Cgas inhibitor

Abstract

The present invention provides a compound. Specifically, the present invention provides a compound having a structure represented by formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, and solvate thereof. The compound can effectively inhibit cGAS and is used for treating or preventing diseases or conditions related to the activity or expression level of the cGAS.

Description

cGAS inhibitors Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to a novel class of compounds, their synthesis methods, and their application as cGAS inhibitors in the preparation of drugs for the treatment of autoimmune diseases and other related diseases. Background Technology

[0002] Innate immunity is the front line of defense against infectious microorganisms such as viruses and bacteria. cGAS (Cyclic GMP-AMP Synthase) is a nucleotide transferase belonging to the Mab-21 (male abnormal 21) family of proteins. It consists of an amino-terminal DNA-binding domain, a catalytic domain in the middle, and a carboxyl-terminal Mab-21 domain.

[0003] The cGAS-STING (Stimulator of Interferon Genes) signaling pathway plays a crucial role in mammalian innate immunity. Foreign cytoplasmic pathogen DNA or mitochondrial DNA can act as immunogenic molecules, activating the cell's innate immune response. In this pathway, cGAS binds to double-stranded DNA (dsDNA) and undergoes a conformational change, using ATP and GTP as substrates to catalyze the production of the second messenger 2'3' circular GMP-AMP (cGAMP). cGAMP binds to and activates STING. Activated STING recruits TBK1, which phosphorylates STING, and then phosphorylates the transcription factor IRF3. Phosphorylated IRF3 dimers and translocates to the nucleus, initiating the expression of type I IFN (interferon) and inflammatory cytokines, leading to antiviral and other immune responses. The cGAS-STING signaling pathway plays a key role in various physiological and pathological processes, including viral infection, cancer, and autoimmune diseases; however, overactivation may lead to autoimmune diseases.

[0004] SAVI (STING-associated vasculopathy with onset in infancy) is a rare autoimmune disease caused by activating mutations in the STING gene. Patients present with early-onset (usually within 2 months of birth) systemic inflammation, cutaneous vascular disease (telangiectasia, pustules, and / or bullae), interstitial lung disease, paratracheal or hilar lymphadenopathy, and pulmonary fibrosis. As the disease progresses, many patients develop features such as ear cartilage scarring and nasal septum perforation.

[0005] Aicardi-Goutières syndrome (AGS) is a group of genetic disorders associated with mutations in multiple genes involved in the cGAS-STING signaling pathway, particularly enzymes involved in DNA metabolism, such as TREX1 and SAMHD1. Mutations in these enzymes that inactivate them prevent cells from properly degrading RNA or DNA. The accumulated nucleic acids then trigger intracellular sensor proteins, leading to abnormal activation of the cGAS-STING signaling pathway. Patients present with early-onset central nervous system inflammation and recurrent fever, joint pain, hepatosplenomegaly, and progressive developmental delay. Furthermore, mutations in the TREX1 gene themselves also increase the risk of systemic lupus erythematosus (SLE).

[0006] Besides related rare diseases, the cGAS-STING signaling pathway is also closely associated with a variety of inflammatory or autoimmune diseases, such as systemic lupus erythematosus, arthritis, and ischemic brain injury. Therefore, developing highly active cGAS inhibitors to suppress excessive activation of the immune system has promising application prospects and social benefits. Summary of the Invention

[0007] The purpose of this invention is to provide a novel class of cGAS inhibitors.

[0008] In a first aspect, the present invention provides a compound, or an optical isomer thereof, of the structure shown in formula (I), a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0009] In formula (I):

[0010] Ring A is selected from aromatic groups having 6-10 carbon atoms or 5- to 10-membered heteroaromatic groups;

[0011] Ring B is selected from 5- to 6-membered heteroaromatic groups;

[0012] X is selected from -O-, -S-, -NR d -、-CR h =CR h -、-C≡C-、or C 1-2 Alkyl groups; each R h Each is independently selected from hydrogen, halogen, or C. 1-2 alkyl;

[0013] R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f , or NRd R d ;

[0014] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, or C 3-6 cycloalkyl;

[0015] R 3 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, CN, OR f SR f , or NR d R d ;

[0016] R is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 9-membered heterocyclic, C 3-8 cycloalkyl-C 1-6 Alkyl, 3- to 8-membered heterocyclic -C 1-6 Alkyl, C 4-8 Cycloalkenyl, C 4-8 Cycloalkenyl-C 1-6 Alkyl, C 2-4 alkenyl-C 3-8 cycloalkyl, C 2- 4-Alynyl-C 3-8 cycloalkyl, C 2-4 alkenyl-C 3-8 cycloalkyl-C 1-6 Alkyl, C 2-4 alkynyl-C 3-8 cycloalkyl-C 1-6 Alkyl, C 2-4 alkenyl-3- to 8-membered heterocyclic groups, C 2-4 alkynyl 3- to 8-membered heterocyclic groups, C 2-4 alkenyl-3- to 8-membered heterocyclic-C 1-6 Alkyl, C 2-4 alkynyl-3-to-8-membered heterocyclic-C 1-6 Alkyl, C 3-8 cycloalkyl-C 4-6 Alkyl, 3- to 8-membered heterocyclic -C 4-6 Alkyl, C 3-8 cycloalkyl-C 2-6 alkenyl, 3- to 8-membered heterocyclic -C2-6 alkenyl, aryl-C 2-6 alkenyl, heteroaryl-C 2-6 alkenyl, C 3-8 cycloalkyl-C 2-6 alkynyl, 3- to 8-membered heterocyclic -C 2-6 alkynyl, aryl-C 2-6 alkynyl, heteroaryl-C 2-6 alkynyl group, C 3-8 cycloalkyl-C 1-4 Alkyl-C 2-6 alkenyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl-C 2-6 alkenyl, aryl-C 1-4 Alkyl-C 2-6 alkenyl, heteroaryl-C 1-4 Alkyl-C 2-6 alkenyl, C 3-8 cycloalkyl-C 1-4 Alkyl-C 2-6 alkynyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl-C 2-6 alkynyl, aryl-C 1-4 Alkyl-C 2-6 alkynyl, heteroaryl-C 1- 4-alkyl-C 2-6 alkynyl group, C 2-4 alkenyl-C 2-6 alkenyl, C 2-4 alkynyl-C 2-6 alkenyl, alkenyl-C 2-6 alkynyl group, C 2-4 alkynyl-C 2-6 alkynyl group, R p -C 3-8 cycloalkyl, R p -C 3-8 cycloalkyl-C 1-6 Alkyl, R p -3- to 8-membered heterocyclic groups, or R p -3-to-8-membered heterocyclic group-C 1-6 Alkyl; R p Selected from C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 cycloalkyl-C 1-4 Alkyl, 3- to 6-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1-4 Alkyl, heteroaryl-C 1-4 Alkyl; each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d R f OC 1-4 Alkyl, C(O)R g C(O)OR f OC(O)R g C(O)NR d R d S(O)2R g CN-C 1-4 Alkyl, R f SC 1- 4-alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S;

[0017] Or R can be selected from equation (Ia) or equation (Ib):

[0018] Indicates a carbon-carbon single bond or a carbon-carbon double bond;

[0019] The site where formula (Ia) or formula (Ib) is connected to other parts of the compound of formula (I);

[0020] Z is selected from N, C, or CR. e ;R e Selected from hydrogen, halogen, or C 1-4 alkyl;

[0021] Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ;

[0022] R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0023] Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR fOC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or two Rs t The carbon atoms bonded to it together form a carbonyl group (C=O); or two R atoms... t Together with the carbon atoms attached thereto, they form a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; each R x Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1- 4-alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0024] R k Or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NRd R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d , or NR d S(O)2R g ;

[0025] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl;

[0026] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、or CN; or two R 5 Together with the carbon atoms attached thereto, they form spirocyclic, bridged, or fused ring structures, which optionally contain 0 or 1 additional heteroatoms selected from N, O, and S; or R 5 and R k Together with the carbon and nitrogen atoms attached thereto, they form a bridged ring or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0027] R 6 and R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R dThe alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, and alkyl groups. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or R 6 and R 7 Together with the carbon atom it is attached to, it forms a 3- to 8-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S, and is optionally substituted by one or more groups selected from the group consisting of halogens, C, and N. 1-4 Alkyl, CN, OR f SR f NR d R d C(O)R g , or S(O)2R g ;

[0028] The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, C(O)R b ; or two Rs dTogether with the nitrogen atom it is attached to, they form a 4- to 8-membered ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, R b OC 1-4 Alkyl groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl; each R b Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl;

[0029] h is selected from 0, 1, 2, 3, or 4;

[0030] m is selected from 0, 1, 2, 3, or 4;

[0031] n is selected from 0, 1, 2, or 3;

[0032] p and q are each independently selected from 0, 1, 2, 3, or 4;

[0033] t is selected from 0, 1, 2, 3, 4, 5, or 6;

[0034] In this context, each of the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR n SR n NR c R c C(O)R m C(O)OR n C(O)NR c R c NR c C(O)R m NR c S(O)2R m, or S(O)2R m The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R c The definitions are as described above; each R m Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl; each R n Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl;

[0035] Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing heteroatoms or not containing heteroatoms.

[0036] In another preferred embodiment, equation (I) is equivalent to equation (II):

[0037] r and s are each independently selected from 0, 1, or 2;

[0038] The definitions of the remaining groups in formula (II) are as described above.

[0039] In another preferred embodiment, equation (I) is equivalent to equation (III):

[0040] Indicates a carbon-carbon double bond or a carbon-carbon triple bond;

[0041] R 8 Selected from C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, C 3-8 cycloalkyl-C 1-4 Alkyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1-4 Alkyl, heteroaryl-C 1-4 Alkyl, C 2-4 alkenyl, or C 2-4 Alkynyl; the alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, ORf SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1- 4-alkyl-S,R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S;

[0042] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl;

[0043] t is selected from 0, 1, 2, or 3;

[0044] R f R d R g The definitions of the remaining groups in formula (III) are as described above.

[0045] In another preferred embodiment, equation (I) is equivalent to equation (IV):

[0046] Ring C is selected from C 3-8 Cycloalkyl or 3- to 8-membered heterocyclic groups;

[0047] R 9 Selected from hydrogen, halogens, C 1-4 Alkyl, OR f SR f NR d R d CN, C 2-4 alkenyl, C 2-4 alkynyl group, C3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 cycloalkyl-C 1-4 Alkyl, 3- to 6-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1- 4-alkyl, heteroaryl-C 1-4 Alkyl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d R f OC 1-4 alkyl;

[0048] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl;

[0049] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、or CN; or two R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0050] t is selected from 0, 1, 2, 3, 4, 5, or 6; h is selected from 0, 1, 2, 3, or 4;

[0051] R f R d The definitions of the remaining groups in formula (IV) are as described above;

[0052] The prerequisite is that when t is selected from 0, 1, 2, or 3, R 9 Cannot be selected from hydrogen, halogens, OR f SR f , or NR d R d .

[0053] In another preferred embodiment, equation (I) is equivalent to equation (V):

[0054] Indicates a carbon-carbon single bond or a carbon-carbon double bond;

[0055] The definitions of each group in formula (V) are as described above.

[0056] In another preferred embodiment, equation (I) is equivalent to equation (VI):

[0057] Indicates a carbon-carbon double bond or a carbon-carbon triple bond;

[0058] The definitions of each group in formula (VI) are as described above.

[0059] In another preferred embodiment, equation (I) is equivalent to equation (VII):

[0060] R 8 Selected from C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl; wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC1-4 Alkyl-S;

[0061] Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0062] Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ;

[0063] t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3;

[0064] R f R d R g A, B, R 1 R 2 R 3 The definitions of m and n are as described above.

[0065] In another preferred embodiment, equation (I) is equivalent to equation (VIII):

[0066] The definitions of each group in formula (VIII) are as described above.

[0067] In another preferred embodiment, equation (I) is equivalent to equation (IX):

[0068] U is selected from CR 10 R 10 NR i 、O、or S;R i Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, C(O)R g R f OC 1-4 Alkyl C(O) or S(O)2R g ;

[0069] Each R 10 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d Rd C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S;

[0070] Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0071] Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ;

[0072] t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3;

[0073] x and y are each independently selected from 0, 1, 2, 3, or 4; k is selected from 0, 1, 2, 3, or 4;

[0074] R f R d R g A, B, R 1 R 2 R 3 The definitions of m and n are as described above.

[0075] In another preferred embodiment, equation (I) is equation (X):

[0076] Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ;

[0077] R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g R f OC 1-6 Alkyl, R f OC 3-6 cycloalkyl C 1- 4-alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0078] Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, R f OC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d Rd NR d S(O)2R g , or NR d S(O)2NR d R d ; or two Rs t The carbon atoms bonded to it together form a carbonyl group (C=O); or two R atoms... t Together with the carbon atoms attached thereto, they form a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; each R x Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0079] R k Or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)Rg C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d , or NR d S(O)2R g ;

[0080] R f R d R g A, B, R 1 R 2 R 3 R 5 R a The definitions of m, n, h, p, q, and t are as described above.

[0081] In another preferred embodiment, equation (I) is equivalent to equation (XI):

[0082] t is selected from 4, 5, or 6;

[0083] Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0084] R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ;

[0085] R 2 Selected from hydrogen, halogens, C 1-4 alkyl;

[0086] R 3 Selected from hydrogen, halogens, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ;

[0087] U is selected from CR 10 R 10 NR i 、O、or S;R iSelected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C(O)R g R f OC 1-4 Alkyl C(O) or S(O)2R g ;

[0088] Each R 10 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S;

[0089] The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, C(O)R b 、; or two Rs d Together with the nitrogen atom it is attached to, they form a 4- to 8-membered ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; each R fEach is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, R b OC 1-4 Alkyl groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl; each R b Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl;

[0090] m is selected from 0, 1, 2, 3, or 4; n is selected from 0, 1, 2, or 3;

[0091] x and y are each independently selected from 0, 1, 2, 3, or 4; k is selected from 0, 1, 2, 3, or 4.

[0092] In another preferred embodiment, equation (I) is equation (XII):

[0093] Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ;

[0094] t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3;

[0095] R d R f The definitions of the remaining groups in formula (XII) are as described above.

[0096] In another preferred embodiment, equation (I) is equation (XIII):

[0097] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、 or CN;

[0098] R6 and R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d , or S(O)2R g The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, etc. 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ;

[0099] h is selected from 0, 1, 2, 3, or 4; p and q are each independently selected from 0, 1, 2, 3, or 4;

[0100] t is selected from 1, 2, 3, or 4;

[0101] The definitions of the remaining groups in formula (XIII) are as described above.

[0102] In another preferred embodiment, equation (I) is equation (XIV):

[0103] Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ;

[0104] R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g S(O)2R g R f OC 1-6 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0105] Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, R f OC 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d Each Rx Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl;

[0106] R k Or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d, or NR d S(O)2R g ;

[0107] t is selected from 1, 2, 3, or 4;

[0108] R d R f R g The definitions of the remaining groups in formula (XIV) are as described above.

[0109] In another preferred embodiment, equation (I) is equation (XV):

[0110] The definition of R is as described above; the definitions of the other groups in formula (XV) are as described above.

[0111] In another preferred embodiment, the compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, is selected from one of the following:

[0112] "*" indicates a chiral center, which includes R- and S-configurations;

[0113] The stereoconfiguration of a carbon-carbon double bond can be chosen from either the E- or Z- configuration.

[0114] A second aspect of the invention provides a pharmaceutical composition comprising the compound described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

[0115] A second aspect of the invention provides the use of the compound described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof, for the preparation of a pharmaceutical composition for treating diseases, conditions, or symptoms related to cGAS activity or expression levels.

[0116] In another preferred embodiment, the disease, symptom, or condition is selected from the group consisting of: SAVI (STING-associated vasculopathy with onset in infancy), AGS syndrome (Aicardi-Goutières syndrome), familial frostbite-like lupus, COPA syndrome, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis or cutaneous lupus, psoriasis, myasthenia gravis, multiple sclerosis, scleroderma, alopecia areata, inflammatory bowel disease, acute cerebral ischemia, acute pulmonary ischemia, Parkinson's disease, ALS, non-alcoholic fatty liver disease, acute pancreatitis, myocardial infarction, chronic heart failure, and various autoimmune diseases and neurodegenerative diseases. Detailed Implementation

[0117] Through long-term and in-depth research, the inventors unexpectedly discovered a class of novel cGAS inhibitors, along with their preparation methods and applications. The compounds of this invention can be applied to the treatment of various diseases related to the activity of said cGAS. Based on the above findings, the inventors completed this invention.

[0118] the term

[0119] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0120] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0121] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0122] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0123] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number definiteness (e.g., C...), it is considered a alkynyl group. 2-8 When alkynyl is used, it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0124] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-8 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below.

[0125] Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring having a conjugated π-electron system. Aryl groups can be substituted or unsubstituted. Some examples of aryl groups are given below; the invention is not limited to the aryl groups described below.

[0126] "Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally nitrogen, oxygen, and sulfur), or a polycyclic group consisting of a heterocyclic group (containing one or more heteroatoms, optional nitrogen, oxygen, and sulfur) fused with an aryl group, with the linking site located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; however, this invention is not limited to the heteroaryl groups described below.

[0127] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system; one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic groups" refer to polycyclic heterocyclic groups in which any two rings share two non-directly connected atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. If a saturated ring and an aromatic ring are present simultaneously in the heterocyclic group (for example, a saturated ring and an aromatic ring fused together), the point of attachment to the parent ring must be on the saturated ring. Note: When the point of attachment to the parent ring is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. Below are some examples of heterocyclic groups; this invention is not limited to the heterocyclic groups described below.

[0128] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0129] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3- 8-cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0130] For convenience and to conform to common understanding, the terms "arbitrary substitution" or "optional substitution" apply only to sites that can be substituted by substituents, and do not include chemically impossible substitutions.

[0131] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt suitable for contact with the tissues of an object (e.g., a human) without producing undesirable side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes salts of the compounds of the present invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of the compounds of the present invention having basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).

[0132] use:

[0133] The present invention provides the use of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients for the inhibition of cGAS.

[0134] The compound of this invention can be used as a cGAS inhibitor.

[0135] This invention is a single inhibitor of cGAS, which aims to prevent, alleviate, or cure diseases by regulating cGAS activity. The diseases referred to include, but are not limited to: SAVI (STING-associated vasculopathy with onset in infancy), AGS syndrome (Aicardi-Goutières syndrome), familial frostbite-like lupus, COPA syndrome, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis or cutaneous lupus, myasthenia gravis, multiple sclerosis, scleroderma, alopecia areata, inflammatory bowel disease, acute cerebral ischemia, acute pulmonary ischemia, Parkinson's disease, ALS, non-alcoholic fatty liver disease, acute pancreatitis, myocardial infarction, chronic heart failure, and various autoimmune diseases and neurodegenerative diseases.

[0136] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and / or compositions thereof, can be formulated together with pharmaceutically acceptable excipients or carriers to obtain compositions that can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections, sterile powders, etc. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (added), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic), and lubricants (such as magnesium stearate, glycerin and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed and is usually given at a pharmaceutically effective dose. Simultaneously, the actual amount of compound administered can be determined by the physician based on the actual situation, including the condition being treated, the chosen route of administration, the actual compound administered, and the patient's individual condition. The dosage of the compound of the present invention depends on the specific purpose of treatment, the route of administration, the patient's condition, and the physician's judgment. The proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, and route of administration.

[0137] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0138] Pharmaceutical Compositions and Administration

[0139] Because the compounds of the present invention have excellent inhibitory activity against cGAS, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to cGAS activity or expression levels.

[0140] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0141] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0142] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0144] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0145] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0146] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0147] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0148] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0149] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0150] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0151] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0152] The main advantages of this invention include:

[0153] 1. A compound as shown in Formula I is provided.

[0154] 2. A novel cGAS inhibitor is provided, as well as its preparation and application, wherein the inhibitor can inhibit cGAS activity at extremely low concentrations.

[0155] 3. A cGAS inhibitor that is well absorbed orally is provided.

[0156] 4. A class of pharmaceutical compositions for treating diseases related to cGAS activity is provided.

[0157] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0158] Some representative compounds of this invention can be prepared by the following synthetic methods. In each of the reaction formulas below, the reagents and conditions in each step can be those conventionally used in this type of preparation method in the art. After the compound structures of this invention are disclosed, the above selections can be made by those skilled in the art based on their knowledge in the art.

[0159] Example

[0160] abbreviation:

[0161] Boc = tert-Butoxycarbonyl

[0162] Bn = benzyl

[0163] CN = cyano

[0164] DBAD = Di-tert-butyl azodicarbonate

[0165] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

[0166] DCM = dichloromethane

[0167] DIPEA or DIEA = N,N-diisopropylethylamine

[0168] DIBAL-H = Diisobutylaluminum hydride

[0169] DMF = N,N-dimethylformamide

[0170] DMSO = dimethyl sulfoxide

[0171] EtOAc or EA = ethyl acetate

[0172] Et = Ethyl

[0173] LiHMDS = Lithium dibis(trimethylsilylamine)

[0174] LDA = Lithium diisopropylamino

[0175] MOMBr = Bromomethyl methyl ether

[0176] Me = methyl

[0177] NMI = N-methylimidazolium

[0178] Ph = phenyl

[0179] PPh3 = Triphenylphosphine

[0180] PMB = p-Methoxybenzyl

[0181] Pd(Ph3)2Cl2 = Palladium dichloride bis(triphenylphosphine)

[0182] TBAF = Tetra-n-Butylammonium Fluoride

[0183] TBS = tert-butyldimethylsilyl

[0184] TBDPS = tert-butyldiphenylsilyl

[0185] TCFH = N,N,N',N'-Tetramethylchloromethylammonium hexafluorophosphate

[0186] TEA = Triethylamine

[0187] TFA = Trifluoroacetic acid

[0188] THF = Tetrahydrofuran

[0189] TMS = Trimethylsilyl

[0190] TsCl = p-Methylbenzenesulfonyl chloride

[0191] Example 1: Preparation of Compound 1

[0192] Compound 1-a (250 mg, 1.98 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 1.0 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Paraformaldehyde (119 mg, 3.96 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 1-b (66 mg, yield 21%) as a white solid.

[0193] Compound 1-b (66 mg, 0.42 mmol), compound 10-g (128 mg, 0.42 mmol), and triphenylphosphine (166 mg, 0.63 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (145 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 1-c (167 mg, 89% yield). MS m / z 445.1 [M+H] + .

[0194] Compound 1-c (167 mg, 0.38 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (172 mg, 0.95 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 1-d (87 mg, yield 40%). MS m / z 453.1 [M+Na] + .

[0195] Compound 1-d (30 mg, 0.07 mmol) and compound 4-i (18 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 1-e (46 mg, 96% yield). MS m / z 691.1 [M+H] + .

[0196] Compound 1-e (46 mg, 0.07 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 1 (4 mg, yield 10%). 1 H NMR (500MHz, DMSO-d) δ13.27(brs,1H),7.47(d,J=1.2Hz,1H),7.43(t,J=8.4Hz,1H),7.31(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H ),5.44(d,J=1.7Hz,1H),4.84(d,J=1.4Hz,2H),3.78(s,6H),2.65-2.58(m,3H),2.45(s,2H),1.92-1.87(m,2H),1.64-1.58(m,2H). MS m / z 594.8[M+H] + .

