol), copper bromide (13 mg, 0.057 mmol), p-toluenesulfonic acid (240 mg, 1.37 mmol), and tetrabutylammonium bromide (740 mg, 2.28 mmol). Purge the solution three times with nitrogen and stir the mixture at room temperature for 4 hours. After the reaction is complete, extract the reaction mixture with ethyl acetate (80 mL × 3) and water (80 mL). Wash the organic phase with saturated sodium chloride (100 mL) and dry the organic phase with anhydrous sodium sulfate. Filter the solution, and concentrate the filtrate under vacuum to obtain the crude product. Use rapid silica gel chromatography to obtain 290 mg of product B14-9.

[0794] MS(ESI)M / Z: 476.1

[0795] 1 H NMR (400MHz, DMSO-d6) δ8.50 (d, J=1.1Hz, 1H), 7.59 (d, J=8.5Hz, 1H), 7.33 (d, J=2.5Hz, 1H), 7.30-7.01 (m, 2H), 4.76 (qd, J=8.8, 8.4, 5.4Hz, 1H), 4.21 (q, J= 7.1Hz, 2H), 3.61 (dd, J=13.9, 8.2Hz, 1H), 3.51 (dd, J=14.0, 4.2Hz, 1H), 3.15 ( t, J=6.1Hz, 2H), 2.23-2.05 (m, 2H), 1.99-1.72 (m, 4H), 1.26 (t, J=7.1Hz, 3H).

[0796] Step 9: To a mixed solution of B14-9 (150 mg, 0.31 mmol) in 1,4-dioxane (6 mL) and water (3 mL), add INT-1 (140 mg, 1.37 mmol), sodium carbonate (99 mg, 0.93 mmol), and tetraphenylphosphine palladium (36 mg, 0.031 mmol). Purge the mixture three times with nitrogen, and stir at 90 °C for 4 hours. After the reaction is complete, cool the reaction solution to room temperature and extract with ethyl acetate (80 mL × 3) and water (80 mL). Wash the organic phase with saturated sodium chloride (100 mL) and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Use rapid silica gel chromatography to obtain 150 mg of product B14-10.

[0797] MS(ESI)M / Z: 614.3

[0798] Step 10: Lithium hydroxide (57 mg, 2.4 mmol) was added to a mixed solution of B14-10 (150 mg, 0.24 mmol) in tetrahydrofuran (5 mL) and water (2 mL), and the mixture was purged three times with nitrogen. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete, the pH was adjusted to 3 with 4 mol of hydrochloric acid. The reaction solution was extracted with ethyl acetate (70 mL × 3) and water (50 mL). The organic phase was washed with saturated sodium chloride (40 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by pre-HPLC (acidic mobile phase) to obtain the product B14 hydrochloride.

[0799] MS(ESI)M / Z: 586.3 [M+H] + .

[0800] 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.17 (s, 1H), 7.34 (d, J=8.7Hz, 2H), 7.31-7.07 (m, 3H), 7 .06-7.02 (m, 3H), 4.36 (p, J=7.0Hz, 1H), 3.86-3.76 (m, 2H), 3.56 (d, J=12.0Hz, 2H), 3.42 (d, J= 6.8Hz, 2H), 3.37-3.28(m, 2H), 3.20-3.06(m, 2H), 3.07-2.96(m, 4H), 2.15(hept, J=6.8Hz, 1H) , 1.97 (q, J=5.2Hz, 2H), 1.76-1.63 (m, 1H), 1.47 (q, J=10.5, 7.9Hz, 3H), 1.02 (d, J=6.6Hz, 6H).

[0801] Example B20 Hydrochloride

[0802] Step A: To a 20 mL solution of B20-1 (0.74 g, 3.94 mmol) and INT-2-1 (0.5 g, 2.63 mmol) in toluene, add cyanomethylenetri-n-butylphosphine (1.27 g, 5.26 mmol). Stir the mixture overnight in a 120°C oil bath, then continue stirring in a 70°C oil bath for 5 hours. After cooling to room temperature, concentrate the mixture under reduced pressure to obtain the crude product. Pass the crude product through a rapid silica gel column chromatography column to obtain 0.48 g of compound B20-2.

[0803] MS(ESI)M / Z: 304.2 [M+H-56] + .

[0804] Step B: Add 5 mL of trifluoroacetic acid to a solution of B20-2 (0.48 g, 1.34 mmol) in dichloromethane (5 mL), and stir at room temperature for 4 hours. Concentrate the reaction solution to obtain 320 mg of crude product B20-3. Use directly in the next step.

[0805] MS(ESI)M / Z: 262.2 [M+H] + .

[0806] Step C: A 20 mL solution of compound B20-3 (0.32 g, 1.23 mmol), INT-2-5 (0.52 g, 1.60 mmol), tris(dibenzylacetone)palladium (0.11 g, 0.12 mmol), 1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (0.15 g, 0.25 mmol), and cesium carbonate (1.20 g, 3.69 mmol) in dioxane was degassed, purged three times with nitrogen, and then stirred at 100 °C for 8 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography to obtain 630 mg of compound B20-4.

[0807] MS(ESI)M / Z: 506.2 [M+H] + .

[0808] Step D: Add 1 mL of trifluoroacetic acid to a solution of B20-4 (0.62 g, 1.23 mmol) in 4 mL of dichloromethane, and stir at room temperature for 4 hours. Concentrate the reaction solution to obtain 600 mg of crude product B20-5 (containing trifluoroacetic acid). Use directly for the next step.

[0809] MS(ESI) M / Z: 386.0 [M+H] + .

[0810] Step E: Triethylamine (0.49 g, 4.8 mmol) was added to a solution of trifluoroacetate (0.6 g, 1.20 mmol) in dichloromethane (10 mL), followed by the dropwise addition of trifluoromethanesulfonic anhydride (0.68 g, 2.4 mmol) at -78°C. The mixture was gradually brought to room temperature and incubated overnight. The solution was quenched with an aqueous sodium bicarbonate solution (2 mL), extracted with ethyl acetate (10 mL × 3), dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure by filtration, and the crude product was passed through a rapid silica gel column to give 300 mg of compound B20-6.

[0811] 1 H NMR (400MHz, Chloroform-d) δ7.92 (d, J=0.8Hz, 1H), 7.59 (t, J=52.8Hz, 1H), 7.13 (d, J=8.7Hz, 1H), 6.93 (d, J=2.5Hz, 1H), 6.84 (dd, J=8.7, 2. 4Hz, 1H), 5.46-5.32 (m, 1H), 4.36 (q, J=7.1Hz, 2H), 4.01 (dd, J=10.2, 7.1Hz, 1H), 3.82-3.56 (m, 3H), 2.69-2.45 (m, 2H), 1.39 (t, J=7.1Hz, 3H).

[0812] Step F: A mixture of B20-6 (0.30 g, 0.58 mmol), INT-1 (0.30 g, 0.87 mmol), dioxane (9 mL), and water (3 mL) was degassed with potassium phosphate (0.37 g, 1.74 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (42.44 mg, 58 μmol). The mixture was purged with nitrogen three times, and then stirred at 90°C for 6 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography to obtain 200 mg of compound B20-7.

[0813] MS(ESI)M / Z: 587.2 [M+H] + .

[0814] Step G: Lithium hydroxide monohydrate (81 mg, 0.34 mmol) was added to a mixture of B20-7 (0.2 g, 0.34 mmol) in tetrahydrofuran (10 mL) and water (3 mL), and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The residue was subjected to preparative-grade HPLC (acidic conditions, 0.1% HCl, column: YMC-Actus Triart C18 ExRS) to give 106 mg of compound B20 hydrochloride.

[0815] 1H NMR (400MHz, DMSO-d6) δ10.85 (d, J=37.5Hz, 1H), 7.99 (s, 1H), 7.56 (t, J=52.3Hz, 1H), 7.28 ( d, J=8.4Hz, 2H), 7.06 (d, J=8.5Hz, 1H), 7.03-6.98 (m, 2H), 6.93-6.86 (m, 2H), 5.15 (p, J=5.8 Hz, 1H), 3.77 (t, J=10.5Hz, 2H), 3.56 (d, J=12.0Hz, 2H), 3.45-3.24 (m, 4H), 3.19-3.05 (m, 4H ), 2.99 (t, J=6.0Hz, 2H), 2.38-2.27 (m, 2H), 2.16 (hept, J=6.7Hz, 1H), 1.03 (d, J=6.6Hz, 6H).

[0816] 19 FNMR (376MHz, DMSO) δ -113.62.

[0817] MS(ESI)M / Z: 558.2 [M+H] +

[0818] Examples B29A and B29B hydrochloride

[0819] Step A: Synthesis of compound B29-2

[0820] Under nitrogen protection, a 2.5 M, 5.96 mL solution of n-butyllithium was added to a tetrahydrofuran (24 mL) solution of diisopropylamine (1.58 g, 15.65 mmol), and the mixture was stirred at -78 °C for 10 min. Compound B29-1 (1 g, 14.91 mmol) was then slowly added, and the mixture was stirred at -78 °C for 1 h. Compound B29-1a (1.89 g, 15.65 mmol) was then added dropwise. After the addition was complete, the reaction mixture was slowly heated to 20 °C and stirred at 20 °C for 0.5 h. The reaction was quenched by pouring the reaction mixture into an aqueous solution of ammonium chloride (20 mL) under a weak nitrogen stream. The mixture was then extracted twice with dichloromethane (40 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure at low temperature to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 350 mg of compound B29-2.

[0821] 1H NMR (400MHz, CHLOROFORM-d) δppm 5.86 (ddt, J=16.97, 10.13, 6.78, 6.78Hz, 1H), 5.15-5.29 (m, 2H), 2.24 (d, J=6.78Hz, 2H), 1.20-1.30 (m, 2H), 0.78-0.90 (m, 2H).

[0822] Step B: Synthesis of compound B29-3

[0823] Under nitrogen atmosphere, a 2.5 M lithium aluminum hydride solution (1.96 mL) was added dropwise to a 10 mL tetrahydrofuran solution of compound B29-2 (350 mg, 3.27 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, and then at 20 °C for 12 h. The reaction was quenched sequentially with water (0.19 mL), 15% NaOH (0.19 mL), and water (0.57 mL) under ice-water bath cooling. The mixture was then dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 250 mg of crude compound B29-3.

