Compound serving as cgas inhibitor

Abstract

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

Description

Compounds as 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] "*" indicates a chiral center;

[0011] A is selected from formula (Ia), formula (Ib), or formula (Ic):

[0012] In equation (Ia), equation (Ib), or equation (Ic), Indicates a carbon-carbon double bond or a carbon-carbon triple bond; This indicates a carbon-carbon single bond or a carbon-carbon double bond. The site where formula (Ia), formula (Ib), or formula (Ic) connects to other segments of the compound of formula (I);

[0013] R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, or CN;

[0014] R 2 and R 2’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, or CN;

[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, OR a SR a NR c R c 、or CN; or two R 3 Together with the carbon atoms connected thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; each R a Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; each R c Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl;

[0016] R 4 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, 3- to 6-membered heterocyclic, aryl, heteroaryl, OR a SR a NR c R c 、or CN;R a and R c The definition is as described above;

[0017] R is selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 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 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups in R 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 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 dS(O)2NR d R d ; or the cycloalkyl or heterocyclic group in said R is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, (R) d’ R d’ )NC 2-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; or two R d Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、or = M; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, cyano C 1-3 Alkyl, (R) d’ R d’ )NC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in R is optionally substituted with =M; c The definitions are as described above; each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6cycloalkyl; M is selected from CR h R i , where R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0018] R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O;

[0019] X is selected from N, C, or CR. e ;R e Selected from hydrogen, halogen, or C 1-4 alkyl;

[0020] Y is selected from O, S, NR b or CR b’ R b’ ;R b Selected from hydrogen or C 1-4 Alkyl groups; each R b’ Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0021] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR a SR a NR c R c 、or CN; or two R 5 Together with the carbon atoms connected to it, it forms a spirocyclic, bridged, or fused ring structure, which optionally contains 0 or 1 additional heteroatoms selected from N, O, and S; R a and R c The definition is as described above;

[0022] R 6 and R 7Each 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, C 3-6 cycloalkyl C 1-4 Alkyl, 3- to 6-membered heterocyclic C 1-4 Alkyl, 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, 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 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 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 ;R d R f R g The definition is as described above;

[0023] a is selected from 0, 1, 2, or 3;

[0024] m is selected from 0, 1, 2, 3, or 4;

[0025] n is selected from 0, 1, 2, 3, or 4;

[0026] p is selected from 0, 1, or 2;

[0027] q and r are each independently selected from 0, 1, 2, 3, or 4;

[0028] s is selected from 0, 1, 2, 3, or 4;

[0029] 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 3-6Cycloalkyl, 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;

[0030] 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.

[0031] In another preferred embodiment, equation (I) is equation (IIa) or equation (IIb):

[0032] The definitions of the groups in formulas (IIa) and (IIb) are as described in the first aspect of the present invention.

[0033] In another preferred embodiment, equation (I) is equation (IIIa) or equation (IIIb):

[0034] The definitions of the groups in formulas (IIIa) and (IIIb) are as described in the first aspect of the present invention.

[0035] In another preferred embodiment, equation (I) is equation (IVa) or equation (IVb):

[0036] The definitions of the groups in formulas (IVa) and (IVb) are as described in the first aspect of this invention.

[0037] In another preferred embodiment, R is selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 dC(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 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups in R 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 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 the cycloalkyl or heterocyclic group in said R is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, R d’ R d’ NC 2-4 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; or two R d Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、or = M; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, cyano C 1- 3-alkyl, R d’ R d’ NC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in the R group is optionally substituted with =M; each R c Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; M is selected from CR h R i , where R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 Alkyl; R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O;

[0038] 'a' can be selected from 0, 1, 2, or 3.

[0039] In another preferred embodiment, R is selected from SR. f NR d1 R d2 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 ;R d1 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1- 4-Hydroalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, R d’ R d’ NC 2-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; provided that R d1 and R d2Cannot be simultaneously selected from hydrogen; or R d1 and R d2 Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、 or = M;

[0040] R c R d R d’ R f R g The definitions of M are as described in the first aspect of this invention.

[0041] In another preferred embodiment, R is selected from C. 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group in R is 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 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 NRd S(O)2R g , or NR d S(O)2NR d R d .

[0042] In another preferred embodiment, equation (I) is equation (Va) or equation (Vb):

[0043] R d1 and R d2 The definition is as described in the first aspect of this invention;

[0044] R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O;

[0045] a is selected from 1, 2, or 3;

[0046] In another preferred embodiment, equation (I) is equation (VIa) or equation (VIb):

[0047] R d The definition is as described in the first aspect of this invention;

[0048] In another preferred embodiment, equation (I) is equation (VIIa) or equation (VIIb):

[0049] The definitions of the groups in formulas (VIIa) and (VIIb) are as described in the first aspect of the present invention.