[0197] Example 2: Preparation of Compound 2

[0198] Compound int-1 (1 g, 4.02 mmol), compound 2-b (603 mg, 6.02 mmol), and triphenylphosphine (1.58 g, 6.02 mmol) were dissolved in tetrahydrofuran (12 mL). Diisopropyl azodicarbonate (1.22 g, 6.02 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 8:1) to give a yellow oily crude product 2-c (2.1 g, 100% yield). MS m / z 332.8 [M+H] + .

[0199] Compound 2-c (2.1 g, 6.34 mmol), compound 2,6-dimethoxyphenylboronic acid (4.62 g, 25.37 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (205 mg, 0.317 mmol), and potassium phosphate (4.04 g, 19.03 mmol) were dissolved in a 1,4-dioxane / water mixture (50 / 10 mL). The reaction mixture was purged with nitrogen and stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 10:1) to give a yellow oily product 2-d (2.21 g, 90% yield). MS m / z 388.9 [M+H] + .

[0200] Compound 2-d (60 mg, 0.154 mmol) and compound 2-e (39 mg, 0.201 mmol) were dissolved in N,N-dimethylformamide (3 mL) at -60 °C, and a solution of potassium tert-butoxide (26 mg, 0.232 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred at -60 °C and slowly raised to room temperature for 2 hours. After the reaction was complete, dilute hydrochloric acid was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow oily product 2-f (21 mg, yield 32%). MS m / z 422.9 [M+H] + .

[0201] Compound 2-f (21 mg, 0.050 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (27 mg, 0.149 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give a white solid crude product 2-g (24 mg, 100% yield). MS m / z 408.8 [M+H] + .

[0202] Compound 2-g (24 mg, 0.059 mmol), compound 3-i (21 mg, 0.076 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (50 mg, 0.177 mmol), and N-methylimidazole (24 mg, 0.295 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give a yellow oily crude product 2-h (44 mg, 100% yield). MS m / z 668.8 [M+H] + .

[0203] Compound 2-h (44 mg, 0.066 mmol) was dissolved in ammonia-methanol solution (4 M, 1.5 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a white solid product 2 (5.11 mg, yield 13%). 1 H NMR (500MHz, DMSO-d6) δ13.23(s,1H),7.48(d,J=1.6Hz,1H),7.43(t,J=8.4Hz,1H),7.29(s,1H),6.79(d,J=8.5Hz,2H),6.66( s,2H),5.44(d,J=1.8Hz,1H),4.05(d,J=5.0Hz,2H),3.76(s,6H),2.54–2.50(m,2H),2.23–2.13(m,2H),2.04–1.91(m,1H)ppm. MS m / z 572.9[M+H] + .

[0204] Example 3: Preparation of Compound 3

[0205] 10 g (100 mg, 0.326 mmol) of compound 3-, 4-bromo-1-butanol (55 mg, 0.36 mmol) and triphenylphosphine (128 mg, 0.489 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (112 mg, 0.489 mmol) was added under nitrogen protection and in an ice bath. The mixture was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a colorless liquid compound 3-a (80 mg, yield 55%).

[0206] Compound 3-a (80 mg, 0.181 mmol) and compound 3-b (38 mg, 0.20 mmol) were dissolved in acetonitrile (2 mL), and then N,N-diisopropylethylamine (70 mg, 0.543 mmol) was added. The reaction was stirred at 50 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (petroleum ether:ethyl acetate = 4:1) to obtain a colorless liquid compound 3-c (30 mg, yield 30%).

[0207] Compound 3-c (30 mg, 0.054 mmol) was dissolved in tetrahydrofuran (1 mL), and then trimethyltin hydroxide (24 mg, 0.137 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 3-d (20 mg, yield 68%). MS m / z 534.3 [M+H] + .

[0208] Compound 3-d (24 mg, 0.045 mmol) and compound 4-i (13 mg, 0.045 mmol) were dissolved in acetonitrile (1 mL). N-methylimidazole (11 mg, 0.135 mmol) and N,N,N',N'-tetramethylchlorourea hexafluorophosphate (19 mg, 0.068 mmol) were added sequentially at room temperature, and the mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain solid compound 3-e (15 mg, yield 42%). MS m / z 794.2 [M+H] + .

[0209] Compound 3-e (15 mg, 0.019 mmol) was dissolved in ammonia-methanol (1 mL, 4 M) and reacted at 50 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 20:1) to obtain solid compound 3-f (6 mg, yield 45%). MS m / z 698.2 [M+H] + .

[0210] Compound 3-f (6 mg, 0.008 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride (2 mg, 1 M) was added under nitrogen protection in an ice bath. The reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 3 (0.3 mg, yield 6%). MS m / z 583.8 [M+1] + .

[0211] Example 4: Preparation of Compound 4

[0212] Compound 4-a (3.7 g, 28.46 mmol) was dissolved in dichloromethane (50 mL), and Dysmartin oxidant (18.1 g, 42.69 mmol) was added under ice bath conditions. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 4-b (2.8 g, 77% yield).

[0213] Compound 4-b (1.0 g, 5.95 mmol) and compound 4-c (2.2 g, 5.95 mmol) were dissolved in tetrahydrofuran (30 mL). The reaction solution was cooled to -60 °C under a nitrogen atmosphere, and a 1 M, 12 mL solution of bis(trimethylsilylamino)lithium tetrahydrofuran was added dropwise. The reaction solution was stirred at this temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 4-d (690 mg, yield 33%).

[0214] Compound 4-d (390 mg, 1.44 mmol) was dissolved in tetrahydrofuran (10 mL), and diisobutylaluminum hydride n-hexane solution (1 M, 4 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with saturated potassium sodium tartrate aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 4-e (115 mg, yield 33%). MS m / z 265.1 [M + Na] + .

[0215] Compound 4-e (115 mg, 0.47 mmol), compound int-1 (117 mg, 0.47 mmol), and triphenylphosphine (185 mg, 0.70 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (161 mg, 0.70 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 4-f (121 mg, yield 54%). MS m / z 473.0 [M+H] + .

[0216] Compound 4-f (121 mg, 0.26 mmol), 2,6-dimethoxyphenylboronic acid (70 mg, 0.38 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (19 mg, 0.03 mmol), and potassium phosphate (165 mg, 0.78 mmol) were dissolved in a dioxane / water mixture (2 mL / 0.5 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to give compound 4-g (101 mg, 74% yield). MS m / z 531.2 [M+H] + .

[0217] Compound 4-g (101 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (86 mg, 0.48 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 4-h (88 mg, 90% yield). MS m / z 539.2 [M+Na] + .

[0218] Compound 4-h (83 mg, 0.16 mmol) and compound 4-i (44 mg, 0.16 mmol) were dissolved in acetonitrile, and N-methylimidazole (66 mg, 0.80 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (67 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 4-j (8 mg, 6% yield). MS m / z 777.2 [M+H] + .

[0219] Compound 4-j (8 mg, 0.01 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude compound 4-k was used directly in the next reaction step.

[0220] Compound 4-k (8 mg, 0.01 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 4 (2 mg, yield 34%). 1H NMR(500MHz,DMSO-d)δ7.46(d,J=1.7Hz,1H),7.44-7.41(m,1H),7.22(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.43(d,J=1.8Hz,1H),5.42 -5.37(m,1H),5.33-5.31(m,1H),5.16-5.12(m,1H),3.76(s,6H),3.18 -3.14(m,2H),3.04-3.01(m,2H),0.58-0.55(m,2H),0.51-0.48(m,2H). MS m / z 566.9[M+H] + .

[0221] Example 5: Preparation of Compound 5

[0222] 10-g (120 mg, 0.39 mmol) of compound N,N-diisopropylethylamine (152 mg, 11.76 mmol) was dissolved in dichloromethane (3 mL), and trifluoromethanesulfonic anhydride (165 mg, 0.59 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 5-b (158 mg, 92% yield). MS m / z 438.9 [M+H] + .

[0223] Compound 5-b (105 mg, 0.24 mmol), tert-butyldimethyl(2-propynoxy)silane (61 mg, 0.36 mmol), bis(triphenylphosphine)palladium dichloride (17 mg, 0.02 mmol), cuprous iodide (9 mg, 0.04 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was heated and stirred overnight at 75 °C under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to give compound 5-c (64 mg, 58% yield). MS m / z 459.2 [M+H] + .

[0224] Compound 5-c (64 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (63 mg, 0.35 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 5-d (58 mg, 94% yield). MS m / z 467.1 [M+Na] + .

[0225] Compound 5-d (50 mg, 0.11 mmol) and compound 4-i (31 mg, 0.11 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (45 mg, 0.55 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (46 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 5-e (21 mg, yield 27%). MS m / z 704.9 [M+H] + .

[0226] Compound 5-e (21 mg, 0.03 mmol) was dissolved in concentrated hydrochloric acid (1 mL). The reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 5 (2 mg, yield 14%). MS m / z 494.8 [M+H] + .

[0227] Example 6: Preparation of Compound 6

[0228] The synthetic route for compound 6-a is described in Synthesis, 2019, 51, 1935.

[0229] The synthesis of intermediates int-1 and int-2 is referenced in patent WO2024233812.

[0230] Compound int-1 (250 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (7.5 mL), and compound 6-a (615 mg, 2.0 mmol) and N,N-diisopropylethylamine (646 mg, 5.0 mmol) were added. The mixture was heated to 70 °C and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a yellow oil 6-b (300 mg, yield 63%). MS m / z 475.1 [M+H] + .

[0231] Compound 6-b (300 mg, 0.63 mmol) and 2,6-dimethoxyphenylboronic acid (229 mg, 1.26 mmol) were dissolved in a mixed solution of dioxane (5 mL) and water (1 mL), followed by the addition of potassium phosphate (401 mg, 1.89 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (22 mg, 0.03 mmol). The mixture was stirred at 80°C for 3 hours under nitrogen protection, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a pale yellow solid compound 6-c (200 mg, yield 60%). MS m / z 533.2 [M+H] + .

[0232] Compound 6-c (60 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 mL), and trimethyltin hydroxide (60 mg, 0.33 mmol) was added. The mixture was then heated to 40 °C and stirred overnight at 40 °C. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 6-d (20 mg, yield 34%). MS m / z 519.2 [M+H] + .

[0233] Compound 6-d (20 mg, 0.039 mmol) and compound int-2 (8.7 mg, 0.039 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (6.4 mg, 0.078 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (11 mg, 0.039 mmol). The mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 6-e (20 mg, yield 72%). MS m / z 725.2 [M+H] + .

[0234] Compound 6-e (20 mg, 0.028 mmol) was dissolved in concentrated hydrochloric acid (1.0 mL) and stirred at room temperature for 0.5 hours. The solution was quenched with water, and the pH was adjusted to 9 with ammonia. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a pale white solid, compound 6 (0.8 mg, yield 5%). MS m / z 568.9 [M+H] + .

[0235] Example 7: Preparation of Compound 7

[0236] 2.0 g (11.76 mmol) of tert-butyldimethyl(prop-2-yn-1-yloxy)silane was dissolved in tetrahydrofuran (40 mL). The reaction mixture was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 5.6 mL) was added dropwise. The reaction mixture was stirred at this temperature for 0.5 h. Oxybutanone (1.3 g, 17.64 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 7-b (2.3 g, 81% yield). MS m / z 265.1 [M + Na] + .

[0237] Compound 7-b (1.0 g, 4.13 mmol) was dissolved in a dichloromethane / water mixture (20 mL / 1 mL), and trifluoroacetic acid (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 7-c (298 mg, yield 56%).

[0238] Compound 7-c (42 mg, 0.33 mmol), compound 10-g (100 mg, 0.33 mmol), and triphenylphosphine (130 mg, 0.50 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (115 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 7-d (125 mg, 92% yield). MS m / z 417.0 [M+H] + .

[0239] Compound 7-d (125 mg, 0.30 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (136 mg, 0.75 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 7-e (105 mg, yield 87%). MS m / z 425.1 [M+Na] + .

[0240] Compound 7-e (50 mg, 0.12 mmol) and compound 4-i (35 mg, 0.12 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (49 mg, 0.60 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (50 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 7-f (24 mg, yield 29%). MS m / z 663.1 [M+H] + .

[0241] Compound 7-f (24 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 7 (2 mg, 10% yield). MS m / z 566.8 [M+H] + .

[0242] Example 8: Preparation of Compound 8

[0243] Compound 8-a (2.0 g, 9.71 mmol) and N,N'-carbonyldiimidazole (1.7 g, 10.68 mmol) were dissolved in tetrahydrofuran (30 mL), and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to -70 °C under a nitrogen atmosphere, and diisobutylaluminum hydride n-hexane solution (1 M, 20 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with potassium sodium tartrate aqueous solution in an ice bath, and stirred at room temperature for 0.5 h. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 8-b (255 mg, yield 14%).

[0244] Compound 8-b (255 mg, 1.34 mmol) and potassium carbonate (278 mg, 2.01 mmol) were dissolved in methanol (5 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (309 mg, 1.61 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 8-c (189 mg, yield 76%).

[0245] Compound 8-c (189 mg, 1.02 mmol) was dissolved in tetrahydrofuran (5 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 0.5 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Formaldehyde (61 mg, 2.04 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 8-d (141 mg, yield 64%). MS m / z 239.1 [M + Na] + .

[0246] Compound 8-d (110 mg, 0.51 mmol), compound int-1 (126 mg, 0.51 mmol), and triphenylphosphine (201 mg, 0.77 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (176 mg, 0.77 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 8-e (198 mg, 87% yield). MS m / z 446.8 [M+H] + .

[0247] Compound 8-e (198 mg, 0.44 mmol), 2,6-dimethoxyphenylboronic acid (120 mg, 0.66 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (26 mg, 0.04 mmol), and potassium phosphate (280 mg, 1.32 mmol) were dissolved in a dioxane / water mixture (3 mL / 0.5 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 8-f (81 mg, yield 36%). MS m / z 505.1 [M+H] + .

[0248] Compound 8-f (81 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (73 mg, 0.40 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 8-g (59 mg, 75% yield). MS m / z 513.2 [M+Na] + .

[0249] Compound 8-g (59 mg, 0.12 mmol) and compound int-2 (27 mg, 0.12 mmol) were dissolved in acetonitrile, and N-methylimidazole (49 mg, 0.60 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (51 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 8-h (23 mg, yield 27%). MS m / z 697.2 [M+H] + .

[0250] Compound 8-h (23 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and titanium tetrachloride (63 mg, 0.30 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound 8-i was used directly in the next reaction step. MS m / z 607.1 [M+H] + .

[0251] Compound 8-i (18 mg, 0.03 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 8 (1 mg, yield 6%). MS m / z 564.8 [M+H] + .

[0252] Example 9: Preparation of Compound 9

[0253] Under ice-water bath conditions, diethyl malonate (6.6 mL, 43.47 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (60%, 1.85 g, 46.37 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution of compound 9-a (5.5 mL, 28.98 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 4:1) to give a colorless oily crude product 9-b (7 g, yield 75%). MS m / z 344.9 [M+Na] + .

[0254] Compound 9-b (7 g, 21.71 mmol) was dissolved in diethyl ether (40 mL) under ice-water bath conditions. Lithium aluminum hydride (1.65 g, 43.42 mmol) was slowly added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched sequentially with ice water, sodium hydroxide solution, and water, and then diluted with ethyl acetate. The resulting mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a yellow oily product 9-c (775 mg, yield 15%). MS m / z 261.1 [M+Na] + .

[0255] Compound 9-c (775 mg, 3.25 mmol) was dissolved in tetrahydrofuran (6 mL) under ice-water bath conditions. After adding n-butyllithium (2.5 M, 1.3 mL), the reaction mixture was stirred at 0 °C for 30 minutes. Then, a tetrahydrofuran (1 mL) solution of p-toluenesulfonyl chloride (620 mg, 3.25 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. Next, n-butyllithium (2.5 M, 1.3 mL) was added, and the reaction mixture was heated to 60 °C and stirred for 6 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a colorless oily product 9-d (220 mg, yield 31%).

[0256] Compound 9-d (220 mg, 0.999 mmol) was dissolved in methanol (4 mL), and palladium on carbon (80 mg) was added. The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a colorless oily product 9-e (114 mg, yield 88%). MS m / z 131.1 [M+H] + .

[0257] Compound 9-e (56 mg, 0.431 mmol), compound 10-g (110 mg, 0.359 mmol), and triphenylphosphine (188 mg, 0.718 mmol) were dissolved in tetrahydrofuran (4 mL). Diisopropyl azodicarbonate (145 mg, 0.718 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to give a yellow oily crude product 9-f (245 mg, 100% yield). MS m / z 418.8 [M+H] + .

[0258] Compound 9-f (110 mg, 0.263 mmol) was dissolved in tetrahydrofuran (4 mL), and trimethyltin hydroxide (143 mg, 0.789 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give a colorless oily product 9-g (53 mg, yield 50%). MS m / z 404.8 [M+H] + .

[0259] Compound 9-g (53 mg, 0.131 mmol), compound 4-i (40 mg, 0.144 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (48 mg, 0.170 mmol), and N-methylimidazole (22 mg, 0.262 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a yellow oily crude product 9-h (72 mg, yield 83%).

[0260] Compound 9-h (40 mg, 0.060 mmol) and cesium carbonate (59 mg, 0.181 mmol) were dissolved in methanol (3 mL), and the reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid product 9 (1.09 mg, yield 3%). MS m / z 568.8 [M+H] + .

[0261] Example 10: Preparation of Compound 10

[0262] Compound 10-a (2.0 g, 17.24 mmol) and imidazole (3.5 g, 51.72 mmol) were dissolved in dichloromethane (40 mL), and tert-butyldiphenylchlorosilane (5.2 g, 18.96 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 10-b (6.0 g, 98% yield).

[0263] Compound 10-b (6.0 g, 16.95 mmol) was dissolved in tetrahydrofuran (100 mL), and diisobutylaluminum hydride n-hexane solution (1 M, 34 mL) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated potassium sodium tartrate aqueous solution, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 10-c (4.3 g, yield 78%). MS m / z 349.2 [M + Na] + .

[0264] Compound 10-c (4.3 g, 13.19 mmol) was dissolved in a dichloromethane / dimethyl sulfoxide (40 mL / 20 mL) mixture, and N,N-diisopropylethylamine (8.5 g, 65.95 mmol) was added dropwise. Sulfur trioxide pyridine (6.3 g, 39.57 mmol) was then added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was diluted with water, and the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 10-d (3.8 g, 78% yield).

[0265] Compound 10-d (3.8 g, 11.73 mmol) and potassium carbonate (2.4 g, 17.59 mmol) were dissolved in methanol (50 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (2.7 g, 14.06 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 10-e (900 mg, yield 24%).

[0266] Compound 10-e (700 mg, 2.19 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and a solution of n-butyllithium in n-hexane (2.5 M, 1.1 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Paraformaldehyde (131 mg, 4.38 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a white solid compound 10-f (569 mg, yield 58%). MS m / z 373.1 [M + Na] + .

[0267] Compound 10-f (80 mg, 0.23 mmol), compound 10-g (70 mg, 0.23 mmol), and triphenylphosphine (91 mg, 0.35 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (80 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 10-h (125 mg, 86% yield). MS m / z 639.0 [M+H] + .

[0268] Compound 10-h (100 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (72 mg, 0.40 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 10-i (48 mg, yield 49%). MS m / z 647.2 [M+Na] + .

[0269] Compound 10-i (41 mg, 0.07 mmol) and compound 4-i (18 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (31 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 10-j (33 mg, yield 57%). MS m / z 885.2 [M+H] + .

[0270] Compound 10-j (33 mg, 0.04 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude compound 10-k was used directly in the next reaction step. MS m / z 789.2 [M+H] + .

[0271] Compound 10-K (28 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 10 (4 mg, yield 21%). 1H NMR (500MHz, DMSO-d) δ13.31(brs,1H),7.48(d,J=1.7Hz,1H),7.43(t,J=8.4Hz,1H),7.31(s,1H),6.79(d,J=8.5Hz,2 H), 6.67 (s, 2H), 6.16 (s, 1H), 5.44 (d, J = 1.8Hz, 1H), 4.85 (s, 2H), 3.78 (s, 6H), 0.89-0.85 (m, 2H), 0.77-0.73 (m, 2H). MS m / z 551.0[M+H] + .

[0272] Example 11: Preparation of Compound 11

[0273] Compound 11-a (3.0 g, 20.55 mmol) and imidazole (4.2 g, 61.64 mmol) were dissolved in dichloromethane (60 mL), and tert-butyldiphenylchlorosilane (6.2 g, 22.61 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 11-b (6.0 g, 76% yield). MS m / z 385.2 [M+Na] + .

[0274] Compound 11-b (5.7 g, 14.84 mmol) was dissolved in an acetone / water mixture (50 mL / 10 mL), and p-toluenesulfonic acid (511 mg, 2.97 mmol) was added. The reaction mixture was heated and stirred at 60 °C for 5 hours. The reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 11-c (4.8 g, 96% yield).

[0275] Compound 11-c (1.0 g, 2.96 mmol) and potassium carbonate (612 mg, 4.44 mmol) were dissolved in methanol (20 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (682 mg, 3.55 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 11-d (785 mg, 79% yield).

[0276] Compound 11-d (525 mg, 1.57 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 0.8 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Formaldehyde (94 mg, 3.14 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 11-e (483 mg, yield 84%). MS m / z 387.2 [M + Na] + .

[0277] Compound 11-e (119 mg, 0.33 mmol), compound 10-g (100 mg, 0.33 mmol), and triphenylphosphine (130 mg, 0.50 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (115 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 11-f (183 mg, 94% yield). MS m / z 595.1 [M+H] + .

[0278] Compound 11-f (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (72 mg, 0.40 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 11-g (88 mg, 90% yield). MS m / z 603.0 [M+Na] + .

[0279] Compound 11-g (21 mg, 0.04 mmol) and compound 4-i (10 mg, 0.04 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (14 mg, 0.18 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (15 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 11-h (15 mg, yield 47%). MS m / z 899.0 [M+H] + .

[0280] Compound 11-h (15 mg, 0.02 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude compound 11-i was used directly in the next reaction step. MS m / z 803.2 [M+H] + .

[0281] Compound 11-i (14 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 11 (4 mg, yield 42%). 1 H NMR (500MHz, DMSO-d) δ13.25(brs,1H),7.48(d,J=1.8Hz,1H),7.42(t,J=8.4Hz,1H),7.31(s,1H),6.78(d,J=8.5Hz,2H),6.65(s, 2H), 5.44 (d, J = 1.9Hz, 1H), 5.36 (s, 1H), 4.81-4.79 (m, 2H), 3.78 (s, 6H), 2.01-1.96 (m, 2H), 0.52-0.50 (m, 2H), 0.44-0.41 (m, 2H). MS m / z564.8[M+H] + .

[0282] Example 12: Preparation of Compound 12

[0283] The synthesis of compound 12-a follows the same method used for the synthesis of intermediates of compound 11.

[0284] Compound 12-a (125 mg, 0.33 mmol), compound 10-g (100 mg, 0.33 mmol), and triphenylphosphine (130 mg, 0.50 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (115 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 12-b (188 mg, 86% yield). MS m / z 669.2 [M+H] + .

[0285] Compound 12-b (100 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (68 mg, 0.37 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 12-c (95 mg, 97% yield). MS m / z 677.2 [M+Na] + .