[0824] 1 H NMR (400MHz, CHLOROFORM-d) δppm 5.82 (ddt, J=17.07, 10.04, 7.03, 7.03Hz, 1H), 5.00-5.15 (m, 2H), 2.53 (s, 2H), 2.13 (d, J=7.03Hz, 2H), 0.31-0.39 (m, 4H)

[0825] Step C: Synthesis of compound B29-4

[0826] At 0 °C, triethylamine (455.05 mg, 4.50 mmol) and TosCl (514.41 mg, 2.70 mmol) were added to a dichloromethane solution (5 mL) of compound B29-3 (250 mg, 2.25 mmol). The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched in an aqueous solution of sodium bicarbonate (20 mL), and then extracted twice with dichloromethane (60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 360 mg of compound B29-4.

[0827] MS(ESI)M / Z: 288.2 [M+Na] + .

[0828] 1H NMR (400MHz, CHLOROFORM-d) δppm7.74 (d, J=8.28Hz, 2H), 7.31 (d, J=8.03Hz, 2H), 5.70 (ddt, J=17.10, 10.20, 7.06, 7.06Hz, 1H), 4.91-5.04 (m, 2H), 4.43 (br t, J=6.02Hz, 1H), 2.81 (d, J=6.27Hz, 2H), 2.43 (s, 3H), 2.00-2.08 (m, 2H), 0.36-0.41 (m, 2H), 0.30-0.35 (m, 2H)

[0829] Step D: Synthesis of compound B29-5

[0830] A solution of compound B29-4 (1 g, 3.77 mmol), palladium acetate (84.60 mg, 376.83 μmol), (R)-2-(6-diphenylmethylpyridin-2-yl)-4-phenyl-4,5-dihydrooxazole (956.43 mg, 2.45 mmol), and diacetoxyiodobenzene (2.43 g, 7.54 mmol) in trifluorotoluene (20 mL) was purged three times with nitrogen, and then the mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched by adding water (20 mL), and then extracted twice with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 900 mg of compound B29-5.

[0831] MS(ESI)M / Z: 324.2 [M+H] + .

[0832] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.66 (d, J=8.23Hz, 2H), 7.33-7.36 (m, 2H), 4.95-5.06 (m, 1H), 3.51 (dd, J=11.74, 3.87Hz, 1H), 2.7 4-2.89(m, 3H), 2.46(s, 3H), 2.06(s, 3H), 1.50-1.56(m, 2H), 0.51-0.57(m, 2H), 0.39-0.46(m, 2H)

[0833] Step E: Synthesis of compound B29-6

[0834] Under nitrogen protection, lithium aluminum hydride (2.5M, 4.45mL) was slowly added dropwise to a mixture of compound B29-5 (0.9g, 2.78mmol) and tetrahydrofuran (20mL) at 0℃. The reaction mixture was then stirred at 60℃ under nitrogen for 12 hours. After cooling to room temperature, the reaction was quenched successively with water (0.42mL), 15% NaOH (0.42mL), and water (1.26mL) under an ice-water bath. The mixture was then dried with Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 710mg of crude compound B29-6.

[0835] MS(ESI)M / Z: 128.2 [M+H] + .

[0836] Step F: Synthesis of compound B29-7

[0837] Triethylamine (1.46 g, 14.39 mmol) and Boc₂O (1.43 g, 6.56 mmol) were added to a 6 mL solution of compound B29-6 (610 mg, 4.80 mmol) in dichloromethane. The mixture was stirred at 20 °C for 1 hour. The solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography to obtain 380 mg of compound B29-7.

[0838] MS(ESI)M / Z: 172.2 [M+H] + .

[0839] 1 H NMR (400MHz, CHLOROFORM-d) δppm 3.89 (br s, 1H), 3.62-3.81 (m, 1H), 3.05-3.41 (m, 3H), 1.94 (br s, 1H), 1.58 (br d, J=5.52Hz, 1H), 1.47 (s, 9H), 0.37-0.60 (m, 3H), 0.22-0.32 (m, 1H)

[0840] Step G: Synthesis of compound B29-8

[0841] CMBP (806.99 mg, 3.34 mmol) was added to an 8 mL solution of compound B29-7 (380 mg, 1.67 mmol) and INT-2-1 (381.47 mg, 2.01 mmol) in toluene. The mixture was stirred at 100 °C for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography to obtain 90 mg of compound B29-8.

[0842] MS(ESI)M / Z: 344.2 [M+H] + .

[0843] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.90 (s, 1H), 7.39-7.72 (m, 1H), 4.65-4.78 (m, 1H), 4.33 (q, J=7.11Hz, 3H), 3.08-3.51 (m, 3H ), 2.54-2.80 (m, 1H), 1.46 (s, 9H), 1.29-1.41 (m, 5H), 0.51-0.79 (m, 2H), 0.28-0.46 (m, 2H).

[0844] Step H: Synthesis of compound B29-9

[0845] A mixture of compound B29-8 (130 mg, 325.46 μmol) and dioxane hydrochloride (2 M, 3 mL) was stirred at 20 °C for 12 hours. The mixture was then concentrated under reduced pressure to give 75 mg of compound B29-9.

[0846] MS(ESI)M / Z: 300.2 [M+H] + .

[0847] 1 H NMR (400MHz, METHANOL-d4) δppm 8.04 (s, 1H), 7.44-7.82 (m, 1H), 5.15 (dt, J=8.34, 4.24Hz, 1H), 4.36 (q, J=7.28Hz, 2H), 3.76 -3.85(m, 1H), 3.65-3.70(m, 1H), 3.26(d, J=12.80Hz, 1H), 3.02(d, J=12.80Hz, 1H), 2.30(br dd, J=13.55, 8.53Hz, 1H), 1.91(br dd, J=13.18, 3.14Hz, 1H), 1.38 (t, J=7.15Hz, 3H), 0.67-0.75 (m, 2H), 0.56-0.62 (m, 1H), 0.34-0.41 (m, 1H).

[0848] Step I: Synthesis of compound B29-10

[0849] To a 1 mL acetonitrile solution of compound B29-9 (75 mg, 223.36 μmol), DIEA (86.60 mg, 670.09 μmol) and compound B29-9a (51.87 mg, 268.04 μmol) were added. The mixture was stirred at 60°C for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 90 mg of compound B29-10.

[0850] MS(ESI)M / Z: 473.2 [M+H] + .

[0851] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.92 (s, 1H), 7.74 (d, J=8.70Hz, 1H), 7.41-7.71 (m, 1H), 7.15 (d, J=1.79Hz, 1H), 7.01 (dd, J =8.70, 1.79Hz, 1H), 4.97-5.11(m, 1H), 4.34(q, J=7.15Hz, 2H), 3.49-3.63(m, 2H), 3.39(br d, J=11.92Hz, 1H), 2.65(br t, J=12.10Hz, 1H), 2.35(br d, J=12.04Hz, 1H), 1.43(br d, J=2.98Hz, 1H), 1.38 (t, J=7.09Hz, 3H), 0.66 (br d, J=6.20Hz, 1H), 0.45-0.56 (m, 3H).

[0852] Step J: Synthesis of compound B29-11

[0853] Tetrahydroxydiboron (102.38 mg, 1.14 mmol) was added to a DMF (2 mL) solution of compound B29-10 (90 mg, 190.34 μmol) and 4,4-bipyridine (8.06 mg, 28.55 μmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with water (10 mL), and then extracted twice with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 90 mg of compound B29-11.

[0854] MS(ESI)M / Z: 443.2 [M+H] + .

[0855] Step K: Synthesis of compound B29-12

[0856] A solution of compound B29-11 (90 mg, 203.22 μmol) and TsOH·H2O (309.25 mg, 1.63 mmol) in acetonitrile (3 mL) was cooled to 0 °C. Then, an aqueous solution of anhydrous potassium iodide (269.88 mg, 1.63 mmol) and sodium nitrite (112.17 mg, 1.63 mmol) (1 mL) was slowly added dropwise to the above reaction solution. The reaction solution was stirred at 20 °C for 2 hours. The reaction solution was diluted with water (10 mL), and then extracted twice with ethyl acetate (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography (0–8% ethyl acetate: n-hexane eluent) to obtain 84 mg of compound B29-12.

[0857] MS(ESI)M / Z: 554.0 [M+H] + .

[0858] 1 H NMR (400MHz, CHLOROFORM-d) δppm 7.91 (s, 1H), 7.41-7.73 (m, 2H), 7.10 (d, J=6.78Hz, 1H), 5.04-5.18 (m, 1H), 4.33 (q, J=7.19Hz, 2H), 3. 44(dt, J=10.73, 1.91Hz, 1H), 3.19-3.29(m, 1H), 3.12-3.19(m, 1H), 2.59(t, J=11.80Hz, 1H), 2.30(br d, J=11.29Hz, 1H), 1.33-1.42(m, 4H), 0.82-0.88(m, 1H), 0.54-0.61(m, 1H), 0.45-0.52(m, 2H)

[0859] Step L: Synthesis of compounds B29-13A & B

[0860] A solution of compound B29-12 (84 mg, 151.69 μmol), compound INT-1 (62.67 mg, 182.03 μmol), Pd(dppf)Cl2 (11.10 mg, 15.17 μmol), anhydrous potassium carbonate (41.93 mg, 303.39 μmol), dioxane (2 mL), and water (0.5 mL) was purged three times with nitrogen. The reaction mixture was then stirred at 90°C under nitrogen for 2 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 90 mg of crude compound. This compound was then separated by chiral separation using SFC (column: Daicel ChiralPak IG (250 × 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 45%, isocrine separation mode) to obtain 40 mg of compound B29-13A (SFC: Rf = 1.467 min) and 50 mg of compound B29-13B (SFC: Rf = 1.828 min).

[0861] MS(ESI)M / Z: 644.2 [M+H] + .

[0862] Step M: Synthesis of compound B29A

[0863] Lithium hydroxide monohydrate (10.42 mg, 248.38 μmol) was added to a mixed solution of compound B29-13A (40 mg, 31.05 μmol) in tetrahydrofuran (4 mL), ethanol (1 mL), and water (1 mL). The reaction solution was stirred at 50°C for 3 hours. After cooling to room temperature, water (2 mL) was added to dilute the reaction solution, and the pH of the reaction solution was adjusted to 3 with 2M dilute hydrochloric acid. The solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column: 52-Welch Ultimate C18 150×30 mm, 5 μm; mobile phase: [H2O (0.05% HCl)-ACN]; gradient: 40%-70% B over 7.0 min) to obtain 3.8 mg of compound B29A hydrochloride.

[0864] MS(ESI)M / Z: 616.2 [M+H] + .