[0050] In another preferred embodiment, equation (I) is equation (VIIIa), equation (VIIIb), equation (VIIIc), equation (VIIId), equation (VIIIe), or equation (VIIIf):

[0051] The definitions of each group in formulas (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), and (VIIIf) are as described in the first aspect of the present invention.

[0052] In another preferred embodiment, equation (I) is equation (IXa), equation (IXb), equation (IXc), equation (IXd), equation (IXe), or equation (IXf):

[0053] The definitions of each group in formulas (IXa), (IXb), (IXc), (IXd), (IXe), and (IXf) are as described in the first aspect of this invention.

[0054] In another preferred embodiment, equation (I) is equation (Xa) or equation (Xb):

[0055] The definitions of the groups in formulas (Xa) and (Xb) are as described in the first aspect of the present invention.

[0056] In another preferred embodiment, equation (I) is equation (XIa) or equation (XIb):

[0057] t is selected from 0, 1, 2, or 3;

[0058] R is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 NRd S(O)2NR d R d ; C in R 1-4 Alkyl, cycloalkyl, heterocyclic, aryl, or 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 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 ;R d R f R g The definition is as described in the first aspect of this invention.

[0059] 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 group of the following:

[0060] The asterisk (*) indicates a chiral center, which includes racemic, R-, and S-configurations.

[0061] 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.

[0062] A third aspect of the invention provides the use of a compound of 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, characterized in that it is used to prepare a pharmaceutical composition for treating diseases, conditions, or symptoms related to cGAS activity or expression levels.

[0063] 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

[0064] 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.

[0065] the term

[0066] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0067] 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.

[0068] 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 1-8Alkyl 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.

[0069] 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.

[0070] 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 limit (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.

[0071] 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 the presence of a carbon number limit (e.g., C...). 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.

[0072] 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.

[0073] "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.

[0074] "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.

[0075] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0076] 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.

[0077] 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.

[0078] 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).

[0079] use:

[0080] 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.

[0081] The compound of this invention can be used as a cGAS inhibitor.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] Pharmaceutical Compositions and Administration

[0086] 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.

[0087] 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.

[0088] "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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0098] 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.

[0099] The main advantages of this invention include:

[0100] 1. A compound as shown in Formula I is provided.

[0101] 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.

[0102] 3. A cGAS inhibitor that is well absorbed orally is provided.

[0103] 4. A class of pharmaceutical compositions for treating diseases related to cGAS activity is provided.

[0104] 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.

[0105] 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.

[0106] Example

[0107] Abbreviations: Boc = tert-Butoxycarbonyl; CN = cyano; DCM = dichloromethane; DIPEA or DIEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; EtOAc or EA = ethyl acetate; Et = ethyl; HATU = N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea; Me = methyl; Ph = phenyl; PMB = p-methoxybenzyl; Pd(PPh3)4 = tetratetraphenylphosphine palladium; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TMS = trimethylsilyl; TsOH = 4-methylbenzenesulfonic acid.

[0108] Example 1: Preparation of Compound 1

[0109] Compound 1-a (75 mg, 0.48 mmol) and compound 1-b (163 mg, 0.96 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (248 mg, 1.92 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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 = 1:1) to give a yellow solid compound 1-c (100 mg, yield 78%). MS m / z 270.1 [M+H] + .

[0110] Compound 1-c (100 mg, 0.37 mmol) was dissolved in methanol (3 mL), followed by the addition of water (3 mL) and lithium hydroxide (36 mg, 1.48 mmol). The mixture was heated to 60 °C and stirred for 30 minutes. The solution was concentrated under reduced pressure to obtain crude compound 1-d (97 mg, 100% yield).

[0111] The synthesis of compound 1-e followed the synthetic route described in patent WO2023 / 183275. Compound 1-e (30 mg, 0.12 mmol) and compound 1-d (47 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of N,N-diisopropylethylamine (47 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (68 mg, 0.18 mmol). The mixture was stirred at room temperature for 60 minutes. 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 compound 1 (15 mg, yield 26%) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 491.8 [M+H]+ . 1 H NMR(500MHz,DMSO-d6)δ11.57-11.47(m,1H),8.61-8.53(m,2H),7.58-7.26(m,1H),7.22-7.06(m,1H),5.77-4.73(m,1 H),3.66-3.55(m,1H),3.53-3.42(m,4H),3.30-2.82(m,2H),2.74-2.67(m,1H),2.33-2.20(m,4H),1.55-1.44(m,3H).