[0286] Compound 12-c (23 mg, 0.04 mmol) and compound 4-i (10 mg, 0.04 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (14 mg, 0.18 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (15 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 12-d (14 mg, 42% yield). MS m / z 915.2 [M+H] + .

[0287] Compound 12-d (14 mg, 0.02 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the resulting crude compound 12-e was used directly in the next reaction step. MS m / z 818.9 [M+H] + .

[0288] Compound 12-e (13 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 12 (1 mg, yield 11%). MS m / z 580.7 [M+H] + .

[0289] Example 13: Preparation of Compound 13

[0290] Compound 12-b (100 mg, 0.15 mmol) was dissolved in methanol (3 mL), and 10% palladium on carbon (10 mg) was added. The reaction mixture was stirred in an ice bath under a hydrogen atmosphere for 0.5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude compound 13-a (100 mg, 99% yield) was used directly in the next reaction. MS m / z 671.2 [M+H] + .

[0291] Compound 13-a (100 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (68 mg, 0.37 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 13-b (96 mg, 97% yield). MS m / z 679.0 [M+Na] + .

[0292] Compound 13-b (23 mg, 0.04 mmol) and compound 4-i (10 mg, 0.04 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (14 mg, 0.18 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (15 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 13-c (16 mg, 48% yield). MS m / z 917.3 [M+H] + .

[0293] Compound 13-c (16 mg, 0.02 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the resulting crude compound 13-d was used directly in the next reaction step. MS m / z 821.3 [M+H] + .

[0294] Compound 13-d (15 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 13 (3 mg, 30% yield). 1 H NMR(500MHz,DMSO-d)δ13.22(brs,1H),7.47-7.46(m,1H),7.42(t,J=8.4Hz,1H),7.26(s,1H),6.80-6.77(m,2H),6.65(s,2H),5.66(s,1H),5.64 -5.60(m,1H),5.51-5.47(m,1H),5.43(d,J=1.5Hz,1H),4.71-4.68(m,2H ),4.37-4.33(m,2H),4.22-4.20(m,2H),3.77(s,6H),2.01-1.97(m,2H). MS m / z 582.8[M+H] + .

[0295] Example 14: Preparation of Compound 14

[0296] Compound 2-d (200 mg, 0.515 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution of lithium hydroxide (37 mg, 1.54 mmol) (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% acetic acid) to give a yellow oily crude product 14-a (64 mg, yield 33%). MS m / z 374.8 [M+H] + .

[0297] Compound 14-a (32 mg, 0.085 mmol), compound 4-i (29 mg, 0.103 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (29 mg, 0.103 mmol), and N-methylimidazole (10 mg, 0.128 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give crude 14-b (41 mg, yield 76%) as a yellow solid. MS m / z 634.7 [M+H] + .

[0298] Under ice-water bath conditions, trimethyl phosphate acetate (24 mg, 0.129 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (60%, 3.5 mg, 0.084 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 30 minutes. Then, a tetrahydrofuran solution of compound 14-b (41 mg, 0.065 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to give a yellow solid product 14-c (13 mg, yield 29%). MS m / z 690.7 [M+H] + .

[0299] Compound 14-c (5 mg, 0.007 mmol) was dissolved in ammonia-methanol solution (4 M, 1 mL), and the reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a white solid product 14 (1.67 mg, yield 39%). MS m / z 594.8 [M+H] + .

[0300] Example 15: Preparation of Compound 15

[0301] Compound 15-a (5 g, 24.24 mmol) was dissolved in tetrahydrofuran (60 mL). Sodium borohydride (1.83 g, 48.49 mmol) was added in batches under nitrogen protection at 20 °C. After 20 minutes, boron trifluoride diethyl ether (6.88 g, 48.49 mmol) was added dropwise at the same temperature. The reaction was stirred at room temperature for one hour until the reaction was complete. The reaction solution was added dropwise to methanol solution and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain colorless liquid compound 15-b (4.1 g, yield 88%).

[0302] Compound 15-b (2 g, 10.4 mmol) was dissolved in dichloromethane (20 mL), and Dysmartin oxidant (6.6 g, 15.6 mmol) was added in portions under ice bath conditions. The reaction was carried out at room temperature for one hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was washed with sodium thiosulfate solution (10%). The organic phases were combined and then washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain a white solid compound 15-c (1.4 g, yield 71%).

[0303] (3-Benzyloxypropyl)triphenylphosphonium bromide (3.87 g, 7.88 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection at -78 °C, lithium bis(trimethylsilylamino)amine (7.88 mL, 1.0 M) was added dropwise. After stirring at this temperature for one hour, a tetrahydrofuran solution of compound 15-c (1 g, 5.26 mmol) was added and reacted at room temperature for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH 5-6 with dilute hydrochloric acid (2 M), and then extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a colorless oily liquid compound 15-d (1.1 g, yield 65%).

[0304] Compound 15-d (500 mg, 1.55 mmol) was dissolved in methanol (15 mL), and then palladium on carbon (10%, 50 mg) and palladium hydroxide on carbon (50 mg) were added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure to obtain crude product 15-e (223 mg, 100% yield). The crude product was used directly in the next step of the reaction.

[0305] Compound 10-g (150 mg, 0.49 mmol), compound 15-e (141 mg, 0.98 mmol), and triphenylphosphine (193 mg, 0.735 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (169 mg, 0.734 mmol) was added under nitrogen protection and in an ice bath. The reaction was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a colorless liquid compound 15-f (200 mg, yield 94%).

[0306] Compound 15-f (100 mg, 0.23 mmol) was dissolved in tetrahydrofuran (1 mL), and then trimethyltin hydroxide (104 mg, 0.58 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 15-g (50 mg, yield 52%). MS m / z 419.2 [M+H] + .

[0307] Compound 15-g (25 mg, 0.06 mmol) and compound 4-i (16 mg, 0.06 mmol) were dissolved in acetonitrile (1 mL). N-methylimidazole (15 mg, 0.18 mmol) and N,N,N',N'-tetramethylchlorourea hexafluorophosphate (25 mg, 0.09 mmol) were added sequentially at room temperature, and the mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain solid compound 15-h (10 mg, yield 25%). MS m / z 679.1 [M+H] + .

[0308] Compound 15-h (10 mg, 0.019 mmol) was dissolved in ammonia-methanol (1 mL, 4 M) and reacted at 50 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 20:1) to obtain solid compound 15 (0.8 mg, yield 9%). MS m / z 582.8 [M+1] + .

[0309] Example 16: Preparation of Compound 16

[0310] Compound 16-a (150 mg, 0.39 mmol) was dissolved in methanol (2 mL), and palladium on carbon (10%, 15 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 16-b (60 mg, 40% yield).

[0311] Compound 16-b (60 mg, 0.16 mmol), compound 10-g (148 mg, 0.16 mmol), and triphenylphosphine (63 mg, 0.24 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (55 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 16-c (59 mg, 100% yield). MS m / z 673.3 [M+H] + .

[0312] Compound 16-c (59 mg, 0.09 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (41 mg, 0.23 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 16-d (56 mg, 97% yield). MS m / z 681.0 [M+Na] + .

[0313] Compound 16-d (31 mg, 0.05 mmol) and compound 4-i (13 mg, 0.05 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (41 mg, 0.18 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (15 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 16-e (14 mg, yield 33%). MS m / z 918.9 [M+H] + .

[0314] Compound 16-e (14 mg, 0.02 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude compound 16-f was used directly in the next reaction step. MS m / z 823.2 [M+H] + .

[0315] Compound 16-f (14 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 16 (3 mg, yield 33%). 1 H NMR(500MHz,DMSO-d)δ13.24(brs,1H),7.46(d,J=1.6Hz,1H),7.41(t,J=8.4 Hz,1H),7.24(s,1H),6.77(d,J=8.5Hz,2H),6.65(s,2H),5.45(s,1H),5.43(d ,J=1.8Hz,1H),4.34(d,J=6.3Hz,2H),4.20(d,J=6.4Hz,2H),4.03(t,J=6.4H z,2H),3.77(s,6H),1.58-1.52(m,2H),1.46-1.43(m,2H),1.19-1.16(m,2H). MS m / z 584.8 [M+H] + .

[0316] Example 17: Preparation of Compound 17

[0317] Compound 17-a (200 mg, 1.82 mmol) was dissolved in tetrahydrofuran (4 mL). A solution of n-butyllithium in n-hexane (2.5 M, 1.09 mL) was added at -78 °C, and the reaction mixture was stirred at -78 °C for 1 hour. Paraformaldehyde (272 mg, 9.08 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 4:1) to give a colorless oily product 17-b (212 mg, yield 83%). MS m / z 163.1 [M + Na] + .

[0318] Compound 17-b (34 mg, 0.245 mmol), compound 10-g (50 mg, 0.163 mmol), and triphenylphosphine (86 mg, 0.327 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (66 mg, 0.327 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 10:1) to give a white solid crude product 17-c (126 mg, 100% yield). MS m / z 450.8 [M+Na] + .

[0319] Compound 17-c (126 mg, 0.294 mmol) was dissolved in tetrahydrofuran (4 mL), and trimethyltin hydroxide (186 mg, 1.03 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 1% acetic acid) to give a white solid product 17-d (91 mg, yield 75%). MS m / z 414.8 [M+H] + .

[0320] Compound 17-d (40 mg, 0.097 mmol), compound 4-i (27 mg, 0.097 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (41 mg, 0.145 mmol), and N-methylimidazole (16 mg, 0.193 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give crude 17-e (110 mg, 100% yield) as a yellow oil. MS m / z 674.7 [M+H] + .

[0321] The crude product 17-e (110 mg, 0.163 mmol) was dissolved in ammonia-methanol solution (4 M, 2.5 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to obtain a yellow solid product 17 (5.4 mg, yield 6%). 1H NMR (500MHz, DMSO-d6) δ13.26(brs,1H),7.46(s,1H),7.42(t,J=8.4Hz,1H),7.31-7.26(m,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.43(d, J=1.8Hz,1H),4.82(s,2H),3.78(s,6H),3.70-3.64(m,2H),3.38-3.34(m,2H),2.67-2.61(m,1H),1.70-1.63(m,2H),1.45-1.36(m,2H)ppm. MS m / z 578.8[M+H] + .

[0322] Example 18: Preparation of Compound 18

[0323] Compound 18-a (200 mg, 1.94 mmol) and 3-bromopropyne (346 mg, 2.91 mmol) were dissolved in N,N-dimethylformamide (6 mL). Cesium carbonate (1.26 g, 3.88 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to give a yellow oily product 18-b (192 mg, 70% yield). MS m / z 142.1 [M+H] + .

[0324] The synthesis of compound 18 was performed using the same method as that used for compound 17. The final product was a yellow solid, product 18 (6 mg). 1 H NMR (500MHz, DMSO-d6) δ13.19(brs,1H),7.47(d,J=1.8Hz,1H),7.43(t,J=8.4Hz,1H),7.30(s,1H),6.79(d,J= 8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz,1H),4.89(s,2H),3.79(s,6H),3.31(s,2H),2.63-2.55(m,8H)ppm. MS m / z 609.8[M+H] + .

[0325] Example 19: Preparation of Compound 19

[0326] Compound 19-a (300 mg, 1.89 mmol), tert-butyldimethyl(2-propynoxy)silane (353 mg, 2.08 mmol), cuprous iodide (36 mg, 0.189 mmol), and bis(triphenylphosphine)palladium dichloride (132 mg, 0.189 mmol) were dissolved in N,N-dimethylformamide (3 mL). Triethylamine (574 mg, 5.67 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain a colorless liquid compound 19-b (372 mg, yield 79%).

[0327] Compound 19-b (190 mg, 0.765 mmol) was added dropwise to methanol (3 mL) at room temperature with methanol hydrochloric acid (4 M, 1.15 mmol). The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The reaction solution was then adjusted to pH 7-9 by adding sodium bicarbonate solution under ice bath conditions. The mixture was then extracted with dichloromethane (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a colorless liquid compound 19-c (80 mg, yield 78%).

[0328] Compound 10-g (50 mg, 0.163 mmol), compound 19-c (26 mg, 0.196 mmol), and triphenylphosphine (64 mg, 0.245 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (56 mg, 0.245 mmol) was added under nitrogen protection and in an ice bath. The reaction was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (dichloromethane:methanol = 35:1) to obtain a colorless liquid compound 19-d (30 mg, yield 44%).

[0329] Compound 19-d (30 mg, 0.071 mmol) was dissolved in tetrahydrofuran (2 mL), and then trimethyltin hydroxide (32 mg, 0.177 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 19-e (25 mg, yield 86%). MS m / z 409.1 [M+H] + .

[0330] Compound 19-e (35 mg, 0.085 mmol) and compound 4-i (24 mg, 0.085 mmol) were dissolved in acetonitrile (1 mL). N-methylimidazole (21 mg, 0.255 mmol) and N,N,N',N'-tetramethylchlorourea hexafluorophosphate (36 mg, 0.128 mmol) were added sequentially at room temperature, and the mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain solid compound 19-f (50 mg, yield 87%). MS m / z 669.1 [M+H] + .

[0331] Compound 19-f (14 mg, 0.021 mmol) was dissolved in methanol (1 mL), and triethylamine (0.05 mL) was added at room temperature. The reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a pale yellow solid compound 19 (2.36 mg, yield 19%). 1 H NMR (500MHz, DMSO-d6) δ13.28(br,1H),8.81(d,J=4.9Hz,1H),7.52(t,J=4.9Hz,1H),7.47(s,1H),7.41(t,J=8.4 Hz,1H),7.34-7.28(m,1H),6.77(d,J=8.5Hz,2H),6.65(br,3H),5.44(d,J=1.7Hz,1H),5.16(s,2H),3.74(s,6H). MS m / z 572.8[M+H] + .

[0332] Example 20: Preparation of Compound 20

[0333] The synthesis of compound 20 was performed using the same method as that used for compound 17. The final product was a pale yellow solid, product 20 (4.2 mg). 1 H NMR(500MHz,DMSO-d6)δ13.25(brs,1H),7.48(s,1H),7.46-7.40(m,1H),7.33-7.27(m,1H),6.79(dd,J=8.5,1.8Hz,2 H),6.66(s,2H),5.44(s,1H),4.76(s,2H),3.78(s,6H),2.04-1.95(m,1H),0.79-0.72(m,2H),0.54-0.49(m,2H)ppm. MS m / z 534.9[M+H] + .

[0334] Example 21: Preparation of compound 21

[0335] tert-Butyldimethyl(2-propynoxy)silane (1 g, 5.47 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (2.75 mL, 6.88 mmol) was added dropwise under nitrogen protection at -78 °C. The mixture was stirred at this temperature for 1 hour, and then tetrahydropyranone (1.72 g, 17.21 mmol) was added. The mixture was then heated to room temperature and reacted for 2 hours. After the reaction was complete, saturated ammonium chloride solution was added to the reaction solution under ice bath, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oily liquid compound 21-b (712 mg, yield 46%).

[0336] Compound 21-b (200 mg, 0.739 mmol) was added dropwise to methanol (3 mL) at room temperature with methanol hydrochloric acid (4 M, 1.11 mmol). The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The pH of the reaction mixture was adjusted to 7-9 by adding sodium bicarbonate solution under ice bath conditions. The mixture was then extracted with dichloromethane (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain a colorless liquid compound 21-c (82 mg, yield 71%).

[0337] Compound 10-g (50 mg, 0.163 mmol), compound 21-c (30 mg, 0.195 mmol), and triphenylphosphine (64 mg, 0.245 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (56 mg, 0.245 mmol) was added under nitrogen protection and in an ice bath. The reaction was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 30:1) to obtain a colorless liquid compound 21-d (40 mg, yield 55%).

[0338] Compound 21-d (40 mg, 0.09 mmol) was dissolved in tetrahydrofuran (2 mL), and then trimethyltin hydroxide (41 mg, 0.225 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 21-e (18 mg, yield 46%). MS m / z 431.1 [M+H]+ .

[0339] Compound 21-e (40 mg, 0.093 mmol) and compound 4-i (26 mg, 0.093 mmol) were dissolved in acetonitrile (1 mL), and N-methylimidazole (23 mg, 0.279 mmol) and N,N,N were added sequentially at room temperature. ’ N ’ -Tetramethylchlorourea hexafluorophosphate (39 mg, 0.140 mmol) was reacted at room temperature for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to give a pale yellow solid compound 21-f (40 mg, yield 62%). MS m / z 691.1 [M+H] + .

[0340] Compound 21-f (40 mg, 0.057 mmol) was dissolved in ammonia-methanol (1 mL, 4 M) and reacted at 50 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel (ethyl acetate) to obtain a pale yellow solid, compound 21 (3.7 mg, yield 11%). MS m / z 595.1 [M+H] + . 1 H NMR(500MHz,DMSO)δ13.28(br,1H),7.53-7.27(m,3H),6.79(dd,J=8.5,1.7Hz,1H),6.66(br,2H),5.58(s,1H),5.51 -5.40(m,1H),4.91(s,2H),3.79(s,6H),3.70-3.61(m,2H),3.49-3.41(m,2H),1.73-1.60(m,2H),1.61-1.48(m,2H). MS m / z 594.8[M+H] + .

[0341] Example 22: Preparation of compound 22

[0342] Compound 22-a (1.00 g, 5.88 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 3.0 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h, and cyclobutanone (535 mg, 7.64 mmol) was added. The reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 22-b (1.40 g, 99% yield) as a white solid.

[0343] Compound 22-b (1.30 g, 5.42 mmol) was dissolved in methanol (20 mL), and hydrogen chloride methanol solution (4 M, 3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 22-c (622 mg, yield 91%).

[0344] Compound 22-c (30 mg, 0.23 mmol), compound 10-g (70 mg, 0.23 mmol), and triphenylphosphine (91 mg, 0.35 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (81 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 22-d (92 mg, 97% yield). MS m / z 414.8 [M+H] + .

[0345] Compound 22-d (92 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (99 mg, 0.55 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 22-e (79 mg, yield 89%). MS m / z 423.0 [M+Na] + .

[0346] Compound 22-e (35 mg, 0.09 mmol) and compound 4-i (24 mg, 0.09 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (37 mg, 0.45 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (128 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 22-f (19 mg, yield 33%). MS m / z 660.9 [M+H] +.

[0347] Compound 22-f (19 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 22 (2 mg, yield 13%). 1 H NMR (500MHz, DMSO) δ13.29(brs,1H),7.45(d,J=1.2Hz,1H),7.42(t,J=8.4Hz,1H),7.26(s,1H),6.79(d,J=8.5Hz,2H),6.64(s ,2H),5.73(s,1H),5.43(d,J=1.8Hz,1H),4.87(s,2H),3.79(s,6H),2.18-2.14(m,2H),2.11-2.06(m,2H),1.69-1.58(m,2H). MS m / z 564.8[M+H] + .

[0348] Example 23: Preparation of compound 23

[0349] Compound 23-a (345 mg, 1.68 mmol), tert-butyldimethyl(2-propynoxy)silane (344 mg, 2.02 mmol), cuprous iodide (32 mg, 0.168 mmol), and bis(triphenylphosphine)palladium dichloride (117 mg, 0.168 mmol) were dissolved in N,N-dimethylformamide (4 mL). Triethylamine (511 mg, 5.05 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether:ethyl acetate = 10:1) to obtain a colorless liquid compound 23-b (400 mg, yield 92%).

[0350] Compound 23-b (200 mg, 0.808 mmol) was added dropwise to methanol (3 mL) at room temperature with methanol hydrochloric acid (4 M, 1.21 mmol). The mixture was stirred at room temperature for 30 minutes until the reaction was complete. The pH of the reaction mixture was adjusted to 7-9 by adding sodium bicarbonate solution under ice bath conditions. The mixture was then extracted with dichloromethane (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a colorless liquid compound 23-c (80 mg, yield 74%).

[0351] Compound 10-g (60 mg, 0.195 mmol), compound 23-c (31 mg, 0.235 mmol), and triphenylphosphine (77 mg, 0.293 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (68 mg, 0.293 mmol) was added under nitrogen protection and in an ice bath. The reaction was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (dichloromethane:methanol = 35:1) to obtain a colorless liquid compound 23-d (64 mg, yield 77%).

[0352] Compound 23-d (64 mg, 0.151 mmol) was dissolved in tetrahydrofuran (2 mL), and then trimethyltin hydroxide (69 mg, 0.379 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 23-e (50 mg, yield 81%). MS m / z 408.1 [M+H] + .

[0353] Compound 23-e (50 mg, 0.122 mmol) and compound 4-i (34 mg, 0.122 mmol) were dissolved in acetonitrile (1 mL). N-methylimidazole (30 mg, 0.366 mmol) and N,N,N',N'-tetramethylchlorourea hexafluorophosphate (51 mg, 0.183 mmol) were added sequentially at room temperature, and the mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain a pale yellow solid compound 23-f (25 mg, yield 30%). MS m / z 668.1 [M+H] + .

[0354] Compound 23-f (25 mg, 0.037 mmol) was dissolved in ammonia-methanol (1 mL, 4 M) and reacted at 50 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (ethyl acetate) to obtain a pale yellow solid compound 23 (3.92 mg, yield 18%). 1H NMR(500MHz,DMSO)δ13.31(br,1H),8.60-8.47(m,2H),7.79(d,J=7.9Hz,1H),7.50-7.37(m,3H) ,7.31(s,1H),6.77(d,J=8.5Hz,2H),6.65(s,2H),5.49-5.41(m,1H),5.11(s,2H),3.72(s,6H). MS m / z 571.8[M+H] + .

[0355] Example 24: Preparation of compound 24

[0356] Dimethoxyphosphonoacetate tert-butyl ester (113 mg, 0.50 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to approximately 5 °C, and 60% sodium hydroxide (24 mg, 0.60 mmol) was added under nitrogen protection. The mixture was stirred for 30 minutes at this temperature, followed by the addition of compound 2-d (130 mg, 0.33 mmol). The mixture was stirred for 1 hour at 5 °C. The solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow solid compound 24-a (90 mg, yield 55%). MS m / z 487.2 [M+H] + .

[0357] Compound 24-a (90 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give a pale yellow oil, compound 24-b (79 mg, 100% yield). MS m / z 453.2 [M+Na] + .

[0358] Compound 24-b (79 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), and triethylamine (55 mg, 0.54 mmol) was added. Isobutyl chloroformate (37 mg, 0.27 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The mixture was then cooled to 5°C, and 1 mL of sodium borohydride (68 mg, 1.8 mmol) aqueous solution was added. The mixture was stirred at 5°C for another 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 24-c (20 mg, yield 26%). MS m / z 439.2 [M+Na] + .

[0359] Compound 24-c (20 mg, 0.048 mmol) and imidazole (9.5 mg, 0.14 mmol) were dissolved in dichloromethane (1.0 mL), and then tert-butyldiphenylchlorosilane (27 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a pale yellow solid compound 24-d (20 mg, yield 64%). MS m / z 677.2 [M+Na] + .

[0360] Compound 24-d (20 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (22 mg, 0.12 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and formic acid was added to adjust the pH to approximately 4. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 24-e (15 mg, 77% yield). MS m / z 663.2 [M+Na] + .