[0865] 1H NMR (400MHz, METHANOL-d4) δppm 7.87 (br s, 1H), 7.37-7.63 (m, 3H), 7.01-7.24 (m, 4H), 4.60-4.77 (m, 1H), 3.86-3.97 (m, 2H), 3.72 (br d, J=10.54Hz, 2H), 3.16-3.29(m, 5H), 3.07-3.16(m, 4H), 2.37-2.50(m, 1H), 2.15-2.31(m, 2H), 1.20-1.32(m, 1H), 1.11(br d, J=6.53Hz, 6H), 0.26-0.42(m, 3H), 0.08-0.20(m, 1H)

[0866] Step N: Synthesis of compound B29B

[0867] Lithium hydroxide monohydrate (15.63 mg, 372.57 μmol) was added to a mixed solution of compound B29-13B (40 mg, 62.10 μmol) in tetrahydrofuran (4 mL), ethanol (1 mL), and water (1 mL). The reaction solution was stirred at 50°C for 3 hours. After cooling to room temperature, water (2 mL) was added to dilute the reaction solution, and the pH of the reaction solution was adjusted to 3 with 2M dilute hydrochloric acid. The solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column: 52-Welch Ultimate C18 150×30 mm, 5 μm; mobile phase: [H2O(0.05% HCl)-ACN]; gradient: 40%-70% B over 7.0 min) to obtain 13.1 mg of compound B29B hydrochloride.

[0868] MS(ESI)M / Z: 616.2 [M+H] + .

[0869] 1H NMR (400MHz, DMSO-d6) δppm 10.16 (br s, 1H), 7.94 (s, 1H), 7.37-7.65 (m, 3H), 7.25 (br d, J=7.03Hz, 1H), 7.21 (br d, J=10.04Hz, 1H), 7.07 (br d, J=8.53Hz, 2H), 4.55-4.67(m, 1H), 3.84(br t, J=11.80Hz, 2H), 3.37-3.52(m, 2H), 3.23-3.31(m, 2H), 3.12-3.22(m, 3H), 2.98-3.10(m, 4H), 2.35(br t, J=11.67Hz, 1H), 2.09-2.22(m, 2H), 1.23(br d, J=10.54Hz, 1H), 1.02(br d, J=6.53Hz, 6H), 0.29-0.41(m, 2H), 0.25(br d, J=4.02Hz, 1H), 0.11 (br d, J=3.76Hz, 1H)

[0870] Example C01 Hydrochloride

[0871] Step C: Synthesis of compound C01-4

[0872] Co1-3a (300 mg, 942.40 μmol), INT2-4 (309.04 mg, 1.13 mmol), Pd2(dba)3 (86.30 mg, 94.24 μmol), Xant Phos (54.53 mg, 94.24 μmol), and Cs2Co3 (921.16 mg, 2.83 mmol) were added to a 5 mL solution of dioxane. Nitrogen gas was purged three times, and the mixture was stirred at 110 °C under nitrogen for 12 hours. After LCMS analysis, the reaction mixture was cooled to room temperature. The solution was dissolved in ethyl acetate and water, and extracted with 300 mL of ethyl acetate (100 mL × 3). The organic phase was washed with 30 mL of water and 30 mL of saturated brine. The organic phases were combined, dried, and concentrated to obtain the crude product. Purification by silica gel column chromatography yielded 170 mg of compound Co1-4.

[0873] MS(ESI)M / Z: 465.0 [M+H] +

[0874] 1H NMR (400MHz, CHLOROFORM-d) δ = 8.05 (d, J = 2.3Hz, 1H), 7.92 (s, 1H), 7.81-7.68 (m, 1H), 7.28 (d, J = 2.4Hz, 1H), 4.98-4.81 (m, 1H), 4.34 (q, J = 7 .1Hz, 2H), 3.65-3.56(m, 1H), 3.49-3.38(m, 1H), 3.24(s, 1H), 2.84-2. 68(m, 1H), 2.27-2.13(m, 2H), 2.04-1.93(m, 2H), 1.38(t, J=7.2Hz, 3H)

[0875] Step D: Synthesis of compound C01-5

[0876] Co1-4 (170.00 mg, 227.30 μmol), INT-1 (86.08 mg, 250.03 μmol), Pd(dppf)Cl2 (16.63 mg, 22.73 μmol), and K2CO3 (94.25 mg, 681.90 μmol) were added to a mixed solution of dioxane (4 mL) and H2O (1 mL). Nitrogen gas was purged three times, and the mixture was stirred at 90 °C for 12 hours under nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, dissolved in ethyl acetate and water, and extracted with 150 mL of ethyl acetate (50 mL × 3). The organic phase was washed with 20 mL of water and 20 mL of saturated brine. The organic phases were combined, dried, and concentrated to obtain the crude product. Purification by silica gel column chromatography yielded 75 mg of compound Co1-5.

[0877] MS(ESI)M / Z: 601.2[M+H] +

[0878] Step E: Synthesis of compound C01

[0879] CO1-5 (70 mg, 116.45 μmol) was dissolved in a mixed solution of THF (1 mL) and MeOH (0.1 mL), and LiOH·H2O (48.87 mg, 1.16 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 6-7 with 2M HCl solution, and the mixture was concentrated under reduced pressure to obtain the crude product. 36.1 mg of compound CO1 hydrochloride was obtained by reverse-phase preparation (column: 20-Welch Ultimate C18 250×50 mm, 5 μm; mobile phase: [H2O (0.05% HCl)-ACN]; gradient: 40%-70% Bover 7.0 min).

[0880] MS(ESI)M / Z: 573.4 [M+H] + .

[0881] 1 H NMR (400MHz, DMSO-d6) δ = 10.13 (br s, 1H), 8.30 (d, J=2.0Hz, 1H), 7.97 (s, 1H), 7.86 (d, J=8.8Hz, 2H), 7.59 (d, J=2.0 Hz, 2H), 7.07 (d, J=8.9Hz, 2H), 4.58-4.53 (m, 1H), 3.99-3.76 (m, 2H), 3.66-3.47 ( m, 2H), 3.42-3.22 (m, 3H), 3.21-3.05 (m, 4H), 3.03-2.95 (m, 2H), 2.70-2.55 (m, 1H ), 2.20-2.08(m, 1H), 2.07-1.89(m, 2H), 1.86-1.55(m, 2H), 1.01(d, J=6.6Hz, 6H)

[0882] Example D11

[0883] Step 1: N,N-diisopropylethylamine (3.49 mL, 21.09 mmol) was added to a dimethyl sulfoxide (DMSO) solution of D11-1 (1 g, 7.03 mmol) and D11-2 (890 mg, 7.73 mmol) in 30 mL. The mixture was stirred at 70 °C for 3 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography. 1.03 g of product D11-3 was obtained.

[0884] MS(ESI)M / Z: 238.2 [M+H] + .

[0885] 1 H NMR (400MHz, DMSO-d6) δ7.65 (dt, J=9.0, 7.9Hz, 1H), 6.66 (dd, J=8.3, 2.7Hz, 1H), 6.25 (dd, J=7.7, 2.8Hz, 1H), 3.66-3.38 (m, 4H), 2.44-2.21 (m, 4H), 2.06 (d, J=7.4Hz, 2H), 1.79 (hept, J=6.8Hz, 1H), 0.88 (d, J=6.6Hz, 6H).

[0886] Step 2: After cooling the acetonitrile (10 mL) solution of D11-3 (1 g, 4.21 mmol) to 0 °C, N-bromosuccinimide (750 mg, 4.21 mmol, 1 eq) was added in portions, and the reaction was carried out for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (30 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (30 mL × 3). The combined organic layers were concentrated under reduced pressure to obtain the residue. The crude product was purified by rapid silica gel chromatography to obtain 1.17 g of product D11-4.

[0887] MS(ESI)M / Z: 316.0, 318.0[M+H] + .

[0888] 1 H NMR (400MHz, DMSO-d6) δ7.84 (t, J=9.1Hz, 1H), 6.68 (dd, J=8.7, 1.8Hz, 1H), 3.46 (t, J=5.1Hz, 4H ), 2.38 (t, J=5.1Hz, 4H), 2.06 (d, J=7.5Hz, 2H), 1.79 (hept, J=6.7Hz, 1H), 0.87 (d, J=6.5Hz, 6H).

[0889] Step 3: To a solution of D11-4 (1.1 g, 3.48 mmol) in 20 mL of 1,4-dioxane (20 mL), add pinacol diboronate (1.33 g, 5.22 mmol), potassium acetate (1.02 g, 10.44 mmol), and Pd(dppf)Cl2 (284.2 mg, 0.35 mmol), followed by nitrogen purging three times. The mixture was stirred at 100 °C for 8 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 460 mg of product D11-5.

[0890] MS(ESI)M / Z: 364.2

[0891] 1 H NMR (400MHz, DMSO-d6) δ7.77 (t, J=8.8Hz, 1H), 6.65 (dd, J=8.4, 3.0Hz, 1H), 3.53 (t, J=5.0Hz, 4H), 2.38 (t, J=5.1Hz, 4H), 2.06 (d, J=7.3Hz, 2H), 1.79 (hept, J=6.8Hz, 1H), 1.26 (s, 12H), 0.87 (d, J=6.5Hz, 6H).

[0892] Step 4: To a solution of INT-2 (100 mg, 0.19 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL), D11-5 (82.8 mg, 0.23 mmol), cesium carbonate (185.7 mg, 0.57 mmol), and XPhos Pd G3 (16 mg, 0.019 mmol) were added, followed by nitrogen purging three times. The mixture was stirred at 100 °C for 3 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel chromatography to obtain 60 mg of product D11-7.

[0893] MS(ESI) M / Z: 619.2

[0894] 1 H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 7.74 (dd, J=10.2, 8.4Hz, 1H), 7.48 (t, J=52.3Hz, 1H), 7.19 (d, J=8.0Hz, 1H ), 7.17-7.08 (m, 2H), 6.75 (dd, J=8.6, 2.0Hz, 1H), 4.38 (dt, J=10.7, 5.7Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 3.51 (t, J =5.0Hz, 4H), 3.13 (d, J = 11.1Hz, 1H), 3.08-2.94 (m, 2H), 2.73-2.61 (m, 1H), 2.42 (t, J = 5.1Hz, 4H), 2.09 (d, J = 7. 4Hz, 2H), 1.98-1.89 (m, 2H), 1.88-1.71 (m, 2H), 1.52-1.39 (m, 1H), 1.28 (t, J=7.1Hz, 3H), 0.89 (d, J=6.6Hz, 6H).

[0895] Step 5: Lithium hydroxide hydrate (40.7 mg, 0.97 mmol) was added to a solution of D11-7 (60 mg, 0.097 mmol) in tetrahydrofuran (5 mL), water (0.5 mL), and methanol (0.5 mL). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction solution was diluted with water (5 mL), the pH was adjusted to 2–3, and the solution was extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative-grade HPLC to obtain 35.91 mg of compound D11.