[0112] Example 2: Preparation of Compound 2

[0113] Compound 2-a (300 mg, 1.38 mmol) and 1-dimethylamine-2-propyne (344 mg, 4.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and triethylamine (1 mL) and palladium dichloride bis(triphenylphosphine) (136 mg, 0.14 mmol) were added. The mixture was heated to 60 °C and stirred 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 = 20:1) to give a yellow solid compound 2-b (30 mg, yield 10%). MS m / z 220.2 [M+H] + .

[0114] Compound 2-b (30 mg, 0.14 mmol) was dissolved in methanol (1 mL), followed by the addition of water (0.2 mL) and lithium hydroxide (13 mg, 0.56 mmol). The mixture was heated to 60 °C and stirred for 30 minutes. The solution was concentrated under reduced pressure to obtain crude compound 2-c (29 mg, 100% yield).

[0115] Compound 1-e (20 mg, 0.078 mmol) and compound 2-c (29 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (30 mg, 0.23 mmol) and 2-chloro-1-methylpyridine iodide (41 mg, 0.16 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 compound 2 (16 mg, 46% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 441.8 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ11.59-11.47(m,1H),9.07-8.94(m,2H),7.59-7.30(m,1H),7.23-7.06(m,1 H),5.82-4.66(m,1H),3.67-3.46(m,4H),2.92-2.66(m,2H),2.34-2.22(m,6H),1.57-1.43(m,3H).

[0116] Example 3: Preparation of Compound 3

[0117] The trifluoroacetate of compound 3-a (169 mg, 0.76 mmol) and methyl 5-fluoropyrimidine-2-carboxylate (60 mg, 0.38 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (295 mg, 2.28 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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 = 1:1) to give a yellow solid compound 3-b (70 mg, 70% yield). MS m / z 262.1 [M+H] + .

[0118] Compound 3-b (70 mg, 0.27 mmol) was dissolved in methanol (3 mL), followed by the addition of water (0.5 mL) and lithium hydroxide (26 mg, 1.08 mmol). The mixture was heated to 60 °C and stirred for 30 minutes. The solution was concentrated under reduced pressure to obtain crude compound 3-c (68 mg, 100% yield).

[0119] Compound 1-e (25 mg, 0.098 mmol) and compound 3-c (38 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (37 mg, 0.29 mmol) and 2-chloro-1-methylpyridine iodide (51 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 compound 3 (24 mg, 51% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 483.9 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ11.57-11.45(m,1H),8.56-8.43(m,2H),7.57-7.27(m,1H),7.22-7.05(m,1H),5.78- 4.72(m,1H),3.65-3.36(m,5H),3.30-2.67(m,3H),2.44-2.32(m,4H),1.75-1.61(m,6H),1.55-1.45(m,3H).

[0120] Example 4: Preparation of Compound 4

[0121] Compound 4-a was synthesized following the synthetic route described in Example 3. Compound 1e (25 mg, 0.098 mmol) and compound 4a (34 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N-methylmorpholine (29 mg, 0.29 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 4 (23 mg, yield 51%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 477.8 [M+Na] + . 1 H NMR(500MHz,DMSO-d6)δ11.56-11.46(m,1H),8.62-8.51(m,2H),7.58-7.26(m,1H),7.23-7.05(m,1 H),5.78-4.71(m,3H),3.64-3.39(m,5H),3.29-2.66(m,3H),2.34-2.18(m,4H),1.56-1.42(m,3H).

[0122] Example 5: Preparation of Compound 5

[0123] Compound 5-a (70 mg, 0.23 mmol) and pyrrolidine (49 mg, 0.69 mmol) were dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (89 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol:ammonia = 10:1:0.2) to give a yellow solid compound 5-b (50 mg, yield 78%). MS m / z 281.1 [M+H]+ .

[0124] Compound 5-b (50 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give crude trifluoroacetate of 5-c (50 mg, 100% yield). MS m / z 181.1 [M+H] + .

[0125] Crude compound 5-c (50 mg, 0.18 mmol) and methyl 5-fluoropyrimidine-2-carboxylate (56 mg, 0.36 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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:ammonia = 10:1:0.2) to give a yellow solid compound 5-d (50 mg, yield 88%). MS m / z 317.1 [M+H] + .