[0361] Compound 24-e (15 mg, 0.023 mmol) and compound 4-i (8 mg, 0.029 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (6.4 mg, 0.078 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (11 mg, 0.039 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid, compound 24-f (15 mg, yield 71%). MS m / z 901.2 [M+H] + .

[0362] Compound 24-f (15 mg, 0.017 mmol) was dissolved in 4 M ammonia-methanol solution (1.0 mL) and stirred overnight at 50 °C. The solution was concentrated under reduced pressure, and tetrahydrofuran (1 mL) was added, followed by 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL). The mixture was stirred for 30 minutes, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a pale yellow solid, compound 24 (1.03 mg, yield 11%). MS m / z 588.8 [M+Na] + .

[0363] Example 25: Preparation of Compound 25

[0364] The synthesis of compound 25-e was performed following the method described for compound 17. A yellow solid product, 25-e (50 mg), was obtained. MS m / z 730.8 [M+H] + .

[0365] Compound 25-e (50 mg, 0.068 mmol) was dissolved in 1,2-dichloroethane (2 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 8:1) to give a yellow solid product 25-f (34 mg, yield 72%). MS m / z 686.8 [M+H] + .

[0366] Compound 25-f (34 mg, 0.050 mmol) was dissolved in ethanol (2 mL) under ice-water bath conditions. Sodium borohydride (6 mg, 0.149 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was quenched with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a yellow solid product 25-g (24 mg, yield 70%). MS m / z 688.8 [M+H] + .

[0367] 25 g (24 mg, 0.035 mmol) of the crude product was dissolved in ammonia-methanol solution (4 M, 1.5 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to give a pale yellow solid product 25 (8.1 mg, yield 39%). 1 H NMR (500MHz, DMSO-d6) δ13.23(brs,1H),7.47(d,J=1.7Hz,1H),7.42(t,J=8. 4Hz,1H),7.30(s,1H),6.78(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz,1 H),4.85-4.76(m,2H),4.52-4.38(m,1H),3.78(s,6H),3.49-3.43(m,1H),2. 26-2.15(m,1H),1.81-1.68(m,2H),1.64-1.54(m,2H),1.52-1.38(m,4H)ppm. MS m / z 592.9 [M+H] + .

[0368] Example 26: Preparation of Compound 26

[0369] Compound 26-a (1.00 g, 5.52 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 3.0 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Formaldehyde (331 mg, 11.04 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 26-b (905 mg, yield 78%). MS m / z 212.2 [M+H] + .

[0370] Compound 26-b (70 mg, 0.33 mmol), compound 10-g (100 mg, 0.33 mmol), and triphenylphosphine (130 mg, 0.50 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (115 mg, 0.50 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 26-c (165 mg, 100% yield). MS m / z 500.2 [M+H] + .

[0371] Compound 26-c (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (91 mg, 0.50 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 26-d (85 mg, yield 88%). MS m / z 508.2 [M+Na] + .

[0372] Compound 26-d (70 mg, 0.14 mmol) and compound 4-i (40 mg, 0.14 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (57 mg, 0.70 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (39 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 26-e (33 mg, yield 31%). MS m / z 746.2 [M+H] + .

[0373] Compound 26-e (33 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), followed by the dropwise addition of trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The resulting crude compound 26-f was used directly in the next reaction step. MS m / z 646.2 [M+H] + .

[0374] Compound 26-f (10 mg, 0.02 mmol) was dissolved in methanol (1 mL), followed by the addition of paraformaldehyde (1 mg, 0.05 mmol), anhydrous zinc chloride (4 mg, 0.03 mmol), and sodium cyanoborohydride (3 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 26-g (7 mg, 70% yield). MS m / z 660.1 [M+H] + .

[0375] Compound 26-g (7 mg, 0.01 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 26 (1 mg, yield 16%). MS m / z 563.9 [M+H] + .

[0376] Example 27: Preparation of Compound 27

[0377] Compound 26-f (15 mg, 0.02 mmol), glycolic acid (3 mg, 0.04 mmol), and N,N-diisopropylethylamine (9 mg, 0.07 mmol) were dissolved in acetonitrile (1 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (11 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 27-a (10 mg, 62% yield). MS m / z 704.2 [M+H] + .

[0378] Compound 27-a (10 mg, 0.01 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 27 (2 mg, yield 22%). MS m / z 607.9 [M+H] + .

[0379] Example 28: Preparation of compound 28

[0380] 10-g (70 mg, 0.229 mmol) of the compound was dissolved in dichloromethane (3 mL) under ice-water bath conditions. Triethylamine (46 mg, 0.457 mmol) and trifluoromethanesulfonic anhydride (97 mg, 0.343 mmol) were added, and the reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a colorless oily product 28-a (109 mg, 100% yield). MS m / z 438.8 [M+H] + .

[0381] Compound 28-a (100 mg, 0.228 mmol), compound 18-b (48 mg, 0.342 mmol), palladium dichloride bis(triphenylphosphine) (16 mg, 0.023 mmol), and cuprous iodide (9 mg, 0.046 mmol) were dissolved sequentially in N,N-dimethylformamide (2.5 mL), followed by the addition of triethylamine (58 mg, 0.570 mmol). The reaction mixture was bubbled under nitrogen for 1 minute and then stirred at 80 °C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow oily product 28-b (18 mg, yield 18%). MS m / z 430.0 [M+H] + .

[0382] Compound 28-b (18 mg, 0.042 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (15 mg, 0.084 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1, 1% acetic acid) to give crude white solid 28-c (19 mg, 100% yield). MS m / z 415.9 [M+H] + .

[0383] Compound 28-c (19 mg, 0.046 mmol), compound 4-i (13 mg, 0.046 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (19 mg, 0.068 mmol), and N-methylimidazole (9 mg, 0.114 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow oily crude product 28-d (35 mg, 100% yield). MS m / z 675.8 [M+H] + .

[0384] The crude product 28-d (35 mg, 0.163 mmol) was dissolved in concentrated hydrochloric acid (2 mL), and the reaction solution was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to obtain a yellow solid product 28 (5.4 mg, yield 18%). 1 H NMR (500MHz, DMSO-d6) δ13.33(brs,1H),7.47(d,J=1.7Hz,1H),7.43(t,J=8.4Hz,1H),7.30(s,1H),6.80(d,J=8. 5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz,1H),3.79(s,6H),3.45(s,2H),2.54-2.51(m,4H),2.45-2.39(m,4H)ppm. MS m / z 579.9[M+H] + .

[0385] Example 29: Preparation of compound 29

[0386] 1,1-Cyclopropanediethanol (1.00 g, 9.80 mmol) and imidazole (2.00 g, 29.41 mmol) were dissolved in dichloromethane (30 mL), and tert-butyldiphenylchlorosilane (2.83 g, 10.30 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 29-a (1.20 g, yield 36%). MS m / z 363.0 [M+Na] + .

[0387] Compound 29-a (1.20 g, 3.53 mmol) was dissolved in a dichloromethane / dimethyl sulfoxide (20 mL / 10 mL) mixture, and N,N-diisopropylethylamine (2.28 g, 17.65 mmol) was added dropwise. Then, pyridine trioxide (1.57 g, 9.90 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was diluted with water, and the mixture was extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 29-b (1.10 g, 92% yield).

[0388] Compound 29-b (1.00 g, 2.96 mmol) and potassium carbonate (612 mg, 4.44 mmol) were dissolved in methanol (20 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (682 mg, 3.55 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 29-c (860 mg, yield 87%).

[0389] Compound 29-c (860 mg, 2.57 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and n-butyllithium hexane solution (2.5 M, 1.3 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 h. Formaldehyde (154 mg, 5.14 mmol) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 29-d (605 mg, yield 64%). MS m / z 387.0 [M + Na] + .

[0390] Compound 29-d (77 mg, 0.21 mmol), compound 10-g (65 mg, 0.21 mmol), and triphenylphosphine (84 mg, 0.32 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (74 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 29-e (128 mg, 93% yield). MS m / z 652.9 [M+H] + .

[0391] Compound 29-e (128 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (89 mg, 0.49 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 29-f (107 mg, yield 86%). MS m / z 661.1 [M+Na] + .

[0392] Compound 29-f (48 mg, 0.08 mmol) and compound 4-i (21 mg, 0.08 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (33 mg, 0.40 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (22 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 29-g (17 mg, 25% yield). MS m / z 899.0 [M+H] + .

[0393] Compound 29-g (17 mg, 0.02 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude compound 29-h was used directly in the next reaction step. MS m / z 803.1 [M+H] + .

[0394] Compound 29-h (15 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 29 (4 mg, yield 38%). 1 H NMR (500MHz, DMSO-d) δ13.25(s,1H),7.47(d,J=1.3Hz,1H),7.43(t,J=8.4Hz,1H),7.30(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d, J=1.5Hz,1H),4.82-4.79(m,1H),4.77(s,2H),3.78(s,6H),3.29(d,J=4.3Hz,2H),0.75(dd,J=6.4,4.0Hz,2H),0.65(dd,J=6.4,4.0Hz,2H). MS m / z 564.8[M+H] + .

[0395] Example 30: Preparation of compound 30

[0396] Compound 22-a (1.00 g, 5.88 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction solution was cooled to -78 °C under a nitrogen atmosphere, and a 2.5 M, 3.0 mL solution of n-butyllithium-hexane was added dropwise. The reaction solution was stirred at this temperature for 0.5 h, and a tetrahydrothiaran-4-one (887 mg, 7.64 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 h. The reaction solution was quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid compound 30-b (1.60 g, 95% yield).

[0397] Compound 30-b (1.00 g, 3.50 mmol) was dissolved in methanol (20 mL), and hydrogen chloride methanol solution (4 M, 2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 30-c (443 mg, yield 74%).

[0398] Compound 30-c (28 mg, 0.16 mmol), compound 10-g (50 mg, 0.16 mmol), and triphenylphosphine (63 mg, 0.24 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (55 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 30-d (45 mg, 60% yield). MS m / z 460.9 [M+H] + .

[0399] Compound 30-d (45 mg, 0.10 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (44 mg, 0.24 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 30-e (42 mg, 95% yield). MS m / z 469.1 [M+Na] + .

[0400] Compound 30-e (42 mg, 0.09 mmol) and compound 4-i (24 mg, 0.09 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (37 mg, 0.45 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (28 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 30-f (19 mg, yield 28%). MS m / z 706.9 [M+H] + .

[0401] Compound 30-f (19 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 30 (6 mg, yield 38%). 1 H NMR(500MHz,DMSO-d)δ7.90(s,1H),7.42(t,J=8.4Hz,1H),7.26(s,1H),7.01(s,1H),6.78(d,J=8.5Hz,2H),6.63( s,2H),5.41(d,J=1.8Hz,1H),4.87(s,2H),3.79(s,6H),2.58-2.54(m,4H),1.95-1.90(m,2H),1.71-1.65(m,2H). MS m / z 610.8[M+H] + .

[0402] Example 31: Preparation of compound 31

[0403] Compound 31-a (500 mg, 3.78 mmol) was dissolved in dichloromethane (10 mL), and imidazole (515 mg, 7.57 mmol) and tert-butyldimethylchlorosilane (855 mg, 5.67 mmol) were added sequentially under ice bath conditions. The mixture was stirred at room temperature for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a white solid compound 31-b (680 mg, yield 73%).

[0404] Compound 31-b (680 mg, 6.76 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (1.72 mL, 3.31 mmol) was added dropwise under nitrogen protection at -78 °C. The mixture was stirred at this temperature for 1 hour, and then paraformaldehyde (250 mg, 8.28 mmol) was added. The mixture was then raised to room temperature and reacted for 12 hours. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution under ice bath, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a white solid compound 31-c (550 mg, yield 72%).

[0405] The synthesis of compound 31-g was performed using the same method as that used for compound 23.

[0406] Compound 31-g (20mg, 0.028mmol) was added dropwise to methanol (3mL) at room temperature with 4M methanol (0.042mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was complete, sodium bicarbonate solution was added to the reaction solution under ice bath to adjust the pH to 7-9. The mixture was then extracted with dichloromethane (3 x 15mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a pale yellow solid compound 31 (5mg, yield 30%). 1 H NMR(500MHz,DMSO)δ13.26(br,1H),7.47(s,1H),7.42(t,J=8.4Hz,1H),7.32(s,5H),6.77(d,J=8.5Hz,2H), 6.65(s,2H),5.44(d,J=1.8Hz,1H),5.27(t,J=5.5Hz,1H),5.07(s,2H),4.49(d,J=5.0Hz,2H),3.73(s,6H). MS m / z 600.8[M+H] + .

[0407] Example 32: Preparation of compound 32

[0408] Compound 10-g (40 mg, 0.131 mmol), compound 32-b (22 mg, 0.196 mmol), and triphenylphosphine (68 mg, 0.261 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (53 mg, 0.261 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 9:1) to give a white solid crude product 32-c (122 mg, 100% yield). MS m / z 424.8 [M+Na] + .

[0409] Compound 32-d (28 mg, 0.123 mmol) was dissolved in tetrahydrofuran (2 mL) under ice-water bath conditions. Sodium hydride (60%, 5 mg, 0.123 mmol) was slowly added, and the reaction mixture was stirred at 0 °C for 30 minutes. Then, a tetrahydrofuran solution of compound 32-c (33 mg, 0.082 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a colorless oily product 32-e (12 mg, yield 29%). MS m / z 522.9 [M+Na] + .

[0410] Compound 32-e (52 mg, 0.104 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid product 32-f (43 mg, yield 93%). MS m / z 466.8 [M+Na] + .

[0411] Compound 32-f (43 mg, 0.097 mmol) and triethylamine (20 mg, 0.194 mmol) were dissolved in tetrahydrofuran (3 mL) under ice-water bath conditions. Isobutyl chloroformate (20 mg, 0.145 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, an aqueous solution of sodium borohydride (22 mg, 0.581 mmol) (0.5 mL) was added, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with ethyl acetate, acidified with dilute hydrochloric acid, and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a colorless oily product 32-g (14 mg, yield 34%). MS m / z 452.9 [M+Na] + .

[0412] Compound 32-g (14 mg, 0.033 mmol) and imidazole (7 mg, 0.049 mmol) were dissolved in dichloromethane (2 mL). Tert-butyldimethylchlorosilane (5.5 mg, 0.081 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 3:1) to give a colorless oily product 32-h (16 mg, 90% yield). MS m / z 566.9 [M+Na] + .

[0413] Compound 32-h (16 mg, 0.029 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (16 mg, 0.088 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, 1% acetic acid) to give a white solid crude product 32-i (20 mg, 100% yield). MS m / z 552.9 [M+Na] + .

[0414] Compound 32-i (20 mg, 0.038 mmol), compound 4-i (10 mg, 0.038 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (16 mg, 0.057 mmol), and N-methylimidazole (6 mg, 0.075 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain a yellow oily crude product 32-j (18 mg, yield 60%).

[0415] Crude product 32-j (18 mg, 0.023 mmol) was dissolved in ammonia-methanol solution (4 M, 1 mL), and the reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain a yellow oily crude product 32-k (5 mg, yield 32%). MS m / z 717.0 [M+Na] + .

[0416] Compound 32-k (5 mg, 0.007 mmol) was dissolved in tetrahydrofuran (1 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.05 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a white solid product 32 (2.63 mg, yield 63%). 1 H NMR (500MHz, DMSO-d6) δ13.21(brs,1H),7.47(d,J=1.7Hz,1H),7.42(t,J=8.4 Hz,1H),7.29(s,1H),6.78(d,J=8.5Hz,2H),6.66(s,2H),5.44(d,J=1.8Hz,1H ),5.13(t,J=6.6Hz,1H),4.56-4.50(m,1H),4.42-4.35(m,1H),3.86-3.81(m, 2H),3.76(s,6H),1.91-1.72(m,4H),1.60-1.50(m,2H),1.47-1.40(m,2H)ppm. MS m / z 580.9 [M+H] + .

[0417] Example 33: Preparation of compound 33

[0418] (Diethoxyphosphino)fluoro-tert-butyl acetate (189 mg, 0.70 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to approximately 5 °C, and 60% sodium hydroxide (28 mg, 0.70 mmol) was added under nitrogen protection. The mixture was stirred for 30 minutes at this temperature, followed by the addition of compound 2-d (180 mg, 0.46 mmol). The mixture was stirred for 1 hour at 5 °C. The solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow solid compound 33-a (100 mg, yield 43%). MS m / z 527.2 [M+Na] + .

[0419] Compound 33-a (100 mg, 0.20 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a pale yellow oily compound 33-b (50 mg, yield 56%). MS m / z 471.2 [M+Na] + .

[0420] Compound 33-b (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 mL), and N,N'-carbonyldiimidazole (27 mg, 0.17 mmol) was added at room temperature. The mixture was stirred for 1 hour, followed by the addition of 1 mL of sodium borohydride (17 mg, 0.45 mmol) aqueous solution, and stirring was continued for another hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 33-c (40 mg, yield 83%). MS m / z 457.2 [M+Na] + .

[0421] Compound 33-c (40 mg, 0.092 mmol) and imidazole (19 mg, 0.28 mmol) were dissolved in dichloromethane (2.0 mL), and then tert-butyldiphenylchlorosilane (38 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give a pale yellow solid compound 33-d (50 mg, yield 81%). MS m / z 695.2 [M+Na] + .

[0422] Compound 33-d (50 mg, 0.074 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (50 mg, 0.28 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and formic acid was added to adjust the pH to approximately 4. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 33-e (40 mg, 82% yield). MS m / z 681.2 [M+Na] + .

[0423] Compound 33-e (40 mg, 0.061 mmol) and compound 4-i (20 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (15 mg, 0.18 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (22 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid, compound 33-f (40 mg, 72% yield). MS m / z 919.2 [M+H] + .

[0424] Compound 34-f (40 mg, 0.044 mmol) was dissolved in methanol (3.0 mL), and N-methylpiperazine (0.5 mL) was added. The mixture was stirred overnight at 50 °C. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 33-g (20 mg, yield 56%). MS m / z 823.2 [M+H] + .

[0425] Compound 33-g (20 mg, 0.024 mmol) was dissolved in tetrahydrofuran (1 mL), then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL) was added. The mixture was stirred for 30 minutes, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a pale yellow solid, compound 33 (9 mg, yield 63%). MS m / z 584.8 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.23(s,1H),7.50-7.39(m,2H),7.29(s,1H),6.79(d,J=8.5Hz,2H),6.66(s,2H),5.44(d,J=1.8H z,1H),5.01-4.95(m,1H),4.07-4.00(m,2H),3.84-3.71(m,8H),2.61-2.53(m,2H),2.46-2.40(m,1H),2.24-2.14(m,2H).

[0426] Example 34: Preparation of compound 34

[0427] Compound 34-a (900 mg, 3.98 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydrogen (60%, 239 mg, 5.97 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour, and iodomethane (1.13 g, 7.96 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 34-b (420 mg, 44% yield).

[0428] Compound 34-b (420 mg, 1.75 mmol) was dissolved in methanol (10 mL), and hydrogen chloride methanol solution (4 M, 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 34-c (189 mg, yield 86%).

[0429] Compound 34-c (25 mg, 0.20 mmol), compound 10-g (60 mg, 0.20 mmol), and triphenylphosphine (79 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (69 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 34-d (83 mg, 100% yield). MS m / z 414.9 [M+H] + .

[0430] Compound 34-d (83 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (115 mg, 0.50 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 34-e (64 mg, 80% yield). MS m / z 423.1 [M+Na] + .

[0431] Compound 34-e (29 mg, 0.07 mmol) and compound 4-i (20 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (20 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 34-f (23 mg, yield 49%). MS m / z 660.9 [M+H] + .

[0432] Compound 34-f (23 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 34 (6 mg, yield 30%). 1 H NMR (500MHz, DMSO-d) δ13.27(brs,1H),7.47(d,J=1.7Hz,1H),7.43(t,J=8.4Hz,1H),7.31(s,1H),6.79(d,J=8.5Hz,2H),6.65( s,2H),5.44(d,J=1.8Hz,1H),4.90(s,2H),3.78(s,6H),3.18(s,3H),0.99(dd,J=7.6,4.9Hz,2H),0.80(dd,J=7.7,5.0Hz,2H). MS m / z 564.8[M+H] + .

[0433] Example 35: Preparation of compound 35

[0434] Compound 35-a (5.63 g, 51.39 mmol) was dissolved in dichloromethane (60 mL). Imidazole (7 g, 102.78 mmol) and tert-butyldimethylchlorosilane (9.29 g, 61.67 mmol) were added sequentially under ice bath conditions. The mixture was stirred at room temperature for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a white solid compound 35-b (5.7 g, yield 59%).

[0435] Compound 35-b (2 g, 10.67 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (3.24 g, 32.02 mmol) was added at room temperature, followed by 3-bromo-1-trimethylsilyl-1-propyne (2.04 g, 10.67 mmol). The mixture was stirred at room temperature for 5 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product 35-c (3.18 g, 100% yield) was used directly in the next step of the reaction.

[0436] Compound 35-c (3.18 g, 10.69 mmol) was dissolved in methanol (20 mL), and potassium carbonate (2.95 g, 21.37 mmol) was added at room temperature. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain a white solid compound 35-d (0.8 g, yield 33%).

[0437] The synthesis of compound 35-h was performed using the same method as that used for compound 23.

[0438] Compound 35-h (20 mg, 0.025 mmol) was dissolved in methanol (1 mL), and N-methylpiperazine (8 mg, 0.075 mmol) was added dropwise at room temperature. The mixture was heated to 50 °C and reacted for 3 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (dichloromethane:methanol = 30:1) to obtain a pale yellow solid compound 35-i (5 mg, yield 28%).

[0439] Compound 35-i (5 mg, 0.007 mmol) was dissolved in tetrahydrofuran (1 mL) solution, and tetrabutylammonium fluoride (4 mg, 0.018 mmol) was added dropwise under ice bath. The mixture was stirred at room temperature for half an hour. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a pale yellow solid compound 35 (2 mg, yield 48%). 1 H NMR (500MHz, DMSO) δ7.45-7.38(m,2H),7.20(s,1H),6.79(d,J=8.5Hz,2H),6.64(s,2H),5.74(br,1H),5.42( d,J=1.8Hz,1H),5.34-5.31(m,1H),4.90(s,2H),4.34-4.23(m,2H),3.78(s,6H),3.77(s,2H),3.69(br,2H). MS m / z 579.9[M+H] + .

[0440] Example 36: Preparation of compound 36

[0441] Compound 36-a (310 mg, 0.85 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (330 mg, 2.55 mmol) and bromomethyl methyl ether (159 mg, 1.28 mmol) were added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 36-b (260 mg, 75% yield).

[0442] Compound 36-b (260 mg, 0.64 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 1.3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 36-c (101 mg, yield 94%).

[0443] Compound 36-c (101 mg, 0.59 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen (60%, 36 mg, 0.89 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour, and iodomethane (167 mg, 1.18 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 36-d (118 mg, 100% yield).

[0444] Compound 36-d (118 mg, 0.59 mmol) was dissolved in dichloromethane (3 mL), and dioxane (4 M, 0.5 mL) solution of hydrogen chloride was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 36-e (29 mg, 35% yield).

[0445] Compound 36-e (29 mg, 0.21 mmol), compound 10-g (60 mg, 0.20 mmol), and triphenylphosphine (79 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (69 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 36-f (32 mg, 36% yield). MS m / z 429.0 [M+H] + .