[0896] MS(ESI)M / Z: 591.2

[0897] 1H NMR (400MHz, DMSO-d6) δ7.87 (s, 1H), 7.81-7.72 (m, 1H), 7.59 (t, J=54.0Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 7 .15 (d, J=6.8Hz, 2H), 6.76 (dd, J=8.5, 2.0Hz, 1H), 4.31 (tt, J=10.1, 4.7Hz, 1H), 3.56 (t, J=5.1Hz, 4H), 3 .08 (dd, J=11.2, 4.1Hz, 1H), 3.00 (t, J=10.3Hz, 2H), 2.76-2.64 (m, 1H), 2.60 (t, J=5.3Hz, 4H), 2.26 (dd, J=7.3, 3.3Hz, 2H), 2.02-1.85 (m, 3H), 1.79 (d, J=13.2Hz, 1H), 1.54-1.37 (m, 1H), 0.91 (d, J=6.5Hz, 6H).

[0898] Example E03A hydrochloride

[0899] Step 1: Dissolve E03A-1 (3.7 g, 18.58 mmol) in dimethyl sulfoxide (40 mL), add (R)-1-BOC-3-hydroxymethylpiperazine (5.02 g, 23.22 mmol) and N,N-diisopropylethylamine (12.01 g, 92.90 mmol), purge three times with nitrogen, and react the solution at 80 °C for 16 hours. After the reaction is complete, cool the reaction solution to room temperature and extract with ethyl acetate (150 mL × 3) and water (150 mL). Wash the organic phase with saturated sodium chloride (150 mL) and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 6 g of product E03A-2.

[0900] MS(ESI)M / Z: 396.2[M+H]+.

[0901] Step 2: Dissolve E03A-2 (3g, 7.59mmol) in methanol (30mL), add sodium borohydride (1.44g, 37.95mmol) under ice bath conditions, purge three times with nitrogen, and react the solution at room temperature for 1 hour. Extract the reaction solution with ethyl acetate (150ml × 3) and saturated ammonium chloride (100ml) solution. Wash the organic phase with saturated sodium chloride (150ml), and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 2.6g of product E03A-3.

[0902] MS(ESI)M / Z: 368.2[M+H]+.

[0903] Step 3: Dissolve E03A-3 (2.7 g, 7.35 mmol) in 50% sulfuric acid (10 mL), and stir the reaction solution at 120 °C for 1 hour. Cool the reaction solution to room temperature, adjust the pH to 10 using sodium hydroxide, and extract with ethyl acetate (100 mL × 3) and water (100 mL). Wash the organic phase with saturated brine (100 mL), and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 1.53 g of product E03A-4.

[0904] MS(ESI)M / Z: 250.2[M+H]+.

[0905] 1 H NMR (400MHz, DMSO-d6) δ8.07 (dd, J=8.9, 2.8Hz, 1H), 8.04 (d, J=2.7Hz, 1H), 7.03 (d, J=9.0Hz, 1H), 4.85-4.65 (m, 2H), 3.81-3.70 (m, 2H), 3.41 (dq, J=13.9, 3.8, 3.4Hz, 2H), 3.26 (ddd, J=12.4, 9.3, 3.2Hz, 1H), 2.94-2.73 (m, 4H), 2.68 (dd, J=12.2, 8.5Hz, 1H).

[0906] Step 4: Dissolve E03A-4 (1.5 g, 6.02 mmol) in tetrahydrofuran (20 mL), then add N,N-diisopropylethylamine (1.17 g, 9.03 mmol) and isobutyraldehyde (1.74 g, 24.08 mmol). Continue stirring at room temperature for 30 minutes, then add sodium triacetoxyborohydride (3.83 g, 18.06 mmol), completely purge with nitrogen, and continue stirring at 50 °C for 4 hours. Cool the reaction solution to room temperature and extract with ethyl acetate (100 mL × 3) and water (100 mL). Wash the organic phase with saturated brine (100 mL) and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 1.63 g of product E03A-5.

[0907] MS(ESI)M / Z: 306.3[M+H]+.

[0908] Step 5: A methanol solution (20 mL) of E03A-5 (1.63 g, 5.34 mmol) was added under nitrogen protection with 10% palladium on carbon (0.57 g, 0.53 mmol). The mixture was then completely purged with hydrogen, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol (80 mL × 3). The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid silica gel chromatography (eluent: 0–7% methanol / dichloromethane) to obtain 1.34 g of product E03A-6.

[0909] MS(ESI)M / Z: 276.3 [M+H] + .

[0910] Step 6: Dissolve E03A-6 (200 mg, 0.73 mmol) in methanol (5 mL), then add hydrochloric acid (1.09 mL, 2 mol / L) under ice bath conditions. Slowly add sodium nitrite (150 mg, 2.19 mmol) dissolved in water (2 mL), and continue stirring under ice bath conditions for 30 minutes. Then add pinacol diboronate (560 mg, 2.19 mmol), purge three times with nitrogen, and stir the reaction mixture at room temperature for 2 hours. Extract the reaction mixture with ethyl acetate (80 mL × 3). Wash the organic phase with saturated brine (70 mL) and dry with anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 120 mg of product E03A-7.

[0911] MS(ESI)M / Z: 387.2 [M+H] + .

[0912] Step 7: Dissolve E03A-7 (110 mg, 0.29 mmol) in a mixed solution of 1,4-dioxane (6 mL) and water (2 mL), then add INT-2 (100 mg, 0.19 mmol), sodium carbonate (60 mg, 0.57 mmol), and tetraphenylphosphine palladium (11 mg, 0.0095 mmol). Purge the mixture three times with nitrogen, and stir at 100 °C for 4 hours. Cool the reaction mixture to room temperature and extract with ethyl acetate (60 mL × 3) and water (60 mL). Wash the organic phase with saturated brine (50 mL) and dry over anhydrous sodium sulfate. Filter, and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by rapid silica gel chromatography to obtain 50 mg of product E03A-8.

[0913] MS(ESI)M / Z: 642.3[M+H]+.

[0914] Step 8: Dissolve E03A-8 (50 mg, 0.078 mmol) in tetrahydrofuran (3 mL) and water (1 mL), then add lithium hydroxide (19 mg, 0.78 mmol), purge with nitrogen, and stir the reaction mixture at room temperature for 16 hours. Adjust the pH of the reaction mixture to 2-3 using 4 mol hydrochloric acid, continue stirring at room temperature for 30 minutes, and extract with ethyl acetate (60 mL × 3). Wash the organic phase with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate, filter, and evaporate to dryness. Purify by pre-HPLC to obtain E03A hydrochloride (20 mg).

[0915] MS(ESI)M / Z: 614.2[M+H]+.

[0916] 1 H NMR (400MHz, DMSO-d6) δ7.87 (s, 1H), 7.53 (dd, J=8.2, 2.1Hz, 1H), 7.43 (t, J=52.3Hz, 1H), 7.41 (d, J=2.1Hz, 1H), 7.15 (d, J =8.2Hz, 1H), 7.08 (dd, J = 8.2, 1.9Hz, 1H), 7.04 (d, J = 2.0Hz, 1H), 7.00 (d, J = 8.3Hz, 1H), 4.96 (d, J = 11.3Hz, 1H), 4.53 (d, J = 11.4Hz, 1H), 4.38-4.26 (m, 1H), 3.61-3.37 (m, 6H), 3.27 (t, J=11.4Hz, 1H), 3.18-3.05 (m, 3H), 3.01 (d, J=7.1Hz, 3H), 2.91 (t, J=10.6Hz, 1H), 2.57 (t, J=11.7Hz, 1H), 2.18-2.04 (m, 1H), 1.93-1.71 (m, 3H), 1.53-1.34 (m, 1H), 0.95 (d, J=6.4Hz, 6H).

[0917] Example E08S hydrochloride

[0918] Step A: Under ice bath conditions, N,N′-dicyclohexylcarbodiimide (16.0 g, 77.3 mmol) was added to a solution of E08S-1 (25.0 g, 77.3 mmol) in dichloromethane (200 mL). After stirring the reaction solution for five minutes, N-benzylglycine ethyl ester (14.9 g, 77.3 mmol) was added. The reaction solution was then brought to room temperature and stirred for another 5 hours. A large amount of white solid precipitated in the reaction solution. The reaction solution was filtered, and the filter cake was washed with dichloromethane (50 mL). The filtrate was concentrated to obtain a colorless liquid product. Methyl tert-butyl ether (20 mL) was added to the product, and the solution was allowed to stand for 10 minutes. After filtration and concentration, 41.4 g of product E08S-2 was obtained.

[0919] MS(ESI)M / Z: 443.2 [M+H-56] + .

[0920] Step B: Add 60 mL of trifluoroacetic acid to a solution of E08S-2 (41.4 g, 83.0 mmol) in 150 mL of dichloromethane and stir at room temperature for 8 hours. Concentrate the reaction solution under reduced pressure, add 150 mL of isopropanol, and stir the mixture in an 80°C oil bath for 2 hours. Concentrate the reaction solution under reduced pressure to obtain a viscous, colorless liquid product. Then add 50 mL of distilled water, followed by dropwise addition of a saturated sodium bicarbonate aqueous solution. A white solid gradually precipitates out until the reaction solution becomes weakly alkaline (pH = 8). Stop adding the saturated sodium bicarbonate aqueous solution, filter and purify to obtain 27 g of product E08S-3.

[0921] MS(ESI)M / Z: 353.2 [M+H] + .

[0922] Step C: Under ice bath conditions, lithium aluminum hydride (8.5 mL, 21.3 mmol, 2.5 M in THF) was added dropwise to a tetrahydrofuran (30 mL) solution of E08S-3 (2.5 g, 7.1 mmol). After the addition was complete, the reaction solution was brought to room temperature and stirred for 10 minutes, then reacted in an oil bath at 70°C for 3 hours. The reaction solution was cooled to room temperature, and sodium hydroxide solution (1 mL, 15%) was added dropwise under ice bath conditions. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was then passed through a rapid silica gel column chromatography column to obtain 1.05 g of product E08S-4.

[0923] MS(ESI)M / Z: 221.2[M+H] + .

[0924] 1 H NMR (400MHz, DMSO-d6) δ7.45-7.08 (m, 5H), 3.51-3.37 (m, 4H), 2.78 (dt, J=11.7, 2.7Hz, 1H), 2.76-2. 54 (m, 4H), 1.89 (td, J=10.7, 3.1Hz, 1H), 1.64 (t, J=10.1Hz, 1H), 1.38 (ddt, J=16.4, 13.6, 7.1Hz, 2H).