[0446] Compound 36-f (32 mg, 0.07 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (34 mg, 0.19 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 36-g (18 mg, yield 58%). MS m / z 437.1 [M+Na] + .

[0447] Compound 36-g (18 mg, 0.04 mmol) and compound 10-i (12 mg, 0.04 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (17 mg, 0.20 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (11 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 36-h (19 mg, 65% yield). MS m / z 674.9 [M+H] + .

[0448] Compound 36-h (19 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 36 (6 mg, yield 37%). 1 H NMR(500MHz,DMSO-d)δ13.27(brs,1H),7.48-7.46(m,1H),7.43(t,J=8.4Hz,1H),7.30(s,1H),6.79(d,J=8.5Hz,2H),6.66 (s,2H),5.44(d,J=1.7Hz,1H),4.81(s,2H),3.78(s,6H),3.14(s,3H),2.60(s,2H),0.66-0.62(m,2H),0.49-0.46(m,2H). MS m / z 578.8[M+H] + .

[0449] Example 37: Preparation of compound 37

[0450] Compound 37-a (36 mg, 0.206 mmol) was dissolved in tetrahydrofuran (4 mL) under ice-water bath conditions. Sodium hydride (60%, 6 mg, 0.154 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. Then, a tetrahydrofuran solution (0.5 mL) of compound 2-d (40 mg, 0.103 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water, adjusted to acidic pH with dilute hydrochloric acid, and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid crude product 37-b (13 mg, yield 31%). MS m / z 433.9 [M+Na] + .

[0451] Compound 37-b (13 mg, 0.032 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (11 mg, 0.063 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, 1% acetic acid) to give crude white solid 37-c (13 mg, 100% yield). MS m / z 419.9 [M+Na] + .

[0452] Compound 37-c (13 mg, 0.033 mmol), compound 4-i (11 mg, 0.039 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (14 mg, 0.049 mmol), and N-methylimidazole (7 mg, 0.082 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow oily crude product 37-d (28 mg, 100% yield). MS m / z 657.8 [M+H] + .

[0453] The crude product 37-d (28 mg, 0.043 mmol) was dissolved in ammonia-methanol solution (4 M, 2 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to obtain a yellow solid 37 (2.2 mg, yield 9%). 1H NMR (500MHz, DMSO-d6) δ13.22(brs,1H),7.47(d,J=1.5Hz,1H),7.43(t,J=8.4Hz,1H),7.26(s,1H),6.79(dd,J=8.4,3.4Hz,2H),6.65(s,2 H),5.44(d,J=1.8Hz,1H),5.43-5.41(m,1H),4.11-4.02(m,2H),3.77(s,6H),2.79-2.69(m,2H),2.58-2.53(m,1H),2.47-2.38(m,2H)ppm. MS m / z 561.9[M+H] + .

[0454] Example 38: Preparation of compound 38

[0455] Compound 38-a (380 mg, 3.80 mmol) and imidazole (517 mg, 7.59 mmol) were dissolved in dichloromethane (6 mL), and tert-butyldimethylchlorosilane (744 mg, 4.93 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give a colorless oily product 38-b (817 mg, 100% yield).

[0456] Trimethyl phosphate acetate (476 mg, 2.61 mmol) was dissolved in tetrahydrofuran (6 mL) under ice-water bath conditions. Sodium hydride (60%, 134 mg, 3.36 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution (2 mL) of compound 38-b (400 mg, 1.87 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12:1) to give a colorless oily product 38-c (296 mg, yield 59%). MS m / z 293.1 [M+Na] + .

[0457] Compound 38-c (296 mg, 1.09 mmol) was dissolved in dichloromethane (5 mL) under ice-water bath conditions, and a solution of diisobutylaluminum hydride in n-hexane (1 M, 2.2 mL) was added. The reaction mixture was stirred at 0 °C and slowly raised to room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane and quenched with water. The mixture was filtered and washed with diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give a colorless oily product 38-d (123 mg, yield 46%). MS m / z 265.1 [M + Na] + .

[0458] Compound 38-d (123 mg, 0.507 mmol) was dissolved in tetrahydrofuran (4 mL) under ice-water bath conditions. Sodium hydride (60%, 30 mg, 0.761 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution of iodomethane (360 mg, 2.54 mmol) (1 mL) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a colorless oily product 38-e (126 mg, 97% yield). MS m / z 279.1 [M+Na] + .

[0459] Compound 38-e (126 mg, 0.491 mmol) was dissolved in tetrahydrofuran (3 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 1.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a colorless oily product 38-f (60 mg, yield 86%).

[0460] Compound 38-f (60 mg, 0.422 mmol) and triethylamine (107 mg, 1.05 mmol) were dissolved in dichloromethane (4 mL) under ice-water bath conditions. p-Toluenesulfonyl chloride (145 mg, 0.760 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) to give a colorless oily product 38-g (83 mg, yield 66%). MS m / z 319.0 [M+Na] + .

[0461] Compound 38-g (83 mg, 0.280 mmol) and compound 10-g (103 mg, 0.336 mmol) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (137 mg, 0.420 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 4:1) to give a yellow oily product 38-h (67 mg, yield 56%). MS m / z 452.9 [M+Na] + .

[0462] Compound 38-h (67 mg, 0.156 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (56 mg, 0.311 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1, 1% acetic acid) to give crude white solid 38-i (62 mg, yield 96%). MS m / z 438.9 [M+Na] + .

[0463] Compound 38-i (30 mg, 0.072 mmol), compound 4-i (22 mg, 0.079 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (30 mg, 0.108 mmol), and N-methylimidazole (15 mg, 0.180 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 16:1) to give a yellow oily crude product 38-j (35 mg, yield 72%). MS m / z 698.9 [M+Na] + .

[0464] The crude product 38-j (35 mg, 0.052 mmol) was dissolved in ammonia-methanol solution (4 M, 2 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a yellow solid product 38 (6.2 mg, yield 21%). 1H NMR(500MHz,DMSO-d6)δ13.22(brs,1H),7.47(d,J=1.8Hz,1H),7.43(t,J=8.4H z,1H),7.27(s,1H),6.78(dd,J=8.5,2.6Hz,2H),6.65(s,2H),5.44(d,J=1.9Hz ,1H),5.20-5.12(m,1H),4.03(d,J=6.6Hz,2H),3.76(s,6H),3.65(d,J=6.9Hz, 2H),3.14(s,3H),2.58-2.52(m,2H),2.46-2.38(m,1H),2.22-2.12(m,2H)ppm. MS m / z 580.9 [M+H] + .

[0465] Example 39: Preparation of compound 39

[0466] Compound 10-g (50 mg, 0.16 mmol), compound 39-a (41 mg, 0.32 mmol), and triphenylphosphine (63 mg, 0.24 mmol) were dissolved in tetrahydrofuran (2 mL), and then di-tert-butyl azodicarbonate (55 mg, 0.24 mmol) was added. The mixture was stirred overnight at 50°C under nitrogen protection. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 39-b (68 mg, 100% yield) as a white solid. MS m / z 417.1 [M+H]+.

[0467] Compound 39-b (68 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (116 mg, 0.64 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and the pH was adjusted to approximately 4 with the addition of formic acid. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 39-c (50 mg, yield 74%). MS m / z 425.2 [M+Na] + .

[0468] Compound 39-c (50 mg, 0.12 mmol) and compound 4-i (30 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (45 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 39-d (50 mg, 70% yield). MS m / z 663.2 [M+H] + .

[0469] Compound 39-d (50 mg, 0.075 mmol) was dissolved in methanol (3.0 mL), and N-methylpiperazine (0.5 mL) was added. The mixture was stirred overnight at 50 °C. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 39 (8 mg, yield 19%). MS m / z 566.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.21(s,1H),7.47(d,J=1.6Hz,1H),7.42(t,J=8.4Hz,1H),7.26(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d, J=1.8Hz,1H),5.20(t,J=7.2Hz,1H),4.60(d,J=7.2Hz,2H),3.76(s,6H),3.52(t,J=5.4Hz,2H),3.43(t,J=5.5Hz,2H),2.09(t,J=5.2Hz,4H).

[0470] Example 40: Preparation of Compound 40

[0471] Compound 34-a (560 mg, 2.48 mmol) and imidazole (500 mg, 7.43 mmol) were dissolved in dichloromethane (30 mL), and tert-butyldiphenylchlorosilane (716 mg, 2.60 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 40-b (1.04 g, 90% yield).

[0472] Compound 40-b (1.00 g, 2.16 mmol) was dissolved in methanol (15 mL), and hydrogen chloride methanol solution (4 M, 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give compound 40-c (818 mg, 100% yield). MS m / z 373.0 [M + Na] + .

[0473] Compound 40-c (500 mg, 1.34 mmol) was dissolved in tetrahydrofuran (10 mL), and red aluminum toluene solution (70%, 773 mg, 2.68 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 0.5 hours. The reaction mixture was quenched with water (1 mL) and dried over anhydrous sodium sulfate. The mixture was filtered through diatomaceous earth, washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 40-d (352 mg, 70% yield). 1 H NMR (500MHz, CDCl3) δ7.73-7.67(m,4H),7.44-7.34(m,6H),5.78(dt,J=15.3,6.0Hz,1H),5.3 5(d,J=15.3Hz,1H), 3.99(dd,J=6.0,1.2Hz,2H), 1.00(q,J=5.5Hz,2H), 0.56(q,J=5.5Hz,2H). MS m / z 375.1[M+Na] + .

[0474] Compound 40-d (68 mg, 0.18 mmol), compound 10-g (55 mg, 0.18 mmol), and triphenylphosphine (71 mg, 0.27 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (62 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 40-e (125 mg, 100% yield). MS m / z 641.0 [M+H] + .

[0475] Compound 40-e (125 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (81 mg, 0.45 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 40-f (63 mg, yield 56%). MS m / z 649.2 [M+Na] + .

[0476] Compound 40-f (44 mg, 0.07 mmol) and compound 4-i (20 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (20 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 40-g (28 mg, yield 44%). MS m / z 886.8 [M+H] + .

[0477] Compound 40-g (28 mg, 0.03 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 40-h (16 mg, yield 64%). MS m / z 790.8 [M+H] + .

[0478] Compound 40-h (16 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.1 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 40 (5 mg, yield 45%). 1 H NMR(500MHz,DMSO-d)δ13.20(s,1H),7.46(s,1H),7.41(t,J=8.4Hz,1H),7.23(s,1H),6.78(d,J=8.4Hz,2H),6.64(s,2H),5.65-5.57 (m,1H),5.51(s,1H),5.43(s,1H),5.31(d,J=15.3Hz,1H),4.60(d,J=6.2Hz,2H),3.77(s,6H),0.83-0.79(m,2H),0.56-0.53(m,2H). MS m / z 552.9[M+H] + .

[0479] Example 41: Preparation of compound 41

[0480] Compound 41-a (64 mg, 0.18 mmol), compound 10-g (55 mg, 0.18 mmol), and triphenylphosphine (71 mg, 0.27 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (62 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 41-b (118 mg, 100% yield). MS m / z 641.0 [M+H] + .

[0481] Compound 41-b (118 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (81 mg, 0.45 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 41-c (88 mg, 78% yield). MS m / z 649.2 [M+Na] + .

[0482] Compound 41-c (45 mg, 0.07 mmol) and compound 4-i (20 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (20 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 41-d (48 mg, yield 76%). MS m / z 886.9 [M+H] + .

[0483] Compound 41-d (48 mg, 0.05 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction mixture was heated and stirred overnight at 50 °C in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 41-e (28 mg, 65% yield). MS m / z 790.8 [M+H] + .

[0484] Compound 41-e (28 mg, 0.04 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.2 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 41 (10 mg, yield 51%). 1H NMR (500MHz, DMSO-d) δ13.20 (brs, 1H), 7.47 (d, J = 1.7Hz, 1H), 7.42 (t, J = 8. 4Hz,1H),7.26(s,1H),6.78(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz, 1H),5.27-5.24(m,1H),5.15-5.11(m,1H),4.50-4.41(m,2H),4.08-4.03(m ,1H),3.76(s,6H),2.80-2.73(m,2H),2.45-2.43(m,1H),2.36-2.32(m,1H). MS m / z 552.9[M+H] + .

[0485] Example 42: Preparation of compound 42

[0486] Trimethyl phosphate acetate (437 mg, 2.40 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydrogen (60%, 96 mg, 2.40 mmol) was added under a nitrogen atmosphere and an ice bath. The reaction mixture was stirred in an ice bath for 1 hour. Then, compound 42-a (200 mg, 2.00 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 42-b (310 mg, 99% yield).

[0487] Compound 42-b (310 mg, 1.99 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (151 mg, 3.97 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction solution was quenched with water (1 mL) and dried over anhydrous sodium sulfate. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 42-c (110 mg, 43% yield).

[0488] Compound 42-c (22 mg, 0.17 mmol), compound 10-g (35 mg, 0.11 mmol), and triphenylphosphine (67 mg, 0.26 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (59 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 42-d (52 mg, 100% yield). MS m / z 417.0 [M+H] + .

[0489] Compound 42-d (52 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (50 mg, 0.28 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 42-e (43 mg, yield 793%). MS m / z 425.1 [M+Na] + .

[0490] Compound 42-e (29 mg, 0.07 mmol) and compound 4-i (20 mg, 0.07 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (29 mg, 0.35 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (20 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 42-f (28 mg, yield 59%). MS m / z 662.9 [M+H] + .

[0491] Compound 42-f (28 mg, 0.04 mmol) was dissolved in ammonia-methanol solution (1 M, 1 mL). The reaction solution was heated and stirred overnight at 50 °C in a sealed tube. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 42 (8 mg, yield 33%). 1 H NMR(500MHz,DMSO-d)δ13.20(brs,1H),7.47(d,J=1.8Hz,1H),7.42(t,J=8.4 Hz,1H),7.26(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz,1 H),5.21-5.17(m,1H),4.54-4.42(m,2H),3.85-3.80(m,1H),3.76(d,J=1.1H z,6H),3.13(s,3H),2.81-2.74(m,2H),2.48-2.45(m,1H),2.38-2.33(m,1H). MS m / z 566.9 [M+H] + .

[0492] Example 43: Preparation of compound 43

[0493] Compound 38-d (23 mg, 0.095 mmol), compound 10-g (32 mg, 0.104 mmol), and triphenylphosphine (75 mg, 0.285 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (58 mg, 0.285 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a colorless oily product 43-b (33 mg, yield 65%). MS m / z 553.0 [M+Na] + .

[0494] Compound 43-b (33 mg, 0.062 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (22 mg, 0.124 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 16:1) to give a white solid product 43-c (26 mg, yield 81%). MS m / z 539.0 [M+Na] + .

[0495] Compound 43-c (26 mg, 0.050 mmol), compound 4-i (15 mg, 0.055 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (18 mg, 0.065 mmol), and N-methylimidazole (10 mg, 0.126 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow oily crude product 43-d (31 mg, yield 79%). MS m / z 777.0 [M+H] + .

[0496] Compound 43-d (31 mg, 0.040 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.12 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a white solid product 43-e (17 mg, yield 64%). MS m / z 684.9 [M + Na] + .

[0497] Compound 43-e (17 mg, 0.026 mmol) was dissolved in ammonia-methanol solution (4 M, 1.5 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to give a pale yellow solid product 43 (6.2 mg, yield 43%). 1 H NMR(500MHz,DMSO-d6)δ13.22(brs,1H),7.47(s,1H),7.42(t,J=8.4Hz,1H) ,7.24(s,1H),6.78(d,J=8.5Hz,2H),6.65(s,2H),5.43(d,J=1.6Hz,1H),5. 10-4.99(m,1H),4.59-4.51(m,1H),4.44(d,J=7.0Hz,2H),3.76(s,6H),3.2 6-3.12(m,2H),2.60-2.53(m,2H),2.33-2.25(m,2H),2.25-2.17(m,1H)ppm. MS m / z 566.9[M+H] + .

[0498] Example 44: Preparation of compound 44

[0499] Compound 44 was synthesized using the same method as Compound 45, yielding a pale yellow solid, compound 44 (29 mg, yield 55%). 1 H NMR (500MHz, DMSO) δ13.18(br,1H),7.48(d,J=1.5Hz,1H),7.42(t,J=8.4Hz,1H),7.26(br,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.45(d,J =1.7Hz,1H),5.15(t,J=7.1Hz,1H),4.60(d,J=7.1Hz,2H),3.86(s,4H) ,3.76(s,6H),2.15-2.06(m,4H),1.57-1.51(m,2H),1.50-1.44(m,2H). MS m / z 622.9[M+H] + .

[0500] Example 45: Preparation of compound 45

[0501] Triethyl phosphonoacetate (1.44 g, 6.44 mmol) was dissolved in tetrahydrofuran (10 mL). Sodium hydrogen (257 mg, 6.44 mmol) was added under nitrogen protection in an ice bath. After stirring at this temperature for one hour, compound 45-a (550 mg, 4.29 mmol) was added and stirred at room temperature for 3 hours. After the reaction was complete, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a colorless liquid compound 45-b (580 mg, yield 68%).

[0502] Compound 45-b (560 mg, 2.82 mmol) was dissolved in tetrahydrofuran (10 mL), and diisobutylaluminum hydride (1 M, 5.65 mmol) was added dropwise under nitrogen protection in an ice bath. The mixture was stirred at this temperature for 1 hour. After the reaction was completed, sodium sulfate decahydrate (5 g) was added to the reaction solution under ice bath and stirred for half an hour. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a colorless liquid compound 45-c (340 mg, yield 77%).

[0503] Compound 10-g (60 mg, 0.196 mmol), compound 45-c (37 mg, 0.235 mmol), and triphenylphosphine (77 mg, 0.294 mmol) were dissolved in tetrahydrofuran. Di-tert-butyl azodicarbonate (68 mg, 0.294 mmol) was added under nitrogen protection in an ice bath. The reaction was stirred at room temperature for one hour until the reaction was complete. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (dichloromethane:methanol = 35:1) to obtain a colorless liquid compound 45-d (80 mg, yield 92%).

[0504] Compound 45-d (80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), and then trimethyltin hydroxide (81 mg, 0.45 mmol) was added. The mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain solid compound 45-e (52 mg, yield 67%). MS m / z 431.1 [M+H] + .

[0505] Compound 45-e (30 mg, 0.07 mmol) and compound 4-i (19 mg, 0.07 mmol) were dissolved in acetonitrile (1 mL). N-methylimidazole (17 mg, 0.21 mmol) and N,N,N',N'-tetramethylchlorourea hexafluorophosphate (29 mg, 0.105 mmol) were added sequentially at room temperature, and the mixture was reacted at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain solid compound 45-f (17 mg, yield 35%). MS m / z 691.1 [M+H] + .

[0506] Compound 45-f (17 mg, 0.025 mmol) was dissolved in methanol (1 mL), and N-methylpiperazine (0.05 mL) was added at room temperature. The reaction was carried out at 50 °C for 8 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a pale yellow solid compound 45 (4.2 mg, yield 28%). 1 H NMR(500MHz,DMSO-d6)δ13.19(br,1H),7.46(s,1H),7.42(t,J=8.4Hz,1H),7. 24(s,1H),6.78(d,J=8.4Hz,2H),6.65(s,2H),5.44(d,J=1.6Hz,1H),5.10(t,J =7.2Hz,1H),4.58(d,J=7.2Hz,2H),3.74(s,6H),3.28-3.25(m,1H),3.22(s,3H ),2.23-2.07(m,2H),1.96-1.79(m,2H),1.78-1.63(m,2H),1.38-1.26(m,2H). MS m / z 594.9 [M+H] + .

[0507] Example 46: Preparation of Compound 46

[0508] Compound 46-a (60 mg, 0.20 mmol), compound 10-g (58 mg, 0.40 mmol), and triphenylphosphine (79 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL), and then di-tert-butyl azodicarbonate (69 mg, 0.30 mmol) was added. The mixture was stirred overnight at 50°C under nitrogen protection. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid compound 46-b (80 mg, 94% yield). MS m / z 433.1 [M+H] + .

[0509] Compound 46-b (80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (130 mg, 0.72 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and the pH was adjusted to approximately 4 with the addition of formic acid. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 46-c (60 mg, yield 78%). MS m / z 441.2 [M+Na] + .

[0510] Compound 46-c (60 mg, 0.14 mmol) and compound 4-i (30 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (45 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 46-d (50 mg, yield 68%). MS m / z 679.2 [M+H] + .

[0511] Compound 46-d (50 mg, 0.075 mmol) was dissolved in methanol (3.0 mL), and N-methylpiperidine (0.5 mL) was added. The mixture was stirred overnight at 50 °C. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 46 (18 mg, yield 42%). MS m / z 582.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.25(s,1H),7.47(d,J=1.4Hz,1H),7.42(t,J=8.4Hz,1H),7.25(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J =1.7Hz,1H),5.20(t,J=7.0Hz,1H),4.60(d,J=7.1Hz,2H),3.77(s,6H),2.60-2.53(m,2H),2.46(dd,J=7.0,4.2Hz,2H),2.31(d,J=4.4Hz,4H).

[0512] Example 47: Preparation of Compound 47

[0513] Trimethyl phosphate acetate (270 mg, 1.48 mmol) was dissolved in tetrahydrofuran (5 mL) under ice-water bath conditions. Sodium hydride (60%, 82 mg, 2.05 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution (1 mL) of compound 47-a (130 mg, 1.14 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a colorless oily product 47-b (150 mg, yield 77%). 1 H NMR (500MHz, CDCl3) δ5.69-5.61(m,1H),3.68(s,3H),3.47-3.39(m,2H),3.36(s,3H),3.28-3.18(m,1H),2.96-2.81(m,2H),2.73-2.56(m,2H)ppm.

[0514] Compound 47-b (150 mg, 0.881 mmol) was dissolved in dichloromethane (4 mL) under ice-water bath conditions, and a solution of diisobutylaluminum hydride in n-hexane (1 M, 1.76 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with dichloromethane and quenched with water. The mixture was washed through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a colorless oily product 47-c (78 mg, yield 62%). 1 H NMR (500MHz, CDCl3) δ5.43-5.36(m,1H),4.02(d,J=7.0Hz,2H),3.41(d,J=6.9Hz ,2H),3.36(s,3H),2.89-2.73(m,2H),2.66-2.53(m,1H),2.52-2.36(m,2H)ppm.

[0515] Compound 47-c (30 mg, 0.211 mmol), compound 10-g (71 mg, 0.232 mmol), and triphenylphosphine (111 mg, 0.422 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (85 mg, 0.422 mmol) was added, and the reaction mixture was stirred at 65 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow oily crude product 47-d (204 mg, 100% yield). MS m / z 453.0 [M+Na] + .

[0516] Crude 47-d (204 mg, theoretical yield: 91 mg, 0.211 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (115 mg, 0.634 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to give a white solid product 47-e (82 mg, yield 93%). MS m / z 438.9 [M+Na] + .

[0517] Compound 47-e (40 mg, 0.096 mmol), compound 4-i (29 mg, 0.105 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (35 mg, 0.125 mmol), and N-methylimidazole (20 mg, 0.240 mmol) were dissolved in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow oily crude product 47-f (68 mg, 100% yield). MS m / z 698.8 [M+Na] + .

[0518] Compound 47-f (68 mg, 0.100 mmol) was dissolved in ammonia-methanol solution (4 M, 2 mL), and the reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid product 47 (14.7 mg, yield 25%). 1 H NMR(500MHz,DMSO-d6)δ13.23(brs,1H),7.47(d,J=1.5Hz,1H),7.42(t,J=8 .4Hz,1H),7.26(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.6H z,1H),5.11-5.01(m,1H),4.49-4.39(m,2H),3.76(s,6H),3.27-3.24(m,2H ),3.21(s,3H),2.67-2.55(m,2H),2.46-2.39(m,1H),2.33-2.16(m,2H)ppm. MS m / z 581.0[M+H] + .

[0519] Example 48: Preparation of Compound 48

[0520] Compound 44-e (25 mg, 0.035 mmol) was dissolved in toluene (1 mL), and formic acid (8 mg, 0.174 mmol) was added. The reaction was stirred at room temperature for 3 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain a white solid compound 48-a (12 mg, yield 51%).

[0521] Compound 48-a (5 mg, 0.007 mmol) was dissolved in ammonia-methanol (0.3 mL, 4 M) and reacted at 50 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1, 2% ammonia) to obtain a white solid compound 48 (0.82 mg, yield 19%). 1 H NMR(500MHz,DMSO-d6)δ13.20(br,1H),7.50-7.36(m,2H),7.26(s,1H),7.20(s,1H),6.79(d,J=8.5Hz,1H),6.65( s,2H),5.43(s,1H),5.37-5.26(m,1H),4.65(d,J=7.0Hz,2H),3.77(s,6H),2.41-2.31(m,4H),2.29-2.20(m,4H). MS m / z 578.8[M+H] + .

[0522] Example 49: Preparation of Compound 49

[0523] Compound 48-a (6 mg, 0.009 mmol) was dissolved in ethanol (0.5 mL), and sodium borohydride (1 mg, 0.026 mmol) was added under ice bath conditions. The reaction was completed after stirring for 10 minutes at this temperature. The reaction solution was quenched with methanol and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 25:1) to obtain a white solid compound 49-a (2 mg, yield 33%).

[0524] Compound 49-a (2 mg, 0.003 mmol) was dissolved in ammonia-methanol (0.2 mL, 4 M) and reacted at 50 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a white solid compound 49 (0.83 mg, yield 48%). MS m / z 580.8 [M+H] + .

[0525] Example 50: Preparation of Compound 50

[0526] Compound 50-a (600 mg, 5.99 mmol) and imidazole (734 mg, 10.79 mmol) were dissolved in dichloromethane (12 mL). Tert-butyldiphenylchlorosilane (2.14 g, 7.79 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 12:1) to give a colorless oily crude product 50-b (2.52 g, 100% yield). MS m / z 361.0 [M+Na] + .

[0527] Triethyl 2-fluoro-2-phosphorylacetate (215 mg, 0.886 mmol) was dissolved in tetrahydrofuran (4 mL) under ice-water bath conditions. Sodium hydride (60%, 47 mg, 1.18 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. A tetrahydrofuran solution (1 mL) of compound 50-b (200 mg, 0.591 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a colorless oily product 50-c (129 mg, yield 51%). MS m / z 449.0 [M+Na] + .

[0528] Compound 50-c (129 mg, 0.302 mmol) was dissolved in dichloromethane (2.5 mL) under ice-water bath conditions, and a solution of diisobutylaluminum hydride in n-hexane (1 M, 0.60 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with dichloromethane and quenched with water. The mixture was washed through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a colorless oily product 50-d (56 mg, yield 48%).

[0529] Compound 50-d (56 mg, 0.146 mmol) was dissolved in tetrahydrofuran (2 mL) under ice-water bath conditions. Sodium hydride (60%, 9 mg, 0.218 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. Iodomethane (83 mg, 0.582 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give a colorless oily product 50-e (35 mg, yield 60%). MS m / z 421.0 [M+Na]+ .

[0530] Compound 50-e (35 mg, 0.088 mmol) was dissolved in tetrahydrofuran (1.5 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.18 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 3:1) to give a colorless oily crude product 50-f (15 mg, 100% yield).

[0531] Compound 50-f (14 mg, 0.087 mmol), compound 10-g (27 mg, 0.087 mmol), and triphenylphosphine (46 mg, 0.175 mmol) were dissolved in tetrahydrofuran (2 mL). Diisopropyl azodicarbonate (35 mg, 0.175 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow oily crude product 50-h (45 mg, 100% yield). MS m / z 470.9 [M+Na] + .

[0532] Compound 50-h (45 mg, 0.100 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (36 mg, 0.201 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to give a white solid crude product 50-i (29 mg, yield 67%). MS m / z 456.9 [M+Na] + .

[0533] Compound 50-i (29 mg, 0.067 mmol), compound 4-i (19 mg, 0.067 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (23 mg, 0.080 mmol), and N-methylimidazole (11 mg, 0.134 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a yellow oily crude product 50-k (33 mg, yield 71%). MS m / z 716.9 [M+Na] + .

[0534] The crude product 50-k (33 mg, 0.048 mmol) was dissolved in ammonia-methanol solution (4 M, 1.5 mL), and the reaction solution was stirred overnight at 50 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid product 50 (5.6 mg, yield 20%). 1 H NMR (500MHz, DMSO-d6) δ13.24(brs,1H),7.47(d,J=1.8Hz,1H),7.43(t,J=8.4Hz,1H),7.28(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d, J=1.8Hz,1H),4.08-3.99(m,2H),3.77(d,J=21.2Hz,2H),3.76(s,6H),3 .18(s,3H),2.62-2.52(m,2H),2.49-2.43(m,1H),2.27-2.18(m,2H)ppm. MS m / z 598.9[M+H] + .

[0535] Example 51: Preparation of compound 51

[0536] Compound 26-c (198 mg, 0.40 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 51-a (128 mg, yield 81%). MS m / z 400.1 [M+H] + .

[0537] Compound 51-a (128 mg, 0.32 mmol) was dissolved in methanol (2 mL), followed by the addition of compound 51-b (84 mg, 0.48 mmol), anhydrous zinc chloride (87 mg, 0.64 mmol), and sodium cyanoborohydride (40 mg, 0.64 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 51-c (141 mg, 79% yield). MS m / z 558.2 [M+H] + .

[0538] The synthesis of compound 51 was performed using the same method as that used for compound 30.

[0539] Compound 51 (3 mg, yield 43%). MS m / z 593.9 [M+H] + . 1H NMR (500MHz, DMSO-d) δ7.43-7.40(m,1H),7.38(d,J=1.4Hz,1H),7.19(s,1H),7.05(s,1H),6.78(d,J=8.4Hz,2H),6.62(s,2H),5.40(d, J=1.7Hz,1H),4.98-4.93(m,1H),4.80(s,2H),4.04-3.99(m,2H),3.77(s,6H),3.66-3.63(m,2H),3.48-3.47(m,3H),2.98-2.95(m,2H).

[0540] Example 52: Preparation of compound 52

[0541] Compound 10-g (55 mg, 0.18 mmol), compound 52-a (43 mg, 0.18 mmol), and triphenylphosphine (71 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL), and then di-tert-butyl azodicarbonate (62 mg, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hours under nitrogen protection. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid compound 52-b (90 mg, 95% yield). MS m / z 528.1 [M+H] + .

[0542] Compound 52-b (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a white solid compound 52-c (40 mg, yield 82%). MS m / z 427.9 [M+H] + .

[0543] Compound 52-c (40 mg, 0.094 mmol), paraformaldehyde (27 mg, 0.9 mmol), and zinc chloride (24.5 mg, 0.18 mmol) were dissolved in methanol (2 mL), followed by the addition of sodium cyanoborohydride (30 mg, 0.48 mmol). The mixture was stirred at 50°C for 3 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid, compound 52-d (40 mg, 97% yield). MS m / z 442.1 [M+H] + .

[0544] Compound 52-d (40 mg, 0.091 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (65 mg, 0.36 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give a pale yellow solid, compound 52-e (25 mg, 65% yield). MS m / z 450.2 [M+Na] + .

[0545] Compound 52-e (25 mg, 0.058 mmol) and compound 4-i (15 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (24 mg, 0.29 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (24 mg, 0.087 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 52-f (30 mg, yield 81%). MS m / z 688.2 [M+H] + .

[0546] Compound 52-f (27 mg, 0.039 mmol) was dissolved in methanol (1.0 mL), and then 7 M ammonia-methanol solution (2 mL) was added. The mixture was stirred overnight at 50 °C. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 52 (7 mg, yield 30%). MS m / z 591.9 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.45-7.31(m,2H),6.96(s,1H),6.78(d,J=8.5Hz,2H),6.61(s,2H),5.39(s, 1H),4.77(s,2H),3.75(s,6H),3.11-2.85(m,5H),2.64(s,3H),1.94-1.84(m,2H),1.66-1.54(m,2H).

[0547] Example 53: Preparation of compound 53

[0548] Compound 53-a (70 mg, 0.56 mmol), compound 28-a (80 mg, 0.18 mmol), and palladium dichloride dichloride (7 mg, 0.01 mmol) were dissolved in DMF (2 mL), followed by the addition of triethylamine (110 mg, 1.09 mmol). The mixture was stirred at 80°C for 4 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 53-b (70 mg, 93% yield). MS m / z 414.1 [M+H] + .

[0549] Compound 53-b (70 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (116 mg, 0.64 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 53-c (60 mg, yield 89%). MS m / z 422.2 [M+Na] + .

[0550] Compound 53-c (37 mg, 0.093 mmol) and compound 53-d (25 mg, 0.062 mmol) were dissolved in dichloromethane (2.0 mL), and then pyridine (0.5 mL) was added. The reaction was carried out at 0°C with the addition of phosphorus oxychloride (46 mg, 0.30 mmol), and stirring was continued for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 53-e (5 mg, yield 10%). MS m / z 786.2 [M+H] + .

[0551] Compound 53-e (5 mg, 0.0063 mmol) was dissolved in dichloromethane (1.0 mL), and DBU (50 mg, 0.33 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 53 (2.5 mg, 70% yield). MS m / z 564.0 [M+H]+. 1H NMR(500MHz,DMSO-d6)δ13.37(br,1H),7.51-7.38(m,2H),7.28(s,1H),6.79(d,J=8.5Hz,2H),6. 65(s,2H),5.43(d,J=1.8Hz,1H),3.88-3.74(m,6H),3.48(s,4H),3.42(s,2H),2.24-2.12(m,4H).

[0552] Example 54: Preparation of compound 54

[0553] Compound 54-a (50 mg, 0.36 mmol), compound 28-a (80 mg, 0.18 mmol), and palladium dichloride dichloride (7 mg, 0.01 mmol) were dissolved in DMF (2 mL), followed by the addition of potassium carbonate (80 mg, 0.58 mmol). The mixture was stirred at 80°C for 4 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 54-b (50 mg, yield 64%). MS m / z 427.1 [M+H] + .

[0554] Compound 54-b (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (87 mg, 0.48 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give a pale yellow solid, compound 54-c (40 mg, yield 83%). MS m / z 435.2 [M+Na] + .

[0555] Compound 54-c (40 mg, 0.097 mmol) and compound 4-i (18 mg, 0.065 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (45 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 54-d (30 mg, yield 69%). MS m / z 673.2 [M+H] + .

[0556] Compound 54-d (30 mg, 0.045 mmol) was dissolved in concentrated hydrochloric acid (2.0 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 54 (14 mg, yield 54%). MS m / z 576.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.10-7.88(m,1H),7.46-7.33(m,2H),7.04(s,1H),6.78(d,J=8.5Hz,2H),6.61(s ,2H),5.39(d,J=1.8Hz,1H),3.78(s,6H),3.40(s,2H),3.01-2.78(m,4H),2.61(s,3H),2.48-2.29(m,4H).

[0557] Example 55: Preparation of compound 55

[0558] Compound 55-a (200 mg, 0.93 mmol), tert-butyldimethyl(2-propynoxy)silane (316.7 mg, 1.86 mmol), bis(triphenylphosphine)palladium dichloride (42.1 mg, 0.06 mmol), and cesium carbonate (912.3 mg, 2.8 mmol) were dissolved in DMF (5 mL). The mixture was stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid product 55-b (175 mg). MS m / z 192.9 [M+H] + .

[0559] Compound 55-b (100 mg, 0.52 mmol), compound 10-g (159 mg, 0.52 mmol), and triphenylphosphine (204.6 mg, 0.78 mmol) were dissolved in tetrahydrofuran (5 mL). Diisopropyl azodicarbonate (179.6 mg, 0.78 mmol) was added, and the reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow oily product 55-c (95 mg). MS m / z 513.1 [M+Na] + .

[0560] 55-C (80 mg, 0.17 mmol) was dissolved in ethanol (6 mL) under ice-water bath conditions. Sodium borohydride (5.3 mg, 0.14 mmol) was added in portions, and the reaction mixture was stirred at -10 °C for 30 minutes. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid product 55-D (45 mg). MS m / z 452.9 [M+H] + .

[0561] Compound 55-d (45 mg, 0.099 mmol), tert-butyldimethylchlorosilane (18.1 mg, 0.12 mmol), and imidazole (8.2 mg, 0.12 mmol) were dissolved in dichloromethane (5 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow oily product and a white solid product 55-e (51 mg). MS m / z 579.4 [M+Na] + .

[0562] The synthesis of compound 55 was performed using the same method as that used for compound 52. The final product was a yellow solid, compound 55 (3.05 mg, yield 11.9%). 1 H NMR(500MHz,DMSO-d6)δ13.33(s,1H),8.76(s,2H),7.46(d,J=1.7Hz,1H),7.36–7.33(m,1H),7.18(d,J=18.1Hz,1H), 6.70–6.62(m,4H),5.48(t,J=6.0Hz,1H),5.43(d,J=1.8Hz,1H),5.27(s,2H),4.36(d,J=5.9Hz,2H),3.67(s,6H).ppm. MS m / z 602.9[M+H] + .

[0563] Example 56: Preparation of compound 56

[0564] The synthesis method of compound 56 is the same as that of compound 45.

[0565] White solid compound 56 (5.85 mg, yield 17%). 1H NMR (500MHz, DMSO-d6) δ13.19(br,1H),7.48(d,J=1.6Hz,1H),7.43(t,J=8.4Hz,1H),7.27(s,1H),6.79(d,J=8.5 Hz, 2H), 6.65 (s, 2H), 5.44 (d, J = 1.7Hz, 1H), 5.24-5.15 (m, 1H), 4.53-4.38 (m, 2H), 3.77 (s, 6H), 3.0-2.77 (m, 5H). MS m / z 561.9[M+H] + .

[0566] Example 57: Preparation of Compound 57

[0567] Compound 57-a (77 mg, 0.34 mmol), compound 10-g (105 mg, 0.34 mmol), and triphenylphosphine (134 mg, 0.51 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then di-tert-butyl azodicarbonate (118 mg, 0.51 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 57-b (168 mg, 95% yield). MS m / z 516.2 [M+H] + .

[0568] The synthesis of compound 57 was performed using the same method as that used for compound 45.

[0569] Compound 57 (7 mg, yield 29%). MS m / z 579.9 [M+H] + . 1 H NMR (500MHz, DMSO-d) δ7.40(t,J=8.4Hz,1H),7.37(d,J=1.7Hz,1H),6.98(s,1H),6.78(d,J=8.5Hz,2H),6.61(s,2H),5.39( d,J=1.8Hz,1H),5.34-5.28(m,1H),4.57(d,J=7.0Hz,2H),3.76(s,6H),3.00-2.89(m,4H),2.64(s,3H),2.32-2.27(m,4H).

[0570] Example 58: Preparation of Compound 58

[0571] The synthesis of compound 58 was performed using the same method as that used for compound 51.

[0572] Compound 58 (4 mg, yield 43%). MS m / z 610.0 [M+H] + . 1 H NMR (500MHz, DMSO-d) δ7.40(t,J=8.4Hz,1H),7.36(d,J=1.7Hz,1H),6.95(s,1H),6.78(d,J=8.5Hz,2H),6.61(s,2H),5.39(d,J=1.8Hz,1H ),5.27(t,J=6.6Hz,1H),5.10-5.05(m,1H),4.56(d,J=7.0Hz,2H),3.76(s,6H),3.65-3.63(m,2H),2.99-2.86(m,6H),2.34-2.26(m,4H).

[0573] Example 59: Preparation of compound 59

[0574] Compound 51-a (110 mg, 0.28 mmol) was dissolved in ethanol (3 mL), and then compound 59-a (30 mg, 0.42 mmol) and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were added. The reaction mixture was heated and stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 59-b (69 mg, yield 53%). MS m / z 472.2 [M+H] + .

[0575] The synthesis of compound 59 was performed using the same method as that used for compound 51.

[0576] Compound 59 (5 mg, yield 25%). MS m / z 621.9 [M+H] + . 1 H NMR (500MHz, DMSO-d) δ7.43-7.39(m,2H),7.09(s,1H),6.78(d,J=8.5Hz,2H),6.62(s,2H),5.40(d,J=1.8Hz,1H),4.80( d,J=0.7Hz,2H),4.58-4.51(m,1H),3.96-3.89(m,2H),3.78(s,6H),3.56-3.45(m,3H),2.73-2.67(m,2H),1.05(s,6H).

[0577] Example 60: Preparation of Compound 60

[0578] The synthesis method of compound 60-g is the same as that of compound 45.

[0579] Compound 60-g (6 mg, 0.009 mmol) was dissolved in dichloromethane (0.5 mL), and dioxane hydrochloride solution (0.1 mL, 4 M) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1, 2% ammonia) to obtain a white solid compound 60 (0.48 mg, yield 9%). MS m / z 551.9 [M+H] + .

[0580] Example 61: Preparation of compounds 61 and 62

[0581] The synthesis of compounds 61 and 62 followed the same method as that used for compound 50. The final results yielded yellow solid compound 61 (7.02 mg, 15% yield) and yellow solid compound 62 (3.37 mg, 7% yield).

[0582] Compound 61: 1 H NMR (500MHz, DMSO-d6) δ13.23(brs,1H),7.48(d,J=1.7Hz,1H),7.43(t,J=8.4Hz,1H),7.28(s,1H),6.78(d,J=8.5Hz,2H),6.66(s,2H),5.44(d,J= 1.8Hz,1H),4.06-3.97(m,2H),3.75(s,6H),3.60(s,2H),3.10(s,3H),2. 60-2.53(m,2H),2.42-2.32(m,1H),2.18-2.07(m,2H),1.39(s,3H)ppm,MS m / z 594.9[M+H] + .

[0583] Compound 62: 1 H NMR(500MHz,DMSO-d6)δ13.22(brs,1H),7.47(d,J=1.1Hz,1H),7.43(t,J=8 .4Hz,1H),7.27(s,1H),6.78(d,J=8.4Hz,2H),6.66(s,2H),5.44(d,J=1.6H z,1H),4.44-4.36(m,1H),4.01(d,J=6.8Hz,2H),3.75(s,6H),3.67(s,2H), 2.47-2.41(m,2H),2.38-2.31(m,1H),2.17-2.03(m,2H),1.41(s,3H)ppm,MS m / z 602.9[M+Na] + .

[0584] Example 62: Preparation of compound 63

[0585] Compound 63-a (600 mg, 3.90 mmol) and imidazole (795 mg, 11.69 mmol) were dissolved in dichloromethane (20 mL), and tert-butyldiphenylchlorosilane (1.18 g, 4.29 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 63-b (989 mg, yield 64%).

[0586] Compound 63-b (800 mg, 2.04 mmol) was dissolved in methanol (20 mL), and potassium carbonate (422 mg, 3.06 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 63-c (511 mg, 78% yield).

[0587] Compound 63-c (90 mg, 0.28 mmol), compound 28-a (80 mg, 0.19 mmol), palladium dichloride bis(triphenylphosphine) (7 mg, 0.01 mmol), cuprous iodide (4 mg, 0.02 mmol), and triethylamine (96 mg, 0.95 mmol) were dissolved in DMF (1 mL). The reaction mixture was heated and stirred at 80 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 63-e (81 mg, 70% yield). MS m / z 608.9 [M+H] + .

[0588] Compound 63-e (81 mg, 0.13 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (61 mg, 0.33 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 63-f (72 mg, 91% yield). MS m / z 616.9 [M+Na] + .

[0589] Compound 63-f (45 mg, 0.08 mmol) and compound 4-i (21 mg, 0.08 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (33 mg, 0.40 mmol) was added dropwise, followed by N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (22 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain compound 63-g (36 mg, yield 59%). MS m / z 854.9 [M+H] +.

[0590] Compound 63-g (36 mg, 0.04 mmol) was dissolved in methanol (1 mL), and N-methylimidazole (34 mg, 0.42 mmol) was added dropwise. The reaction mixture was heated at 50 °C overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 63-h (10 mg, yield 32%). MS m / z 758.9 [M+H] + .

[0591] Compound 63-h (10 mg, 0.01 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.05 mL) was added dropwise under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 63 (1 mg, yield 14%). MS m / z 520.8 [M+H] + .

[0592] Example 63: Preparation of Compound 64

[0593] Compound 64 was synthesized using the same method as compound 28, yielding solid compound 64 (9 mg, 53% yield). MS m / z 578.0 [M+H] + . 1 H NMR(500MHz,DMSO-d)δ7.46-7.42(m,2H),7.23(s,1H),6.80(d,J=8.5Hz,2H),6.64(s,2H),5 .42(d,J=1.9Hz,1H),3.78(s,6H),3.56-3.52(m,4H),2.57-2.52(m,4H),2.45-2.41(m,4H).

[0594] Example 64: Preparation of Compound 65

[0595] Compound 65-a (300 mg, 2.34 mmol) was dissolved in methanol (3 mL), and then dimethyl (1-diazo-2-oxopropyl)phosphonate (540 mg, 2.81 mmol) and potassium carbonate (647 mg, 4.68 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours until the reaction was complete. The reaction solution was then extracted with water and ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a colorless liquid compound 65-b (100 mg, yield 34%).

[0596] Compound 28-a (45 mg, 0.102 mmol), compound 65-b (15 mg, 0.123 mmol), and palladium dichloride (4 mg, 0.005 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Triethylamine (31 mg, 0.306 mmol) was added under nitrogen protection. The mixture was stirred at 80 °C for 2 hours until the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain a colorless liquid compound 65-c (40 mg, 94% yield).

[0597] The synthesis of compound 65 was performed by referring to the synthesis of compound 28, yielding a white solid compound 65 (4.6 mg, two-step yield 9.3%). 1 H NMR (500MHz, DMSO-d6) δ13.37(br,1H),7.48(d,J=1.6Hz,1H),7.43(t,J=8.4Hz,1H),7.30(s,1H),6.78(d,J=8.5Hz,2H),6.66(s,2H),5.44(d ,J=1.7Hz,1H),5.32(t,J=4.7Hz,1H),3.81-3.69(m,8H),3.16(t,J=10.9Hz,2H),2.28(d,J=6.5Hz,2H),1.49-1.41(m,2H),1.08-0.95(m,2H). MS m / z 562.9[M+H] + .

[0598] Example 65: Preparation of Compound 66

[0599] The synthesis of compound 66-a is described in the Journal of Organic Chemistry, 2024, 89, 6193–6204.