[0925] Step D: Di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) was added to a solution of E08S-4 (1.0 g, 4.5 mmol) in 20 mL of dichloromethane, and the mixture was stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure to obtain a crude product, which was then passed through a rapid silica gel column chromatography column to yield 1.3 g of product E08S-5.

[0926] MS(ESI)M / Z: 321.2[M+H] + .

[0927] 1 H NMR (400MHz, DMSO-d6) δ7.66-6.98 (m, 5H), 4.31 (t, J=5.2Hz, 1H), 4.07 (s, 1H), 3.73 (d, J=13.2Hz, 1H), 3.51 (d, J=13.4Hz, 1H), 3.37 (d, J=13 .4Hz, 1H), 3.30-3.21 (m, 1H), 2.95 (s, 1H), 2.73 (ddt, J=11.1, 3.5, 1.9Hz, 1H), 2.65 (dt, J=11.4, 1.9Hz, 1H), 1.97-1.70 (m, 4H), 1.38 (s, 9H).

[0928] Step E: At -78°C, oxalyl chloride (0.79 g, 6.24 mmol) was added dropwise to a 30 mL solution of dichloromethane containing dimethyl sulfoxide (0.73 g, 9.36 mmol). The reaction mixture was stirred for 15 minutes. Then, a 15 mL solution of dichloromethane containing E08S-5 (1.0 g, 3.12 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour. Then, triethylamine (1.58 g, 15.6 mmol) was added. The reaction mixture was stirred at -78°C for 15 minutes, then gradually raised to 0°C and stirred for another hour. The reaction mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.74 g of product E08S-6.

[0929] MS(ESI)M / Z: 319.2 [M+H] + .

[0930] 1 H NMR (400MHz, Chloroform-d) δ9.74 (t, J=2.3Hz, 1H), 7.37-7.24 (m, 5H), 4.65-4.54 (m, 1H), 3.96-3.80 (m, 1H), 3.53 (d, J=13.2Hz, 1H) , 3.44(d, J=13.1Hz, 1H), 3.15-3.00(m, 1H), 2.91-2.74(m, 3H), 2.74-2.65(m, 1H), 2.27-2.18(m, 1H), 2.13-1.97(m, 1H), 1.44(s, 9H).

[0931] Step F: At -78°C, n-butyllithium (1.3 mL, 3.32 mmol, 1 eq) in tetrahydrofuran (18 mL) was added dropwise. The reaction mixture was stirred at -78°C for 0.5 hours to obtain aryllithium reagent. At -78°C, E08S-6 (0.53 g, 1.66 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 820 mg of crude product E08S-7.

[0932] MS(ESI)M / Z: 493.2, 495.2[M+H] + .

[0933] Step H: At -78°C, oxalyl chloride (0.63 g, 4.98 mmol) was added dropwise to a 35 mL solution of dichloromethane containing dimethyl sulfoxide (0.52 g, 6.64 mmol). The reaction mixture was stirred for 15 minutes. Then, a 5 mL solution of dichloromethane containing E08S-7 (0.82 g, 1.06 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour. Then, triethylamine (0.84 g, 8.3 mmol) was added. The reaction mixture was stirred at -78°C for 15 minutes, then gradually raised to 0°C and stirred for another hour. The reaction mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.6 g of product E08S-8.

[0934] MS(ESI)M / Z: 491.2 [M+H] + .

[0935] 1H NMR (400MHz, Chloroform-d) δ7.84 (dd, J=6.4, 2.6Hz, 1H), 7.61 (dt, J=7.6, 3.5Hz, 1H), 7. 25-7.21 (m, 5H), 7.05 (dd, J=10.4, 8.7Hz, 1H), 4.80-4.59 (m, 1H), 4.00-3.77 (m, 1H), 3.60 (ddd, J=16.1, 8.0, 2.6Hz, 1H), 3.52 (d, J=13.2Hz, 1H), 3.40 (d, J=13.1Hz, 1H), 3.22-3.04 (m, 2H), 2.82-2.64 (m, 2H), 2.18 (dd, J=11.5, 3.5Hz, 1H), 2.12-2.03 (m, 1H), 1.37 (s, 9H).

[0936] 19 F NMR (376MHz, CDCl3) δ-112.38, -112.58.

[0937] Step I: At room temperature, add 2 mL of trifluoroacetic acid to a solution of E08S-8 (0.6 g, 1.22 mmol) in 10 mL of dichloromethane. Continue stirring the reaction solution overnight at room temperature. Concentrate the reaction solution under reduced pressure to obtain 0.62 g of product E08S-9. The product does not require purification.

[0938] MS(ESI)M / Z: 391.0 [M+H] + .

[0939] 1 H NMR (400MHz, Chloroform-d) δ7.93 (dd, J=6.3, 2.6Hz, 1H), 7.71 (ddd, J=8.7, 4.3, 2.5Hz, 1H), 7.55-7.39 (m, 5H), 7. 08 (dd, J=10.8, 8.8Hz, 1H), 4.48 (s, 1H), 4.38 (s, 2H), 4.00-3.89 (m, 1H), 3.86-3.71 (m, 5H), 3.48 (d, J=5.1Hz, 2H).

[0940] Step J: Cesium carbonate (1.99 g, 6.1 mmol) was added to a solution of N,N-dimethylacetamide (25 mL) containing E08S-9 (0.62 g, 1.22 mmol). The reaction solution was reacted in an oil bath at 70°C for 1 hour. The reaction solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water (50 mL x 3), then with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.35 g of product E08S-10.

[0941] MS(ESI)M / Z: 371.0 [M+H] + .

[0942] 1 H NMR (400MHz, Chloroform-d) δ8.02 (d, J=2.6Hz, 1H), 7.48 (dd, J=9.0, 2.6Hz, 1H), 7.38-7.28 (m, 5H), 6.77 (d, J=9.1Hz, 1H), 3.76-3.66 (m, 1 H), 3.60 (s, 2H), 3.51 (s, 1H), 3.05 (d, J=11.4Hz, 1H), 3.01-2.85 (m, 2H), 2.60-2.50 (m, 2H), 2.40 (d, J=12.2Hz, 1H), 2.15 (t, J=10.7Hz, 1H).

[0943] Step K: At room temperature, triethylsilane (1 mL) was added dropwise to a trifluoroacetic acid (7 mL) solution of E08S-10 (0.35 g, 0.94 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid, and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed first with saturated sodium bicarbonate aqueous solution (30 mL × 2), then with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.33 g of product E08S-11.

[0944] MS(ESI)M / Z: 357.2 [M+H] + .

[0945] 1H NMR (400MHz, Chloroform-d) δ7.38-7.26 (m, 5H), 7.14 (dd, J=8.8, 2.5Hz, 1H), 7.09-7.04 (m, 1H), 6 .62 (d, J=8.8Hz, 1H), 3.66 (dt, J=11.9, 2.8Hz, 1H), 3.57 (t, J=9.5Hz, 2H), 3.06 (brs, 1H), 2.96 (d, J=11.2Hz, 1H), 2.92-2.76 (m, 3H), 2.65 (ddd, J=16.2, 5.2, 3.6Hz, 1H), 2.26 (t, J=11.3Hz, 1H), 1.9 5(t, J=10.7Hz, 1H), 1.83 (ddt, J=13.1, 5.9, 3.6Hz, 1H), 1.70 (dddd, J=13.0, 11.5, 9.9, 5.5Hz, 1H).

[0946] Step L: Under ice bath conditions, 2-chloropropionyl chloride (0.14 g, 1.12 mmol) was added dropwise to a solution of E08S-11 (0.2 g, 0.56 mmol) in 1,2-dichloroethane (15 mL). After the addition was complete, the reaction solution was reacted in an oil bath at 85°C for 2.5 hours. The reaction solution was concentrated, and then methanol (10 mL) was added. The reaction solution was then reacted in an oil bath at 70°C for 1.5 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.1 g of product E08S-12.

[0947] MS(ESI)M / Z: 267.2 [M+H] + .

[0948] 1 H NMR (400MHz, Chloroform-d) δ7.17 (dd, J=8.8, 2.4Hz, 1H), 7.09 (d, J=2.4Hz, 1H), 6.63 (d, J=8.9Hz, 1H), 4.88 (brs, 1H), 3.76 (dd, J=11.0, 3.0 Hz, 1H), 3.33-3.26 (m, 1H), 3.21-3.07 (m, 2H), 3.07-2.91 (m, 2H), 2.89 -2.77(m, 1H), 2.77-2.61(m, 2H), 1.97-1.85(m, 1H), 1.83-1.64(m, 1H).

[0949] Step M: N,N-diisopropylethylamine (0.143 g, 1.11 mmol) was added to a solution of E08S-12 (0.1 g, 0.37 mmol) and isobutyraldehyde (80 mg, 1.11 mmol) in dichloromethane (10 mL). After stirring at room temperature for 10 minutes, sodium borohydride acetate (0.24 g, 1.11 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 0.11 g of product E08S-13. MS (ESI) M / Z: 323.2 [M+H] + .

[0950] 1 H NMR (400MHz, Chloroform-d) δ7.14 (dd, J=8.8, 2.5Hz, 1H), 7.07 (d, J=2.5Hz, 1H), 6.63 (d, J=8.9Hz, 1H), 3.69-3.57 (m, 1H), 3. 04 (s, 1H), 2.97-2.75 (m, 4H), 2.66 (ddd, J=16.2, 5.4, 3.5Hz, 1H), 2.29-2.01 (m, 3H), 1.95-1.69 (m, 4H), 0.92 (d, J=6.7Hz, 6H).

[0951] Step N: Add E08S-13 (0.11 g, 0.34 mmol), pinacol diborate (0.13 g, 0.51 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (42 mg, 51 μmol), potassium acetate (0.13 g, 1.36 mmol), and 1,4-dioxane (15 mL) to a flask. React the solution in an oil bath at 90 °C for 5 hours. Then, extract the solution with ethyl acetate (30 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Pass the crude product through a rapid silica gel column chromatography column to obtain 90 mg of compound E08S-14.

[0952] MS(ESI)M / Z: 371.2 [M+H] + .

[0953] Step O: Potassium phosphate (0.153 g, 0.72 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (19.6 mg, 24.0 μmol) were added to a mixture of E08S-14 (90 mg, 0.24 mmol), INT-2 (0.13 g, 0.24 mmol), dioxane (9 mL), and water (3 mL). The reaction mixture was degassed, purged with nitrogen three times, and then stirred in an oil bath at 90°C for 6 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 60 mg of product E08S-15.