[0600] Compound 66-a (3.2 g, 17.88 mmol) was dissolved in dichloromethane (40 mL), followed by the addition of imidazole (4.87 g, 71.52 mmol) and tert-butyldiphenylchlorosilane (9.83 g, 35.76 mmol). The mixture was stirred at room temperature for 2 hours under nitrogen protection. The solution was quenched with water, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 66-b (2.5 g, yield 34%), a pale yellow oil.

[0601] Compound 66-b (500 mg, 1.20 mmol) was dissolved in dimethyl sulfoxide (5 mL), and sodium bicarbonate (302 mg, 3.60 mmol) and potassium iodide (598 mg, 3.60 mmol) were added. The mixture was stirred at 110 °C for 1.5 hours. Water was added, and the mixture was extracted with petroleum ether. The organic phase was concentrated under reduced pressure to give crude compound 66-c. The crude product was used directly in the next reaction (430 mg, 100% yield).

[0602] Compound 66-c (430 mg, 1.22 mmol) was dissolved in methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (469 mg, 2.44 mmol) and potassium carbonate (337 mg, 2.44 mmol) were added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 66-d (300 mg, 71% yield), a pale yellow oil.

[0603] Compound 66-d (59 mg, 0.17 mmol), compound 28-a (37 mg, 0.084 mmol), and palladium dichloride dichloride (7 mg, 0.01 mmol) were dissolved in dimethyl sulfoxide (2 mL), followed by the addition of triethylamine (0.5 mL). The mixture was stirred at 80°C for 1.5 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) to give a pale yellow solid, compound 66-e (45 mg, yield 84%). MS m / z 637.1 [M+H] + .

[0604] Compound 66-e (45 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (51 mg, 0.28 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 66-f (40 mg, 91% yield). MS m / z 645.2 [M+Na] + .

[0605] Compound 66-f (40 mg, 0.064 mmol) and compound 4-i (20 mg, 0.072 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (28 mg, 0.10 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 66-g (50 mg, yield 88%). MS m / z 883.2 [M+H] + .

[0606] Compound 66-g (50 mg, 0.057 mmol) was dissolved in methanol (2.0 mL), and then 0.5 mL of methylimidazole was added. The mixture was stirred at 50 °C for 6 hours. The solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 66-h (30 mg, yield 67%). MS m / z 786.9 [M+H] + .

[0607] Compound 66-h (30 mg, 0.038 mmol) was dissolved in tetrahydrofuran (2.0 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 66 (15 mg, yield 72%). MS m / z 549.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.36(s,1H),7.52-7.39(m,2H),7.31(s,1H),6.79(d,J=8.5Hz,2H),6.66(s,2H),5.44(d,J=1.9 Hz,1H),5.08(s,1H),3.77(s,6H),2.47-2.43(m,2H),1.48(t,J=7.6Hz,2H),0.45(q,J=4.8Hz,2H),0.28(q,J=4.7Hz,2H).

[0608] Example 66: Preparation of Compound 67

[0609] Compound 67-a Reference: Agricultural and biological chemistry, 1990, 54, 1531-1536.

[0610] Trimethyl phosphate acetate (328 mg, 1.80 mmol) was dissolved in tetrahydrofuran (4 mL). Sodium hydroxide (65 mg, 1.62 mmol, 60%) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes under nitrogen protection. Then, compound 67-a (180 mg, 0.90 mmol) was added, and the mixture was slowly heated to room temperature and stirred for 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a pale yellow oily compound 67-b (200 mg, yield 87%).

[0611] Compound 67-b (200 mg, 0.78 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to -60°C, and a 1 M solution of diisobutylaluminum hydride in n-hexane (2.34 mL, 2.34 mmol) was added. The mixture was stirred at -60°C for 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a pale yellow oily compound 67-c (120 mg, yield 67%).

[0612] Compound 10-g (50 mg, 0.16 mmol), compound 67-c (55 mg, 0.24 mmol), and triphenylphosphine (126 mg, 0.48 mmol) were dissolved in tetrahydrofuran (1 mL), followed by the addition of di-tert-butyl azodicarbonate (55 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen protection. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a pale yellow solid, compound 67-d (80 mg, 95% yield). MS m / z 539.2 [M+Na] + .

[0613] Compound 67-d (80 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (108 mg, 0.60 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 67-e (71 mg, 91% yield). MS m / z 525.2 [M+Na] + .

[0614] Compound 67-e (36 mg, 0.072 mmol) and compound 4-i (20 mg, 0.072 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (28 mg, 0.10 mmol) were added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 67-f (50 mg, 91% yield). MS m / z 763.2 [M+H] + .

[0615] Compound 67-f (50 mg, 0.065 mmol) was dissolved in methanol (2.0 mL), and then 0.5 mL of methylimidazole was added. The mixture was stirred at 50 °C for 4 hours. The solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 67-g (30 mg, yield 69%). MS m / z 666.9 [M+H] + .

[0616] Compound 67-g (30 mg, 0.045 mmol) was dissolved in tetrahydrofuran (2.0 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (1 mL) was added. The mixture was stirred at room temperature for 3 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 67 (11 mg, yield 41%). MS m / z 616.9 [M+Na] + . 1 H NMR(500MHz,DMSO-d6)δ13.22(s,1H),7.49-7.38(m,2H),7.27(s,1H),6.7 8(d,J=8.3Hz,2H),6.66(s,2H),5.44(s,1H),5.08(t,J=6.9Hz,1H),4.64- 4.52(m,2H),4.20(s,1H),3.76(s,6H),2.30-2.18(m,1H),2.11-1.98(m,2 H),1.93-1.79(m,1H),1.56-1.44(m,2H),1.31-1.23(m,2H),1.07(s,3H).

[0617] Example 67: Preparation of Compound 68

[0618] Triethyl 2-fluoro-2-phosphorylacetate (1.88 g, 7.76 mmol) was dissolved in tetrahydrofuran (10 mL) under ice-water bath conditions. Sodium hydride (60%, 358 mg, 8.96 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. A tetrahydrofuran solution (2 mL) of compound 68-a (1.28 g, 5.97 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 18:1) to give a yellow oily product 68-b (555 mg, yield 31%). MS m / z 325.1 [M + Na] + .

[0619] Compound 68-b (555 mg, 1.83 mmol) was dissolved in dichloromethane (6 mL) under ice-water bath conditions, and a solution of diisobutylaluminum hydride in n-hexane (1 M, 3.70 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with dichloromethane and quenched with water. The mixture was washed through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a colorless oily product 68-c (436 mg, yield 91%).

[0620] Compound 68-c (436 mg, 1.67 mmol) and imidazole (228 mg, 3.35 mmol) were dissolved in dichloromethane (6 mL), and tert-butyldiphenylchlorosilane (598 mg, 2.18 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a colorless oily product 68-d (770 mg, yield 92%).

[0621] Compound 68-d (600 mg, 1.20 mmol) was dissolved in ethanol (6 mL), and pyridine 4-methylbenzenesulfonic acid (135 mg, 0.541 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a colorless oily product 68-e (400 mg, yield 86%). 1H NMR (500MHz, CDCl3) δ7.72-7.67(m,4H),7.46-7.36(m,6H),4.10(d,J=18.6Hz,2H),3.62 -3.52(m,2H),2.82-2.71(m,1H),2.52-2.33(m,3H),2.17-2.07(m,1H),1.05(s,9H)ppm.

[0622] Compound 68-e (400 mg, 1.04 mmol) was dissolved in dichloromethane (6 mL) under ice-water bath conditions. After adding Dys-Martin oxidant (1.32 g, 3.12 mmol), the reaction mixture was stirred at room temperature for 1 hour. Once the reaction was complete, the mixture was quenched with saturated sodium thiosulfate solution and extracted with dichloromethane (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily product 68-f (260 mg, yield 65%).

[0623] Compound 68-f (260 mg, 0.680 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (196 mg, 1.02 mmol) were dissolved in methanol (4 mL) under ice-water bath conditions. Potassium carbonate (188 mg, 1.36 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a yellow oily product 68-g (238 mg, yield 93%). 1 H NMR (500MHz, CDCl3) δ7.74-7.66(m,4H),7.47-7.37(m,6H),4.15-4.02(m,2H),3.08-2.99(m,1H),2.99-2. 90(m,1H),2.82-2.74(m,1H),2.74-2.65(m,1H),2.61-2.54(m,1H),2.19(d,J=2.3Hz,1H),1.05(s,9H)ppm. MS m / z 400.9[M+Na] + .

[0624] Compound 68-g (50 mg, 0.132 mmol), compound 28-a (58 mg, 0.132 mmol), palladium dichloride bis(triphenylphosphine) (9 mg, 0.013 mmol), and cuprous iodide (5 mg, 0.026 mmol) were dissolved sequentially in N,N-dimethylformamide (2 mL), and triethylamine (33 mg, 0.330 mmol) was added. The reaction mixture was bubbled under nitrogen for 1 minute and then stirred at 80 °C for 2 hours. After the reaction mixture cooled to room temperature, it was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dipetroleum ether: ethyl acetate = 6:1) to give a yellow oily product 68-i (47 mg, yield 53%). MS m / z 689.1 [M + Na] + .

[0625] Compound 68-i (47 mg, 0.070 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (25 mg, 0.140 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to obtain a yellow oily crude product 68-j (50 mg, 100% yield). MS m / z 675.0 [M+Na] + .

[0626] Compound 68-j (50 mg, 0.077 mmol), compound 4-i (21 mg, 0.077 mmol), N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (28 mg, 0.100 mmol), and N-methylimidazole (16 mg, 0.191 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a yellow solid product 68-l (15 mg, yield 21%). MS m / z 935.0 [M+Na] + .

[0627] Compound 68-l (15 mg, 0.016 mmol) was dissolved in methanol (2 mL), and N-methylimidazole (7 mg, 0.082 mmol) was added. The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a yellow oily crude product 68-m, which was directly used in the next reaction step.

[0628] The crude product 68-m (theoretical yield: 13.42 mg, 0.016 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a yellow solid product 68 (5.2 mg, yield 55%). 1 H NMR (500MHz, DMSO-d6) δ7.48-7.42(m,2H),7.28(s,1H),6.80(dd,J=8.5,2.0Hz,2H),6.65(s,2H),5.43(d,J=1.9Hz,1H),5. 07(t,J=5.8Hz,1H),3.85(dd,J=19.9,4.9Hz,2H),3.78(s,6H),3.28-3.20(m,1H),3.06-2.94(m,2H),2.44-2.33(m,2H)ppm. MS m / z 579.0[M+H] + .

[0629] Example 68: Preparation of compound 69

[0630] The synthesis method of compound 69-b is the same as that of compound 65-c.

[0631] Compound 69-b (87 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (33 mg, 0.34 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a colorless liquid compound 69-c (65 mg, yield 92%).

[0632] The synthesis of compound 69 was performed by referring to the synthesis of compound 28, yielding a white solid compound 69 (5.37 mg, yield 18%). 1H NMR(500MHz,DMSO-d6)δ13.56(s,1H),8.49(s,1H),8.22(br,1H),7.51-7.32(m,3H),7.25-7.18(m,1H),6.81-6.77(m,1H),6.65(s ,1H),5.47-5.40(m,1H),3.78(s,6H),2.82(br,2H),2.72(s,3H),2.55(s,2H),2.31(br,2H),1.65-1.54(m,2H),1.51-1.36(m,2H). MS m / z 576.1[M+H] + .

[0633] Example 69: Preparation of Compound 70

[0634] Compound 70-d was synthesized using the same method as compound 54.

[0635] Compound 70-d (20 mg, 0.030 mmol) was dissolved in methanol (2.0 mL), and methylimidazole (0.5 mL) was added. The mixture was stirred at 50 °C for 6 hours. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 70 (5 mg, yield 29%). MS m / z 578.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.46-7.38(m,2H),7.16(s,1H),6.80(d,J=8.5Hz,2H),6.63(s,2H),5.41(d,J=1.8Hz,1H), 4.72(s,1H),3.78(s,6H),3.69(s,2H),2.72-2.58(m,4H),2.23-2.13(m,1H),1.74-1.62(m,2H),1.42-1.33(m,2H).

[0636] Example 70: Preparation of Compound 71

[0637] Compound 71-a (500 mg, 4.34 mmol) and 3-bromopropyne (620 mg, 5.21 mmol) were dissolved in acetonitrile (10 mL), and cesium carbonate (1554 mg, 4.77 mmol) was added. The mixture was stirred at room temperature for 24 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a pale yellow oil, compound 71-b (450 mg, yield 68%). MS m / z 154.1 [M+H] + .

[0638] Compound 28-a (50 mg, 0.11 mmol), compound 71-b (34 mg, 0.22 mmol), and palladium dichloride dichloride (7 mg, 0.01 mmol) were dissolved in DMSO (2 mL), followed by the addition of triethylamine (0.5 mL). The mixture was stirred at 80°C for 1 hour under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 71-c (50 mg, 99% yield). MS m / z 442.1 [M+H] + .

[0639] Compound 71-c (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (80 mg, 0.44 mmol) was added. The mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1) to give a pale yellow solid, compound 71-d (40 mg, yield 83%). MS m / z 450.2 [M+Na] + .

[0640] Compound 71-d (40 mg, 0.094 mmol) and compound 4-i (26 mg, 0.094 mmol) were dissolved in DMF (2.0 mL), followed by the addition of methylimidazole (31 mg, 0.38 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (39 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 71-e (20 mg, yield 31%). MS m / z 688.1 [M+H] + .

[0641] Compound 71-e (20 mg, 0.029 mmol) was dissolved in methanol (2.0 mL), and methylimidazole (0.5 mL) was added. The mixture was stirred at 50 °C for 6 hours. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 71 (6 mg, yield 35%). MS m / z 592.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.46-7.37(m,2H),7.14(s,1H),6.80(d,J=8.5Hz,2H),6.63(s,2H),5.40(d,J= 1.8Hz,1H),4.44(s,1H),3.85(s,2H),3.78(s,6H),2.70-2.60(m,4H),1.55-1.41(m,4H),1.11(s,3H).

[0642] Example 71: Preparation of Compound 72

[0643] Compound 72 was synthesized using the same method as compound 63, yielding solid compound 72 (10 mg, 51% yield). MS m / z 579.0 [M+H] + . 1 H NMR (500MHz, DMSO) δ7.46(d,J=1.8Hz,1H),7.41(t,J=8.4Hz,1H),7.27(s,1H),6.77(d,J=8.5Hz,2H),6.65(s,2H),5.43 (d,J=1.9Hz,1H),4.48(s,1H),3.77(s,6H),3.52–3.47(m,4H),2.43(s,2H),1.42–1.36(m,2H),1.13(d,J=12.1Hz,2H).

[0644] Example 72: Preparation of Compound 73

[0645] Compound 73-a (2 g, 11.35 mmol) was dissolved in tetrahydrofuran (20 mL), and methyl magnesium bromide (22.7 mL, 22.7 mmol) was added dropwise under nitrogen protection at -78 °C. The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was added with water and extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain colorless liquid compound 73-b (590 mg, yield 21%).

[0646] Compound 73-b (500 mg, 2.6 mmol) was dissolved in dichloromethane (5 mL), and imidazole (354 mg, 5.2 mmol) and tert-butyldimethylchlorosilane (470 mg, 3.12 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain colorless liquid compound 73-c (700 mg, yield 88%).

[0647] Compound 73-c (700 mg, 2.28 mmol) was dissolved in methanol (15 mL), and palladium on carbon (10%) was added at room temperature. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain colorless liquid compound 73-d (290 mg, yield 59%).

[0648] Compound 73-d (290 mg, 1.34 mmol) was dissolved in dichloromethane (3 mL), and Dys-Martin oxidant (852 mg, 2.01 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was washed successively with sodium thiosulfate solution and sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined. The organic phase was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain colorless liquid compound 73-e (280 mg, yield 97%).

[0649] Compound 73-f (210 mg, 0.524 mmol) was dissolved in tetrahydrofuran (1 mL). Under nitrogen protection at -78 °C, bis(trimethylaminosilyl)lithium (0.5 mL, 0.5 mmol) was added. After stirring for 1 hour under this atmosphere, compound 73-e (75 mg, 0.349 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution and then extracted with ethyl acetate (3 x 10 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain a colorless liquid compound 73-g (24 mg, yield 27%).

[0650] The synthesis of compound 73 was performed by referring to the synthesis of compound 45, yielding a white solid compound 73 (2.28 mg, yield 54%). 1H NMR (500MHz, DMSO-d6) δ13.20(s,1H),7.48(d,J=1.8Hz,1H),7.42(t,J=8.4Hz,1H),7.27(s,1H),6.79(d,J=8.5Hz,2H),6.66(s,2H),5. 44(d,J=1.9Hz,1H),5.04(s,1H),4.97-4.90(m,1H),4.02-3.93(m,2H),3.76(s,6H),2.43-2.32(m,4H),2.05-2.00(m,2H),1.16(s,3H). MS m / z 581.0[M+H] + .

[0651] Example 73: Preparation of Compound 74

[0652] Compounds 74-a (1.60 g, 7.55 mmol) and 74-b (2.13 g, 6.29 mmol) were dissolved in a mixture of ethanol and water (20 mL / 2 mL), and potassium hydroxide (846 mg, 15.10 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 74-c (1.62 g, 64% yield).

[0653] Compound 74-c (1.10 g, 2.78 mmol) was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide tetrahydrofuran solution (1 M, 4 mL) was added dropwise under an ice bath and nitrogen atmosphere. The reaction mixture was stirred under an ice bath for 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 74-d (386 mg, yield 34%). MS m / z 435.6 [M + Na] + . 1 H NMR(500MHz,DMSO-d)δ7.64-7.58(m,4H),7.48-7.42(m,6H),4.87(s,1H),3.65(d,J=6.3Hz,2H),2.92-2.85( m,1H),2.69-2.63(m,1H),2.62-2.56(m,1H),2.50-2.46(m,1H),2.41-2.35(m,1H),1.22(s,6H),1.00(s,9H).

[0654] Compound 74-d (150 mg, 0.36 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 74-e (36 mg, yield 57%).

[0655] Compound 74 was synthesized using the same method as compound 43, yielding a pale yellow solid (9 mg, 27% yield). MS m / z 634.9 [M+Na] + . 1 H NMR(500MHz,DMSO-d)δ13.22(brs,1H),7.47(d,J=1.5Hz,1H),7.42(t,J=8.4Hz,1H),7.28(s,1H),6.78(dd,J=8.4,1.0Hz,2H),6.65(s,2H),5.4 4(d,J=1.7Hz,1H),4.85(s,1H),4.07-3.99(m,2H),3.76(d,J=1.5Hz,6H ),2.76-2.69(m,1H),2.44-2.33(m,3H),2.19-2.13(m,1H),1.18(s,6H).

[0656] Example 74: Preparation of Compound 75

[0657] Dimethoxyphosphonoacetate tert-butyl ester (577 mg, 2.57 mmol) was dissolved in tetrahydrofuran (8 mL) under ice-water bath conditions. Sodium hydride (60%, 103 mg, 2.57 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. A tetrahydrofuran solution (2 mL) of compound 75-a (220 mg, 1.72 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a colorless oily product 75-b (372 mg, 96% yield). MS m / z 249.2 [M+Na] + .

[0658] Compound 75-b (58 mg, 0.255 mmol), compound 10-g (60 mg, 0.196 mmol), and triphenylphosphine (77 mg, 0.294 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropyl azodicarbonate (59 mg, 0.294 mmol) was added, and the reaction mixture was stirred at 65 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a colorless oily product 75-d (87 mg, yield 86%). MS m / z 537.0 [M+Na] + .

[0659] Compound 75-d (107 mg, 0.208 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a yellow oily product 75-e (93 mg, yield 98%). MS m / z 481.0 [M+Na] + .

[0660] Compound 75-e (98 mg, 0.203 mmol) and triethylamine (41 mg, 0.406 mmol) were dissolved in tetrahydrofuran (3 mL) under ice-water bath conditions. Isobutyl chloroformate (41 mg, 0.304 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, an aqueous solution of sodium borohydride (46 mg, 1.22 mmol) (0.5 mL) was added, and the reaction mixture was stirred at 0 °C and slowly raised to room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a colorless oily product 75-f (43 mg, yield 48%). MS m / z 467.0 [M+Na] + .

[0661] Compound 75-f (43 mg, 0.097 mmol) and imidazole (13 mg, 0.193 mmol) were dissolved in dichloromethane (3 mL). Tert-butyldiphenylchlorosilane (35 mg, 0.126 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) to give a colorless oily product 75-g (62 mg, yield 94%). MS m / z 705.2 [M+Na] + .

[0662] Compound 75-g (62 mg, 0.091 mmol) was dissolved in tetrahydrofuran (3 mL), and trimethyltin hydroxide (49 mg, 0.272 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to obtain a colorless oily crude product 75-h (64 mg, 100% yield). MS m / z 691.1 [M+Na] + .

[0663] Compounds 75-h (35 mg, 0.052 mmol), 4-i (15 mg, 0.052 mmol), N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (22 mg, 0.078 mmol), and N-methylimidazole (11 mg, 0.130 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 12:1) to give a yellow solid 75-j (33 mg, yield 68%).

[0664] Compound 75-j (33 mg, 0.036 mmol) was dissolved in methanol (2 mL), and N-methylimidazole (15 mg, 0.178 mmol) was added. The reaction mixture was stirred overnight at 50 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 40:1) to give a yellow solid product 75-k (12 mg, yield 41%).

[0665] Compound 75-k (12 mg, 0.014 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid product 75 (6.61 mg, yield 77%). 1H NMR(500MHz,DMSO-d6)δ13.22(brs,1H),7.47(d,J=1.8Hz,1H),7.43(t,J=8.4Hz,1H), 7.27(s,1H),6.78(d,J=8.5Hz,2H),6.66(s,2H),5.44(d,J=1.9Hz,1H),5.17(t,J=6.5 Hz,1H),4.41(s,1H),3.89-3.87(m,2H),3.87-3.82(m,2H),3.76(s,6H),2.44-2.36(m ,1H),2.06-1.99(m,1H),1.89-1.80(m,1H),1.63-1.45(m,4H),0.83-0.70(m,2H)ppm. MS m / z 616.9[M+Na] + .

[0666] Example 75: Preparation of Compound 76

[0667] (Diethoxyphosphino)fluoro-tert-butyl acetate (200 mg, 0.74 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to approximately 5 °C, and 60% sodium hydroxide (30 mg, 0.74 mmol) was added under nitrogen protection. The mixture was stirred for 10 minutes at this temperature, followed by the addition of compound 76-a (250 mg, 0.60 mmol). The mixture was stirred for 1 hour at 5 °C. The solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a yellow solid compound 76-b (150 mg, yield 47%). MS m / z 555.2 [M+Na] + .

[0668] Compound 76-b (150 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a pale yellow oily compound 76-c (90 mg, yield 67%). MS m / z 499.2 [M+Na] + .

[0669] Compound 76-c (90 mg, 0.19 mmol) was dissolved in tetrahydrofuran (4 mL), and N,N'-carbonyldiimidazole (47 mg, 0.29 mmol) was added at room temperature. The mixture was stirred for 1 hour, and then 1 mL of sodium borohydride (29 mg, 0.76 mmol) aqueous solution was added at 0°C. The mixture was stirred for another hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 76-d (50 mg, yield 57%). MS m / z 485.2 [M+Na] + .

[0670] Compound 76-d (50 mg, 0.11 mmol) and imidazole (37 mg, 0.55 mmol) were dissolved in dichloromethane (2.0 mL), and then tert-butyldiphenylchlorosilane (60 mg, 0.22 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give a pale yellow solid compound 76-e (70 mg, 92% yield). MS m / z 723.2 [M+Na] + .

[0671] Compound 76-e (70 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (72 mg, 0.40 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and formic acid was added to adjust the pH to approximately 4. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 76-f (50 mg, yield 73%). MS m / z 709.2 [M+Na] + .

[0672] Compound 76-f (50 mg, 0.073 mmol) and compound 4-i (20 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (15 mg, 0.18 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (22 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid, compound 76-g (50 mg, 73% yield). MS m / z 969.2 [M+H] + .

[0673] Compound 76-g (50 mg, 0.053 mmol) was dissolved in methanol (3.0 mL), and N-methylimidazole (0.5 mL) was added. The mixture was stirred overnight at 50 °C. The solution was then quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid compound 76-h (30 mg, yield 67%). MS m / z 873.2 [M+H] + .

[0674] Compound 76-h (30 mg, 0.035 mmol) was dissolved in tetrahydrofuran (1 mL), then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (0.2 mL) was added. The mixture was stirred for 30 minutes, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a pale yellow solid, compound 76 (15 mg, yield 69%). MS m / z 612.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ13.22(s,1H),7.50-7.38(m,2H),7.27(s,1H),6.79(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8Hz,1H),5.00-4.90(m, 1H),3.98(dd,J=24.4,3.2Hz,2H),3.89-3.81(m,2H),3.76(s,6H),2.57 -2.53(m,2H),1.74-1.63(m,1H),1.60-1.42(m,4H),0.86-0.71(m,2H).

[0675] Example 76: Preparation of Compound 77

[0676] The synthesis of compound 77 followed the same method as that for compound 75, and the final product 77 was a yellow solid (3.38 mg, yield 47%). 1H NMR(500MHz,DMSO-d6)δ13.21(brs,1H),7.47(d,J=1.7Hz,1H),7.42(t,J=8.4Hz,1H), 7.25(s,1H),6.78(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.9Hz,1H),4.38(t,J=5.2 Hz,1H),3.87-3.81(m,4H),3.76(s,6H),2.58-2.53(m,1H),2.45-2.40(m,1H),2.00-1 .94(m,1H),1.61(s,3H),1.59-1.52(m,2H),1.50-1.45(m,2H),0.81-0.69(m,2H)ppm. MS m / z 631.0[M+Na] + .

[0677] Example 77: Preparation of Compound 78

[0678] Compounds 74-a (289 mg, 1.36 mmol) and 78-a (500 mg, 1.36 mmol) were dissolved in ethanol (10 mL), followed by the addition of water (2 mL). The mixture was cooled to approximately 5 °C, and potassium hydroxide (112 mg, 2.00 mmol) was added. The mixture was then heated to room temperature and stirred overnight. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a yellow oily compound 78-b (300 mg, yield 52%).

[0679] Compound 78-b (240 mg, 0.57 mmol) and cuprous iodide (164 mg, 0.86 mmol) were dissolved in tetrahydrofuran (5 mL). A 1.6 M lithium methyl ether solution (0.6 mL, 0.95 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a pale yellow oily compound 78-c (150 mg, 60% yield).

[0680] Compound 78-c (150 mg, 0.34 mmol) was dissolved in tetrahydrofuran (4 mL), and tetrabutylammonium fluoride (444 mg, 1.70 mmol) was added at room temperature. The mixture was stirred for 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow oily compound 78-d (60 mg, yield 87%).

[0681] Compound 78-d (60 mg, 0.30 mmol) was dissolved in dichloromethane (4.0 mL), followed by the addition of pyridine (142 mg, 1.80 mmol) and p-toluenesulfonyl chloride (172 mg, 0.90 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily compound 78-e (75 mg, 71% yield). MS m / z 379.2 [M+Na] + .

[0682] Compound 78-e (75 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL), and compound 10-g (95 mg, 0.31 mmol) and DIPEA (163 mg, 1.26 mmol) were added. The mixture was stirred overnight at 80 °C. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid, compound 78-f (25 mg, yield 24%). MS m / z 513.2 [M+Na] + .

[0683] Compound 78-f (25 mg, 0.051 mmol) was dissolved in tetrahydrofuran (2 mL), and trimethyltin hydroxide (36 mg, 0.20 mmol) was added. The mixture was stirred overnight at room temperature. The solution was quenched with water, and formic acid was added to adjust the pH to approximately 4. Extraction was performed with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 78-g (20 mg, yield 83%). MS m / z 499.2 [M+H] + .

[0684] Compound 78-g (20 mg, 0.042 mmol) and compound 4-i (12 mg, 0.042 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), followed by the addition of N-methylimidazole (15 mg, 0.18 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (22 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow solid, compound 78-h (30 mg, 97% yield). MS m / z 499.2 [M+H] + .

[0685] Compound 78-h (30 mg, 0.041 mmol) was dissolved in methanol (2 mL), then N-methylimidazole (0.5 mL) was added. The mixture was stirred at 60°C for 6 hours, quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a pale yellow solid, compound 78 (15 mg, yield 58%). MS m / z 663.0 [M+Na] + . 1 H NMR (500MHz, DMSO-d6) δ13.22(s,1H),7.50-7.38(m,2H),7.26(s,1H),6.78(d,J=8.5Hz,2H),6.65(s,2H),5.44(d,J=1.8 Hz,1H),5.04(s,1H),3.86-3.81(m,2H),3.76(s,6H),1.60-1.40(m,6H),1.25(dd,J=6.7,2.2Hz,6H),0.88-0.70(m,3H).

[0686] Example 78: Inhibition of cGAS enzyme activity by the compound

[0687] The inhibition of cGAS enzyme activity by the compound was detected using the kinase-Glo method. The compound was serially diluted with DMSO. 150 nL of the diluted compound was transferred to a 384-well plate (DMSO final concentration 1%) and centrifuged at 1000 rpm for 1 min. 2.5 μL of working enzyme solution was added, and the plate was incubated at 25°C for 10 min. The working concentration of cGAS enzyme was 200 nM. 2.5 μL of ATP / GTP / DNA was added to initiate the reaction, and the plate was incubated at 25°C for 180 min. The final concentrations of ATP / GTP were 100 μM and DNA were 60 nM. 10 μL of kinase-Glo max solution was added to a 384-well plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 10 min. Fluorescence values ​​were read using BMG. The inhibition rate (%) was calculated using the following formula: (DMSO well control reading - compound well reading) / (DMSO well control reading - blank control reading) × 100%. The blank control wells contained DMSO and buffer solution, while the DMSO wells contained DMSO and enzyme solution. The IC50 values ​​for each compound were... 50 The values ​​were analyzed using the nonlinear regression method in XLFit 5.5.0 software. Enzyme inhibitory activity data for some representative compounds are shown in Table 1.

[0688] Table 1: Inhibitory activity of compounds against cGAS enzyme

[0689] Example 79: Inhibition of IFN-β cytokine expression in THP1 cells by the compound

[0690] Collect healthy THP1 cells (passaged at least three times after resuscitation), centrifuge at 350g for 5 minutes, discard the supernatant, and resuspend the cells in complete culture medium (RPMI 1640 + 10% FBS + 1% P / S). Use CountStar to determine cell number and viability. Resuspend the cells in induction medium (added with 0.05mM 2-mercaptoethanol) and adjust the cell density to 1×10⁶ cells / year. 6 Cells / mL. Add 100 μL THP-1 cells (1 × 10⁻¹) to each well of a 96-well plate. 5 (samples / well), then add 100 μL of 2×PMA, and incubate at 37°C with 5% CO2 for 24 hours. The final PMA concentration is 10 ng / mL.

[0691] The compound was diluted according to a specific concentration gradient. The 96-well plate was removed, centrifuged, and the culture medium was discarded. The plate was gently washed twice with PBS, then once with culture medium. 50 μL of culture medium and 50 μL of 2× compound were added, and the plate was incubated at 37°C with 5% CO2 for 1 hour. Then, 50 μL of culture medium containing 2× compound and 50 μL of 4× Lipofectamine-coated ISD were added for ISD transfection. The final ISD concentration was 2 μg / mL. The plate was incubated at 37°C with 5% CO2 for 24 hours. The supernatant was then collected, and the IFN-β concentration in the supernatant was detected using an IFN-β ELISA kit.

[0692] Data processing: For the ELISA results of each drug treatment group, GraphPad was used to fit the inhibition rate curve and generate IC50. 50 The cell activity data of some representative compounds are shown in Table 2.

[0693] Table 2: Inhibitory activity of compounds on IFN-β cytokine expression in THP1 cells

[0694] Example 80: Pharmacokinetics in Mice

[0695] Instruments: SCIEX Triple Quad 6500+ triple quadrupole liquid chromatography-mass spectrometry (LC-MS / MS), operating software Analyst 1.7.2 (Applied Biosystems, Inc.); ExionLC liquid chromatography system; Microsoft Excel for data calculation and processing. Pharmacokinetic parameters were calculated using WinNolin 8.2 software and the statistical method of moments. These mainly included kinetic parameters Tmax and T...1 / 2 Cmax, AUC 0-24h wait.

[0696] Animals: Three male C57BL / 6N or C57BL / 6J mice, weighing 25-30g, were purchased and housed in the laboratory of the experimental animal center for 3 days before use. The mice were fasted for 12 hours before and 4 hours after administration, but had free access to water during the experiment. The compound was accurately weighed, added to the solvent, and vortexed and sonicated until a homogeneous suspension was formed, thus preparing a solution of the appropriate concentration.

[0697] Drug samples: Take multiple structurally similar samples (with a molecular weight difference of more than 2 units), weigh them accurately, and administer them together (cassette PK).

[0698] Blood samples were collected from the cheek at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after oral administration. 20 μL of plasma sample (20 μL of blank plasma was added to both blank and internal standard blank samples) was transferred to a 1.5 mL centrifuge tube, and 200 μL of internal standard (50% methanol-acetonitrile solution (concentration 100 ng / mL)) solution was added (200 μL of 50% methanol-acetonitrile solution was added to double blank samples). The sample was vortexed for 5 minutes, centrifuged at 6000 g and 4 °C for 3 minutes, and 80 μL was added to 80 μL of water. After thorough mixing, the mixture was analyzed by LC-MS / MS.

[0699] Compounds were accurately weighed and formulated into different concentrations, then quantitatively analyzed by mass spectrometry to establish a standard curve. The concentrations of the compounds in plasma were then measured to determine the concentrations at different time points. All data were acquired and processed using relev...

Claims

1. A compound with the structure shown in formula (I), or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate: In formula (I): Ring A is selected from aromatic groups having 6-10 carbon atoms or 5- to 10-membered heteroaromatic groups; Ring B is selected from 5- to 6-membered heteroaromatic groups; X is selected from -O-, -S-, -NR d -、-CR h =CR h -、-C≡C-、or C 1-2 Alkyl groups; each R h Each is independently selected from hydrogen, halogen, or C. 1-2 alkyl; R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f , or NR d R d ; R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, or C 3-6 cycloalkyl; R 3 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, CN, OR f SR f , or NR d R d ; R is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 9-membered heterocyclic, C 3-8 cycloalkyl-C 1-6 Alkyl, 3- to 8-membered heterocyclic -C 1-6 Alkyl, C 4-8 Cycloalkenyl, C 4-8 Cycloalkenyl-C 1-6 Alkyl, C 2-4 alkenyl-C 3-8 cycloalkyl, C 2- 4-Alynyl-C 3-8 cycloalkyl, C 2-4 alkenyl-C 3-8 cycloalkyl-C 1-6 Alkyl, C 2-4 alkynyl-C 3-8 cycloalkyl-C 1-6 Alkyl, C 2-4 alkenyl-3- to 8-membered heterocyclic groups, C 2-4 alkynyl-3- to 8-membered heterocyclic groups, C 2-4 alkenyl-3- to 8-membered heterocyclic-C 1-6 Alkyl, C 2-4 alkynyl-3-to-8-membered heterocyclic-C 1-6 Alkyl, C 3-8 cycloalkyl-C 4-6 Alkyl, 3- to 8-membered heterocyclic -C 4-6 Alkyl, C 3-8 cycloalkyl-C 2-6 alkenyl, 3- to 8-membered heterocyclic -C 2-6 alkenyl, aryl-C 2-6 alkenyl, heteroaryl-C 2-6 alkenyl, C 3-8 cycloalkyl-C 2-6 alkynyl, 3- to 8-membered heterocyclic -C 2-6 alkynyl, aryl-C 2-6 alkynyl, heteroaryl-C 2-6 alkynyl group, C 3-8 cycloalkyl-C 1-4 Alkyl-C 2-6 alkenyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl-C 2-6 alkenyl, aryl-C 1-4 Alkyl-C 2-6 alkenyl, heteroaryl-C 1-4 Alkyl-C 2-6 alkenyl, C 3-8 cycloalkyl-C 1-4 Alkyl-C 2-6 alkynyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl-C 2-6 alkynyl, aryl-C 1-4 Alkyl-C 2-6 alkynyl, heteroaryl-C 1- 4-alkyl-C 2-6 alkynyl group, C 2-4 alkenyl-C 2-6 alkenyl, C 2-4 alkynyl-C 2-6 alkenyl, alkenyl-C 2-6 alkynyl group, C 2-4 alkynyl-C 2-6 alkynyl group, R p -C 3-8 cycloalkyl, R p -C 3-8 cycloalkyl-C 1-6 Alkyl, R p -3- to 8-membered heterocyclic groups, or R p -3-to-8-membered heterocyclic group-C 1-6 Alkyl; R p Selected from C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 cycloalkyl-C 1-4 Alkyl, 3- to 6-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1-4 Alkyl, heteroaryl-C 1-4 Alkyl; each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d R f OC 1-4 Alkyl, C(O)R g C(O)OR f OC(O)R g C(O)NR d R d S(O)2R g CN-C 1-4 Alkyl, R f SC 1- 4-alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S; Or R can be selected from equation (Ia) or equation (Ib): Indicates a carbon-carbon single bond or a carbon-carbon double bond; The site where formula (Ia) or formula (Ib) is connected to other parts of the compound of formula (I); Z is selected from N, C, or CR. e ;R e Selected from hydrogen, halogen, or C 1-4 alkyl; Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ; R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or two Rs t The carbon atoms bonded to it together form a carbonyl group (C=O); or two R atoms... t Together with the carbon atoms attached thereto, they form a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; each R x Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1- 4-alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; R k or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d , or NR d S(O)2R g ; Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、or CN; or two R 5 Together with the carbon atoms attached thereto, they form spirocyclic, bridged, or fused ring structures, which optionally contain 0 or 1 additional heteroatoms selected from N, O, and S; or R 5 and R k Together with the carbon and nitrogen atoms attached thereto, they form a bridged ring or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; R 6 and R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, and alkyl groups. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or R 6 and R 7 Together with the carbon atom it is attached to, it forms a 3- to 8-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S, and is optionally substituted by one or more groups selected from the group consisting of halogens, C, and N. 1-4 Alkyl, CN, OR f SR f NR d R d C(O)R g , or S(O)2R g ; The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, C(O)R b ; or two Rs d Together with the nitrogen atom attached thereto, they form a 4- to 8-membered ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; Each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, R b OC 1-4 alkyl; Each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl; Each R b Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; h is selected from 0, 1, 2, 3, or 4; m is selected from 0, 1, 2, 3, or 4; n is selected from 0, 1, 2, or 3; p and q are each independently selected from 0, 1, 2, 3, or 4; t is selected from 0, 1, 2, 3, 4, 5, or 6; in, Each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR n SR n NR c R c C(O)R m C(O)OR n C(O)NR c R c NR c C(O)R m NR c S(O)2R m , or S(O)2R m The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R c The definitions are as described above; each R m Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl; each R n Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing heteroatoms or not containing heteroatoms.

2. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (II): r and s are each independently selected from 0, 1, or 2; The definitions of the remaining groups in formula (II) are as described in claim 1.

3. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (III): Indicates a carbon-carbon double bond or a carbon-carbon triple bond; R 8 Selected from C 3-8 cycloalkyl, 3- to 8-membered heterocyclic, C 3-8 cycloalkyl-C 1-4 Alkyl, 3- to 8-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1-4 Alkyl, heteroaryl-C 1-4 Alkyl, C 2-4 alkenyl, or C 2-4 Alkynyl; the alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1- 4-alkyl-S,R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S; Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl; t is selected from 0, 1, 2, 3, or 4; R f R d R g The definitions of the remaining groups in formula (III) are as described in claim 1.

4. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (IV): Ring C is selected from C 3-8 Cycloalkyl or 3- to 8-membered heterocyclic groups; R 9 Selected from hydrogen, halogens, C 1-4 Alkyl, OR f SR f NR d R d CN, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 3-6 cycloalkyl-C 1-4 Alkyl, 3- to 6-membered heterocyclic -C 1-4 Alkyl, aryl, heteroaryl, aryl-C 1- 4-alkyl, heteroaryl-C 1-4 Alkyl; the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d R f OC 1-4 alkyl; Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 alkyl; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、or CN; or two R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; t is selected from 0, 1, 2, 3, 4, 5, or 6; h is selected from 0, 1, 2, 3, or 4; R f R d The definitions of the remaining groups in formula (IV) are as described in claim 1; The prerequisite is that when t is selected from 0, 1, 2, or 3, R 9 Not selected from hydrogen, halogen, OR f SR f , or NR d R d .

5. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (V): Indicates a carbon-carbon single bond or a carbon-carbon double bond; The definitions of each group in formula (V) are as described in claim 1.

6. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (VI): Indicates a carbon-carbon double bond or a carbon-carbon triple bond; The definitions of each group in formula (VI) are as described in claim 1.

7. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (VII): R 8 Selected from C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl; wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S; Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl; Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ; t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3; R f R d R g A, B, R 1 R 2 R 3 The definitions of m and n are as described in claim 1.

8. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (VIII): The definitions of each group in formula (VIII) are as described in claim 1.

9. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (IX): U is selected from CR 10 R 10 NR i 、O、or S;R i Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, C(O)R g R f OC 1-4 Alkyl C(O) or S(O)2R g ; Each R 10 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S; Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl; Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ; t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, 3, or 4; k is selected from 0, 1, 2, 3, or 4; R f R d R g A, B, R 1 R 2 R 3 The definitions of m and n are as described in claim 1.

10. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (X): Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ; R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g R f OC 1-6 Alkyl, R f OC 3-6 cycloalkyl C 1- 4-alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, R f OC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or two Rs t The carbon atoms bonded to it together form a carbonyl group (C=O); or two R atoms... t Together with the carbon atoms attached thereto, they form a 3- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; each R x Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; R k or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d , or NR d S(O)2R g ; R f R d R g A, B, R 1 R 2 R 3 R 5 R a The definitions of m, n, h, p, q, and t are as described in claim 1.

11. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (XI): t is selected from 4, 5, or 6; Each R a Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl; R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ; R 2 Selected from hydrogen, halogens, C 1-4 alkyl; R 3 Selected from hydrogen, halogens, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ; U is selected from CR 10 R 10 NR i 、O、or S;R i Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C(O)R g R f OC 1-4 Alkyl C(O) or S(O)2R g ; Each R 10 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g S(O)2R g R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R f OC 1-4 Alkyl-O, CN-C 1-4 Alkyl-O, R f SC 1-4 Alkyl-O, R d R d NC 1-4 Alkyl-O, R f OC 1-4 Alkyl-S, CN-C 1-4 Alkyl-S, R f SC 1-4 Alkyl-S, or R d R d NC 1-4 Alkyl-S; The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, C(O)R b 、; or two Rs d Together with the nitrogen atom it is attached to, they form a 4- to 8-membered ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, R b OC 1-4 Alkyl groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl; each R b Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; m is selected from 0, 1, 2, 3, or 4; n is selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, 3, or 4; k is selected from 0, 1, 2, 3, or 4.

12. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (XII): Each R a Each is independently selected from hydrogen, halogen, C 1-4 Alkyl, CN, OR f SR f , or NR d R d ; t is selected from 1, 2, 3, or 4; t' is selected from 0, 1, 2, or 3; R d R f The definitions of the remaining groups in formula (XII) are as described in claim 11.

13. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (XIII): R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR f SR f NR d R d 、 or CN; R 6 and R 7 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d , or S(O)2R g The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d ; h is selected from 0, 1, 2, 3, or 4; p and q are each independently selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4; The definitions of the remaining groups in formula (XIII) are as described in claim 11.

14. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (XIV): Y is selected from NR k O, S, S(O), S(O)2 or CR t R t ; R k Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R g S(O)2R g R f OC 1-6 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; Each R t Each is independently selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, R f OC 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR x SR x NR x R x C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR d C(O)NR d R d OC(O)NR d R d NR d C(O)OR f OC(O)OR f S(O)2R g S(O)2NR d R d NR d S(O)2R g , or NR d S(O)2NR d R d Each R x Each is independently selected from the following groups: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, R f OC 1-4 Alkyl, CN-C 1-4 Alkyl, R f SC 1-4 Alkyl, R d R d NC 1-4 Alkyl, R g C(O)-C 1-4 Alkyl, R f OC(O)-C 1-4 Alkyl, R g C(O)OC 1-4 Alkyl, R d R d NC(O)-C 1-4 Alkyl, R f OC 3-6 cycloalkyl C 1-4 Alkyl, or R f O-3-to-6-membered heterocyclic C 1-4 alkyl; R k or R t Each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein may optionally and independently be substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g OC(O)NR d R d NR d C(O)OR f S(O)2R g S(O)2NR d R d , or NR d S(O)2R g ; t is selected from 1, 2, 3, or 4; R d R f R g The definitions of the remaining groups in formula (XIV) are as described in claims 11 and 13.

15. The compound according to claim 1, characterized in that, Equation (I) is equivalent to equation (XV): The definition of R is as described in claim 1; the definitions of the remaining groups in formula (XV) are as described in claim 11.

16. The compound of claim 1, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, selected from the group consisting of: "*" indicates a chiral center, which includes both R- and S-configurations; The stereoconfiguration of a carbon-carbon double bond can be chosen from either the E- or Z- configuration.

17. A pharmaceutical composition, characterized in that, The compound comprising any one of claims 1 to 16, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

18. Use of a compound of any one of claims 1 to 16, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, characterized in that, Used to prepare pharmaceutical compositions for treating diseases, conditions, or symptoms related to cGAS activity or expression levels.

19. The use as described in claim 18, characterized in that, The diseases, symptoms, or conditions described are selected from the following group: SAVI (STING-associated vasculopathy with onset in infancy), AGS syndrome (Aicardi-Goutières syndrome), familial frostbite-like lupus, COPA syndrome, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis or cutaneous lupus, psoriasis, myasthenia gravis, multiple sclerosis, scleroderma, alopecia areata, inflammatory bowel disease, acute cerebral ischemia, acute pulmonary ischemia, Parkinson's disease, ALS, non-alcoholic fatty liver disease, acute pancreatitis, myocardial infarction, chronic heart failure, and various autoimmune diseases and neurodegenerative diseases.

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