[0954] MS(ESI)M / Z: 626.2 [M+H] + .

[0955] 1 H NMR (400MHz, Chloroform-d) δ7.88 (s, 1H), 7.48 (t, J=52.8Hz, 1H), 7.34 (d, J=9.4Hz, 1H), 7.21 (s, 1H), 7.13 (d, J=8.1Hz, 1H), 7.01 (dd, J=8.1, 2.1Hz, 1H), 6.97 (d, J=2.1Hz, 1H), 6.83 (d, J=8.7Hz, 1H), 4.72-4.54 (m, 1H), 4.32 (q, J=7.1Hz, 2H), 3.78 (d, J =11.5Hz, 1H), 3.47-3.31(m, 1H), 3.21-3.07(m, 3H), 3.00-2.81(m, 4H), 2.79-2.69(m, 1H), 2.61-2.43(m, 1H), 2.26-2.06(m, 3 H), 2.02-1.96 (m, 1H), 1.95-1.77 (m, 4H), 1.75-1.67 (m, 1H), 1.64-1.50 (m, 2H), 1.36 (t, J=7.1Hz, 3H), 0.94 (d, J=6.8Hz, 6H).

[0956] Step P: Lithium hydroxide monohydrate (40.3 mg, 0.96 mmol) was added to a mixture of tetrahydrofuran (6 mL), methanol (2 mL), water (2 mL), and the mixture of E08S-15 (60 mg, 96 μmol). The reaction mixture was then stirred at room temperature for 12 hours. The pH of the reaction solution was adjusted to 3 with 2N hydrochloric acid, and then extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was then subjected to preparative-grade HPLC (acidic conditions, 0.1% HCl, column: YMC-Actutus Triart C18 ExRS) to obtain 13.8 mg of solid E08S hydrochloride.

[0957] 1 H NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.51 (t, J=52.4Hz, 1H), 7.36 (dd, J=8.7, 2.2Hz, 1H), 7.26 (s, 1H), 7.16 (d, J=8.2Hz, 1H), 7.10 (d d, J=8.1, 2.0Hz, 1H), 7.07 (d, J=2.1Hz, 1H), 6.97 (d, J=8.8Hz, 1H), 4.55-4.41 (m, 1H), 4.11 (d, J=12.5Hz, 1H), 3.60 (t, J=12.5Hz, 2H), 3.51-3.45 (m, 1H), 3.28-3.17 (m, 2H), 3.17-3.03 (m, 3H), 3.00 (d, J=7.7Hz, 2H), 2.92-2.78 (m, 2H), 2.77-2.65 (m, 1H), 2.60 (t, J=11.5 Hz, 1H), 2.17 (hept, J=6.8Hz, 1H), 2.06-1.85 (m, 3H), 1.82-1.73 (m, 1H), 1.72-1.61 (m, 1H), 1.58-1.45 (m, 1H), 1.02 (t, J=6.6Hz, 6H).

[0958] 19 F NMR (376MHz, DMSO) δ-112.95, -113.78, -114.19, -115.03.

[0959] MS(ESI)M / Z: 598.2 [M+H] + .

[0960] Example E21R Formate

[0961] Step A: Cesium carbonate (42.5 g, 0.13 mol) was added to a solution of E21R-1 (15 g, 65.1 mmol) and E21R-1a (15.8 g, 71.7 mmol) in 200 mL of dimethyl sulfoxide. The mixture was stirred in an oil bath at 110 °C for 2 hours. After cooling to room temperature, the reaction solution was adjusted to pH 3 with HCl (2N), and then extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with water (100 mL x 3), then with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 29 g of compound E21R-2.

[0962] MS(ESI)M / Z: 374.0 [M+H-56] + .

[0963] 1 H NMR (400MHz, Chloroform-d) δ7.95 (d, J=2.4Hz, 1H), 7.60 (dd, J=8.8, 2.4Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.45 (dt, J=13.4, 2 .1Hz, 1H), 4.08-3.92(m, 2H), 3.80-3.67(m, 1H), 3.47-3.39(m, 1H), 3.19-3.06(m, 1H), 2.93(d, J=11.7Hz, 1H), 1.44(s, 9H).

[0964] Step B: Iron powder (18.8 g, 0.34 mol) was added to a solution of E21R-2 (29 g, 67.4 mmol) in acetic acid (200 mL), and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was first concentrated under reduced pressure to remove a large amount of acetic acid, and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with water (200 mL), then with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain the crude product, which was further purified to obtain 16 g of compound E21R-3.

[0965] MS(ESI)M / Z: 326.0, 328.0[M+H-56] + .

[0966] 1H NMR (400MHz, Chloroform-d) δ8.58 (brs, 1H), 7.12 (dd, J=8.6, 2.2Hz, 1H), 6.92 (d, J=2.2Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 4.73-4 .49 (m, 1H), 4.25 (d, J=13.2Hz, 1H), 3.63-3.40 (m, 2H), 3.00 (q, J=14.4, 13.6Hz, 2H), 2.75 (td, J=11.9, 3.6Hz, 1H), 1.49 (s, 9H).

[0967] Step C: Under ice bath conditions, iodomethane (2.9 g, 20.2 mmol) was added to a solution of E21R-3 (3.86 g, 10.1 mmol) and cesium carbonate (6.6 g, 20.2 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was then gradually brought to room temperature and stirred for 2 hours. The reaction mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The organic phases were washed with water (100 mL x 3), then with saturated brine (50 mL). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography (eluting buffer: 0-15% ethyl acetate / petroleum ether) to obtain 4 g of compound E21R-4.

[0968] MS(ESI)M / Z: 340.2 [M+H-56] + .

[0969] 1 H NMR (400MHz, Chloroform-d) δ7.16 (dd, J=8.6, 2.2Hz, 1H), 7.08 (d, J=2.1Hz, 1H), 6.67 (d, J=8.6Hz, 1H), 4.63 (d, J=13.6Hz, 1H), 4.25 (d, J=13.3Hz, 1H), 3.48 (dt, J=11.1, 2.6Hz, 1H), 3.42-3.31 (m, 4H), 2.99 (q, J=13.3, 12.6Hz, 2H), 2.73 (td, J=11.8, 3.7Hz, 1H), 1.48 (s, 9H).

[0970] Step D: Borane dimethyl sulfide (19 mL, 38 mmol, 2 M) was added to a tetrahydrofuran (25 mL) solution of E21R-4 (3 g, 7.6 mmol), and the reaction mixture was stirred in an oil bath at 60°C for 2 hours. The reaction was quenched with methanol, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 22 g of compound E21R-5.

[0971] MS(ESI)M / Z: 382.0 [M+H] + .

[0972] 1 H NMR (400MHz, Chloroform-d) δ6.74 (dt, J=8.5, 1.9Hz, 1H), 6.61 (d, J=2.0Hz, 1H), 6.51 (dd, J=8.5, 2.0Hz, 1H), 4.26-3. 91 (m, 2H), 3.58 (d, J=12.0Hz, 1H), 3.37-3.09 (m, 2H), 3.09-2.94 (m, 2H), 2.84 (s, 3H), 2.78-2.55 (m, 2H), 1.48 (s, 9H).

[0973] Step E: Add 5 mL of trifluoroacetic acid to a solution of E21R-5 (2.2 g, 5.8 mmol) in 15 mL of dichloromethane, and stir at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure to obtain 2.5 g of crude product E21R-6. Use directly in the next step.

[0974] MS(ESI)M / Z: 282.0 [M+H] + .

[0975] Step F: Under ice bath conditions, sodium borohydride acetate (3.7 g, 17.4 mmol) was added to a solution of E21R-6 (1.64 g, 5.8 mmol) and isobutyraldehyde (1.26 g, 17.4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.7 g of crude product E21R-7.

[0976] MS(ESI)M / Z: 338.2 [M+H] + .

[0977] 1 H NMR (400MHz, Chloroform-d) δ6.72 (d, J=8.5Hz, 1H), 6.58 (d, J=2.2Hz, 1H), 6.50 (d, J=8.5Hz, 1H), 3.53 (d, J=11.5Hz, 1H ), 3.36-3.03(m, 3H), 3.05-2.90(m, 1H), 2.90-2.69(m, 5H), 2.27-2.03(m, 3H), 1.92-1.73(m, 2H), 0.92(d, J=6.6Hz, 6H).

[0978] Step G: At -78°C, n-butyllithium (2 mL, 5.14 mmol, 2.5 M) was added dropwise to a tetrahydrofuran (40 mL) solution of E21R-7 (0.87 g, 2.57 mmol). The reaction was stirred at -78°C for another half hour, followed by the addition of isopropanol pinacol borate (0.96 g, 5.14 mmol). The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography to obtain 0.86 g of compound E21R-8.

[0979] MS(ESI)M / Z: 386.2 [M+H] + .

[0980] 1 H NMR (400MHz, Chloroform-d) δ7.18 (dd, J=8.0, 1.4Hz, 1H), 6.97 (d, J=1.5Hz, 1H), 6.68 (d, J=8.0Hz, 1H), 3.69 (d, J=11.6Hz, 1H), 3. 47-3.21 (m, 1H), 3.17-3.07 (m, 2H), 3.00-2.76 (m, 6H), 2.27-2.04 (m, 3H), 1.93-1.73 (m, 2H), 1.32 (s, 12H), 0.92 (d, J=6.5Hz, 6H).

[0981] Step H: Potassium phosphate (1.05 g, 4.95 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.12 g, 0.17 mmol) were added to a mixture of E21R-8a (0.88 g, 1.65 mmol), INT-2 (0.7 g, 1.81 mmol), dioxane (25 mL), and water (8 mL). The reaction mixture was degassed, purged with nitrogen three times, and then stirred in an oil bath at 90°C for 4 hours. The reaction mixture was then extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography to obtain 0.94 g of compound E21R-9.

[0982] MS(ESI)M / Z: 641.2 [M+H] + .

[0983] 1H NMR (400MHz, Chloroform-d) δ7.89 (s, 1H), 7.50 (t, J=52.8Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 7.00 (dd, J=8.1, 2.1Hz, 1H ), 6.95 (d, J=2.1Hz, 1H), 6.92 (s, 1H), 6.86 (d, J=8.2Hz, 1H), 6.71 (d, J=8.2Hz, 1H), 4.78-4.61 (m, 1H), 4.32 (q, J=7. 1Hz, 2H), 3.67 (d, J=11.5Hz, 1H), 3.49-3.37 (m, 1H), 3.31-3.09 (m, 5H), 3.02-2.78 (m, 6H), 2.53-2.38 (m, 1H), 2.27- 2.05 (m, 4H), 2.02-1.91 (m, 1H), 1.90-1.78 (m, 2H), 1.71-1.52 (m, 2H), 1.36 (t, J=7.1Hz, 3H), 0.94 (d, J=6.5Hz, 6H).

[0984] Step I: Lithium hydroxide monohydrate (0.31 g, 7.35 mmol) was added to a mixture of tetrahydrofuran (15 mL), methanol (5 mL), water (5 mL), and E21R-9 (0.94 g, 1.47 mmol). The reaction mixture was then stirred at room temperature for 12 h. The pH of the reaction mixture was adjusted to 3 with formic acid, and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the crude product was passed through a rapid silica gel column (eluent containing 0.5% formic acid) to give 0.68 g of compound E21R formate.

[0985] MS(ESI)M / Z: 613.2 [M+H] + .

[0986] 1H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.54 (t, J=52.4Hz, 1H), 7.18 (d, J=7.9Hz, 1H), 7.14-7.05 (m, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 6.78 (s, 2H), 4.55 (tt, J=9.9, 4.0Hz, 1H), 3.86 (d, J=11.4Hz, 1H), 3. 46-3.19(m, 5H), 3.18-2.98(m, 3H), 2.95-2.86(m, 1H), 2.84(s, 3H), 2.72-2.56(m, 4H), 2.40-2.28 (m, 1H), 2.10-1.82 (m, 2H), 1.77 (d, J=12.9Hz, 1H), 1.64-1.44 (m, 1H), 0.95 (dd, J=6.6, 2.0Hz, 6H).

[0987] 19 F NMR (376MHz, DMSO) δ-112.98, -113.82, -114.02, -114.86.

[0988] The configuration of E21R was confirmed by single-crystal X-ray diffraction, as follows:

[0989] Instrument parameters:

[0990] Equipment number: CAS-TJ-SCXRD-01;

[0991] Instrument: Rigaku Oxford Diffraction XtaLAB Synergy-S;

[0992] Detector: HyPix-6000HE area detector;

[0993] Cryogenic system: Oxford Cryostream 800;

[0994] Light source: Micro-focus sealed X-ray tube, Cu Kα

[0995] Phototube voltage: 50kV, phototube current: 1mA.

[0996] Experimental Section: Free compound E21R was precipitated as a crystal in methanol-dichloromethane (v:v, 1:2). A crystal measuring 0.2 × 0.1 × 0.05 mm was selected. 3The single crystal was tested. The diffraction experiment temperature T = 150.01(11)K. The diffraction collection range 2θ = 5.798 to 133.104°, and the diffraction index range -17≤h≤17, -8≤k≤8, -19≤1≤20. A total of 24490 diffraction points were collected in the diffraction experiment, of which 5360 were independent diffraction points (Rint = 0.1091). With the assistance of Olex2 (Dolomanov, OV, Bouhrhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, H. (2009), J. Appl. Cryst. 42, 339-341), the structure was analyzed using SHELXT (Sheldrick, GM2015. ActaCryst. A71, 3-8), and SHELXL (against F) was used. 2 (Sheldrick, GM2015. ActaCryst. C71, 3-8) The structure was refined using this method. Of the 5360 independent diffraction points, 391 parameters participated in the structure refinement. After refinement, the structure was based on F... 2 The goodness of fit is 1.081, R1 = 0.1108 and wR2 = 0.2407 for I >= 2σ(I). The residual electron density values ​​are 0.96 and

[0997] Experimental conclusion: The detected crystal belongs to the monoclinic crystal system, space group P21. Cell parameters. α=90°, β=115.517(5)°, γ=90°, Z = 2. The calculated density Dc = 1.287 g / cm³, the linear absorption coefficient μ(Cu Kα) of the unit cell = 1.489 mm⁻¹, and the number of electrons in the unit cell F(000) = 648.0. The absolute configuration was determined based on anomalous scattering, with a Flack parameter of 0.034 (13). The structure of the tested crystal was determined as follows:

[0998] The molecular structure ellipsoid diagram of E21R is shown in Figure 2.

[0999] Example E21s

[1000] E21S was prepared using E21S-1 as the raw material, referring to the preparation process of E21R.

[1001] MS(ESI)M / Z: 613.2 [M+H] + .

[1002] 1H NMR (400MHz, DMSO-d6) δ7.85 (s, 1H), 7.59 (t, J=52.7Hz, 1H), 7.14 (d, J=8.2Hz, 1H), 7.05 (dd, J=8.2, 2.0 Hz, 1H), 6.97 (d, J = 2.2Hz, 1H), 6.89 (s, 1H), 6.73-6.63 (m, 2H), 4.57-4.45 (m, 1H), 3.70 (d, J = 13.9Hz, 1H) , 3.29-3.13 (m, 3H), 3.09-2.96 (m, 5H), 2.81 (s, 3H), 2.70 (dd, J=18.0, 7.4Hz, 1H), 2.43 (d, J=11.9Hz, 1H) , 2.29-2.19 (m, 3H), 2.00-1.81 (m, 4H), 1.68 (d, J = 12.9Hz, 1H), 1.53-1.41 (m, 1H), 0.88 (d, J = 6.5Hz, 6H).

[1003] Example E29R hydrochloride

[1004] Step A: E29R-1 was obtained by referring to the synthesis method of E17R-4. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 130.41 μmol) was added to a solution of E29R-1 (50 mg, 84.74 μmol) and isobutyric acid (15 mg, 170.25 μmol) in pyridine (1 mL). The mixture was stirred at 50 °C for 1 h. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a rapid silica gel column chromatography column to obtain 60 mg of compound E29R-2.

[1005] MS(ESI)M / Z: 660.3 [M+H] + .

[1006] Step B: Lithium hydroxide monohydrate (20 mg, 476.60 μmol) was added to a mixed solution of E29R-2 (60 mg, 90.89 μmol) in tetrahydrofuran (1 mL), water (0.2 mL), and methanol (0.1 mL). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and subjected to preparative-grade HPLC (column: 52-Welch Xtimate C18 150 × 30 mm, 5 μm; mobile phase: [H2O (0.05% HCl)-ACN]; gradient: 60%-90% B, 7.0 min) to give 13.76 mg of compound E29R hydrochloride.

[1007] MS(ESI)M / Z: 632.1 [M+H] + .

[1008] 1 H NMR (400MHz, METHANOL-d4) δppm 7.85-7.37 (m, 2H), 7.31-6.75 (m, 5H), 4.70 (br d, J=12.0Hz, 1H), 4.59 (br d, J=12.4Hz, 1H), 4.43-4.31(m, 1H), 4.27-4.13(m, 1H), 4.09-3.85(m, 3H), 3.52-3.36(m, 1H), 3.20-3.02(m, 3H), 2.99-2.74(m, 2H), 2.74-2.50(m, 2H), 2.24-1.79(m, 4H), 1.18-1.11(m, 6H).

[1009] Example E48R

[1010] Compound E48R was prepared by referring to Example E29R.

[1011] MS(ESI)M / Z: 633.2 [M+H] + .

[1012] 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.68-7.37 (m, 1H), 7.22-7.17 (m, 2H), 7.13-7.07 (m, 1H), 7.0 5 (d, J=2.0Hz, 1H), 6.93 (d, J=8.7Hz, 1H), 4.53-4.42 (m, 1H), 4.34 (dd, J=2.5, 10.6Hz, 1H), 3.94 (br dd, J=9.1, 10.6Hz, 1H), 3.80(br s, 1H), 3.65-3.55 (m, 2H), 3.21-3.14 (m, 1H), 3.10-2.89 (m, 4H), 2.80 (s, 6H), 2.73-2.64 (m, 1H), 2.61-2.52 (m, 2H), 2.03-1.84 (m, 2H), 1.80-1.71 (m, 1H), 1.52 (q, J=12.7Hz, 1H)

[1013] Example E41R

[1014] Step 1: At -78°C, 0.6 mL of butyllithium (1.58 mmol) was added to a 25 mL solution of E21R-5 (0.4 g, 1.1 mmol) in tetrahydrofuran. After half an hour, 0.39 g of 2.1 mmol of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane was added, and the reaction mixture was stirred at -78°C for 2 hours. The reaction mixture was then extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography to obtain 320 mg of compound E41R-6.

[1015] MS(ESI)M / Z: 430.2 [M+H] + .

[1016] 1 H NMR (400MHz, Chloroform-d) δ7.36 (s, 1H), 7.26 (s, 1H), 6.90-6.70 (m, 1H), 4.16-4.03 (m, 2H) , 3.76 (s, 1H), 3.49-3.05 (m, 4H), 3.01 (s, 3H), 2.91-2.67 (m, 2H), 1.48 (s, 9H), 1.32 (s, 12H).

[1017] Step 2: Potassium phosphate (0.48 g, 2.25 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (55 mg, 75 μmol) were added to a mixture of E41R-6 (0.32 g, 0.75 mmol), INT-2 (0.4 g, 0.75 mmol), dioxane (25 mL), and water (8 mL). The reaction mixture was degassed, purged three times with nitrogen, and then stirred in an oil...

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; in: Ring A is selected from 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; Ring B is selected from 5 to 10-membered heteroaryl, 3 to 10-membered monocyclic heterocyclic, 5 to 14-membered spirocyclic, 5 to 14-membered bridged heterocyclic and 5 to 14-membered fused heterocyclic; The ring C is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups; Ring D is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic groups; Ring E is selected from 3- to 10-membered monocyclic heterocyclic groups, 5- to 14-membered spirocyclic heterocyclic groups, 5- to 14-membered bridged heterocyclic groups, and 5- to 14-membered fused heterocyclic groups; R is selected from hydrogen atom, deuterium atom, deuterated C. 1-6 Alkyl, C 1-6 Alkyl and Halogenated C 1-6 alkyl; R a R b R c R d R e They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, -NR n1 R n2 Halogen, cyano, hydroxyl, -SR s -C(O)NR n1 R n2 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently selected from a deuterium atom, a deuterated C atom, or a cycloalkyl group. 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or two R atoms on adjacent ring atoms a Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. b Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. c Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. d Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; or two R atoms on adjacent ring atoms. e Together with the atoms attached to them, they form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkyl groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 -C(O)NR n3 R n4 -SR s -C(O)R s -S(O) q R s -S(O)2NR n1 hydroxyl, hydroxyC 1-6 It is substituted by one or more substituents selected from alkyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R a R b R c R d and R e Any two atoms in the group and the atoms bonded to them together form a 3- to 20-membered heterocyclic group, a 3- to 20-membered cycloalkyl group, a 3- to 20-membered cycloalkenyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the 3- to 20-membered heterocyclic group, the 3- to 20-membered cycloalkyl group, the 3- to 20-membered cycloalkenyl group, the 6- to 10-membered aryl group, and the 5- to 10-membered heteroaryl group are each independently and optionally selected from a deuterium atom, a deuterated C atom, or a deuterated C atom. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; R n1 R n2 R n3 and R n4 They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy; R s They may be the same or different each time they appear, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; n is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; p is 0, 1, 2 or 3; t can be 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4; and q can be 0, 1, or 2.

2. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, wherein, Ring A is selected from 5- to 6-membered heteroaryl groups containing 1-3 N atoms or from 5- to 6-membered heterocyclic groups containing 1- to 3 N atoms; and / or R a Selected from hydrogen atoms or halogenated C atoms 1-4 Alkyl; and / or m is 0 or 1; and / or R is selected from hydrogen atoms and C. 1-4 Alkyl group, preferably with hydrogen atoms.

3. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1 or 2, wherein, Selected from 4. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the compound is a compound of general formula (II) or general formula (IIa), its stereoisomer, or its pharmaceutically acceptable salt: in: x 1 Selected from N or CR x1 ; x 2 Selected from N or CR x2 ; x 3 Selected from N or CR x3 ; x 4 Selected from N or CR x4 ; x 5 Selected from N or CR x5 ; x 6 Selected from N or CR x6 ; x 7 Selected from N or CR x7 ; x 8 Selected from N or CR x8 ; R x1 R x2 R x3 R x4 R x5 R x6 R x7 R x8 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl and Halogenated C 1-6 Alkoxy; R e1 R e2 They may be the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, and deuterated C atoms. 1-6 Alkyl, deuterated C 1-6 Alkoxy, C 1-6 Alkyl, halogen, cyano, -NR n1 R n2 C 1-6 Alkoxy, hydroxy, hydroxy C 1-6 Alkyl, -SR s -C(O)NR n1 R n2 -S(O) q R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R s Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups; Or R x2 and R x3 R x2 and R x1 R x3 and R x4 These atoms, together with the atoms attached to them, form 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 3- to 10-membered heterocyclic groups, 3- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from deuterium atoms, deuterated C atoms, etc. 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R x5 and R x4 Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more of the following substituents: alkynyl, 3 to 8-membered heterocyclic, 3 to 8-membered cycloalkyl, 3 to 8-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R x6 And one of the R e2 Together with the atoms bonded to them, they form a ring F; the ring F is arbitrarily bounded by z R atoms. f replace; Ring F is selected from 5- to 10-membered heterocyclic groups and 5- to 10-membered heteroaryl groups; R f Selected from deuterium atoms and deuterated C 1-6 Alkyl, halogen, oxo group, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 Alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; Or R x8 And one of the R b Together with the atoms bonded to them, they form 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, or 5- to 10-membered heteroaryl groups; wherein the 5- to 10-membered heterocyclic groups, 5- to 10-membered cycloalkenyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups are each independently selected from halogens, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, -NR n3 R n4 hydroxyl, hydroxyC 1-6 Alkyl, -SR s -C(O)NR n3 R n4 -C(O)R s -S(O) u R s -S(O)2NR n1 C 2-6 alkenyl, C 2-6 It is substituted by one or more substituents selected from alkynyl, 3 to 10-membered heterocyclic, 3 to 10-membered cycloalkyl, 3 to 10-membered cycloalkenyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; z can be 0, 1, 2, 3, or 4; Ring B, Ring E, R b R n1 R n2 R n3 R n4 R s n, u, q are as defined in claim 1.

5. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein, Ring B is selected from 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 8-membered bridged heterocyclic, 5- to 8-membered fused heterocyclic, 5- to 8-membered spirocyclic and phenyl; and / or, R b It is a hydrogen atom.

6. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein, Selected from Where * indicates a connection to ring C or x 1 The rings they belong to are connected.

7. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein, R e R e1 and R e2 The same or different, and each independently selected from hydrogen atoms, optionally substituted with 3 to 6-membered cycloalkyl groups, are C atoms. 1-4 Alkyl, Halogenated C 1-4 Alkyl, 3- to 6-membered cycloalkyl, hydroxy C 1-4 Alkyl, -C(O)R s and -C(O)NR n1 R n2 ;R s Selected from C 1-4 Alkyl, C 1-4 Alkoxy and 3- to 6-membered cycloalkyl; R nl and R n2 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-4 Alkyl; preferably, R e R e1 and R e2 The same or different, and each independently selected from -CH2CH(CH3)2, -CH2CHF2, cyclopropyl, hydrogen atom, methyl, ethyl, isopropyl, tert-butyl, -CHF2、 -CH2CF3、 And / or, ring E is selected from 6-membered monocyclic heterocyclic groups, 6- to 9-membered fused heterocyclic groups and 6- to 9-membered bridged heterocyclic groups.

8. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein, Same or different, and each selected independently 9. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 8, wherein x 1 Selected from N, CH and CF; or x 2 Selected from CH, C-Cl and CF; or x 3 Selected from N, CH, CF, C-CH3, C-CN, C-CF3 and -C-CHF2; or x 4 Selected from N, CH and CF; or x 5 Selected from C-CN, C-OCH3, CH and CF; or x 6 Selected from N, C-OCH3, C-CN, CH and CF; or x 7 Selected from N and CH; or x 8 Selected from N, CH and CF.

10. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 4 to 9, wherein R x1 R x2 R x3 R x4 R x5 R x6 R x7 and R x8 The same or different, and each independently selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl groups, cyano groups, hydrogen atoms, and halogens.

11. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 4 to 10, wherein R x2 and R x3 The atoms attached to it together form 3- to 6-membered heterocyclic groups and 3- to 6-membered cycloalkenyl groups that can be optionally substituted with halogens.

12. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein... Same or different, and each selected independently * indicates that it is connected to end B of the ring.

13. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein... Same or different, and each selected independently 14. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein R d and R e The atoms bonded to it together form an optional C 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 3- to 8-membered heterocyclic groups substituted with alkyl-C(O)- or oxo groups; preferably, R d and R e The atoms attached to it together form 3 to 8-membered heterocyclic groups that may be optionally substituted with methyl, -CD3, CH3-C(O)- or oxo groups.

15. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 4 to 14, wherein ring F is a 5- to 8-membered heterocyclic group; preferably, ring F is a 5- to 8-membered heterocyclic group containing 1 to 3 identical or different heteroatoms; more preferably, ring F is a 5- to 8-membered heterocyclic group containing 1 or 2 identical or different heteroatoms; even more preferably, ring F is a 5- to 8-membered heterocyclic group containing 2 identical or different heteroatoms; even more preferably, ring F is a 5- to 8-membered nitrogen-containing heterocyclic group, which, in addition to containing a N atom, further contains 1 heteroatom selected from N, O, and S; even more preferably, ring F is a 6-membered nitrogen-containing heterocyclic group, which, in addition to containing a N atom, further contains 1 heteroatom selected from N and O.

16. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 4 to 15, wherein R f Selected from hydrogen atoms, C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, oxo group; preferably, R f It is selected from hydrogen atom, methyl, -CD3, CH3-C(O)- and oxo group.

17. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 16, wherein ring F is selected from... The letters D and E indicate the positions of rings D and E.

18. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 4 to 17, wherein rings F and R f The structural units are selected from The letters D and E indicate the positions of rings D and E.

19. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein... Same or different, and each selected independently 20. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein... Same or different, and each selected independently 21. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein the compound, its stereoisomer, or its pharmaceutically acceptable salt is represented by general formula (I-1a), general formula (I-1b), general formula (I-2a), general formula (I-2a'), general formula (I-2a”), general formula (I-2b), general formula (I-2b'), or general formula (I-2b”). in, x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e1 Ring F, R f z is as defined in claims 4 to 20.

22. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 21, wherein the compound is of the general formula (I-1c), general formula (I-1d), general formula (I-2c), general formula (I-2c'), general formula (I-2c”), general formula (I-2d), general formula (I-2d'), general formula (I-2d”), general formula (I-1ca), general formula (I-1da), general formula (I-2ca), general formula (I-2) Compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, represented by the formulas (I-2ca”), (I-2da”), (I-2da’), (I-2da”), (I-1cb), (I-1db), (I-2cb’), (I-2cb”), (I-2db”), (I-2db’), (I-2db”), and (I-2db”) in, X is selected from -(CR f1 R f2 ) s -O-, -(CR fl R f2 ) s NR f3 -, -O-(CR fl R f2 ) s , -NR f3 -(CR fl R f2 ) s ; Y does not exist or is selected from -CR f1 R f2 -; s is selected from 0, 1, 2, or 3; R f1 R f2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-4 Alkyl, halogen; preferably, R fl R f2 All are hydrogen atoms; R f3 Selected from hydrogen atoms, C 1-4 Alkyl, halogen, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkyl-C(O)-, oxo group; preferably, R f3 Selected from hydrogen atom, methyl group, -CD3, CH3-C(O)-, oxo group; x 1 x 2 x 3 x 4 x 5 x 6 x 7 x 8 R e1 As defined in claims 1 to 21.

23. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein the compound is selected from: Preferably, the pharmaceutically usable salt of the compound is a hydrochloride or a formate, wherein the number of hydrochloric acid molecules in the hydrochloride is, for example, 1, 2, or 3, and the number of formic acid molecules in the formate is, for example, 1, 2, or 3. More preferably, the pharmaceutically acceptable salt of the compound has any of the following structures:

24. A crystal form of a compound, wherein the compound is... The compound is At that time, the crystal system of the crystal form is monoclinic, the space group is C2, and the unit cell parameters are: α=90°, β=105.432(3)°, γ=90°; The compound is At that time, the crystal system of the crystal form is monoclinic, the space group is P21, and the unit cell parameters are: α=90°, β=115.517(5)°, γ=90°.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a crystal form according to claim 24, and one or more pharmaceutically acceptable carriers.

26. Use of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 23, or the crystal form according to claim 24, or the pharmaceutical composition according to claim 25, in the preparation of a medicament for an sGC agonist and / or activator.

27. Use of the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, or the crystal form according to claim 24, or the pharmaceutical composition according to claim 25, in the preparation of a medicament for treating and / or preventing diseases mediated by sGC agonists and / or activators.

28. Use of the compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, or the crystal form according to claim 24, or the pharmaceutical composition according to claim 25, in the preparation of a medicament for the treatment and / or prevention of heart failure, hypertension, chronic kidney disease and diabetic nephropathy, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases, nonproliferative diabetic retinopathy and dementia, and diabetic foot ulcers.

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