[0126] Compound 5-d (25 mg, 0.08 mmol) was dissolved in methanol (2 mL), followed by the addition of water (0.5 mL) and lithium hydroxide (8 mg, 0.32 mmol). The mixture was heated to 60°C and stirred for 30 minutes. After cooling to room temperature, 2 M hydrochloric acid was added dropwise until the pH of the system was around 4. The solution was then concentrated under reduced pressure to obtain crude compound 5-e (24 mg, 100% yield).

[0127] Compound 1-e (20 mg, 0.078 mmol) and compound 5-e (24 mg, 0.078 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (61 mg, 0.47 mmol), N-methylmorpholine (48 mg, 0.47 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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:ammonia = 10:1:0.2) to give compound 5 (29 mg, 68% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 539.0 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ11.60-11.45(m,1H),8.62-8.48(m,2H),7.58-7.26(m,1H),7.22-7.05(m,1H),5.78-4.71(m,2 H),3.63-3.43(m,5H),3.13-3.04(m,2H),2.97-2.67(m,3H),2.47-2.24(m,8H),1.74-1.61(m,4H),1.55-1.42(m,3H).

[0128] Example 6: Preparation of Compound 6

[0129] Compound 6-a (70 mg, 0.236 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a yellow oily crude product 6-b (69 mg), which was directly used in the next reaction. MS m / z 197.2 [M+H] + .

[0130] Compound 6-b (69 mg, 0.235 mmol), methyl 5-fluoropyrimidine-2-carboxylate (37 mg, 0.235 mmol), and diisopropylethylamine (121 mg, 0.938 mmol) were sequentially dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction mixture was alkalized with ammonia 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 concentrated reaction mixture was then purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to give a white solid product 6-c (25 mg, yield 32%). MS m / z 333.0 [M+H] + .

[0131] Compound 6-c (25 mg, 0.075 mmol) and lithium hydroxide (9 mg, 0.376 mmol) were dissolved sequentially in methanol / water (2 / 1 mL), 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. The resulting crude product was dissolved in acetonitrile and then concentrated under reduced pressure to obtain a white solid crude product 6-d (37 mg), which was directly used in the next reaction. MS m / z 319.0 [M+H] + .

[0132] Compound 6-d (20 mg, 0.062 mmol), compound 1-e (16 mg, 0.062 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (47 mg, 0.124 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). Diisopropylethylamine (24 mg, 0.185 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. 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 (dichloromethane:methanol = 20:1, 2% ammonia) to give a white solid product 6 (15 mg, yield 44%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d6)δ11.57–11.47(m,1H),8.61–8.48(m,2H),7.61–7.26(m,1H),7.23–7.03(m,1H),5.95–4.56(m,2H),3.63–3 .52(m,4H),3.47–3.40(m,4H),3.30–3.23(m,2H),3.02–2.84(m,3H),2.74–2.62(m,1H),2.41–2.26(m,8H),1.55–1.44(m,3H)ppm. MS m / z 554.9[M+H] + .

[0133] Example 7: Preparation of Compound 7

[0134] Compound 7-a (245 mg, 1.48 mmol) was dissolved in water (3 mL), and then potassium hydroxide (83 mg, 1.48 mmol) was added. The mixture was reacted at 100 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0135] Compound 1-e (16 mg, 0.06 mmol) was dissolved in acetonitrile (1 mL), and then compound 7-b (12 mg, 0.12 mmol), N,N-diisopropylethylamine (23 mg, 0.18 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 0.09 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain solid compound 7 (7.09 mg, yield 33%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified).1 H NMR(500MHz,DMSO-d)δ11.57-11.40(m,1H),7.56-7.43(m,1H),7.23-7.12(m,1H),6.85-6.63(m,2H),5.73-5.34(m,1H),5.07-5.01(m,1 H),4.79-4.20(m,1H),4.17-4.13(m,1H),3.67-3.56(m,1H),3.54-3.43(m,1H),3.18-3.08(m,1H),2.83-2.73(m,1H),1.55-1.38(m,3H). MS m / z 360.8[M+Na] + .

[0136] Example 8: Preparation of Compound 8

[0137] Compound 8-a (10 mg, 0.07 mmol) and di-tert-butyl dicarbonate (61 mg, 0.28 mmol) were dissolved in tert-butanol (1 mL), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) was added. The mixture was stirred at 60 °C for 18 hours. The solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) to give a yellow solid compound 8-b (7 mg, 50% yield). MS m / z 221.1 [M+Na] + .

[0138] The trifluoroacetate of compound 8-c (40 mg, 0.16 mmol) and compound 8-b (7 mg, 0.035 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (62 mg, 0.48 mmol) was added. The mixture was heated to 90 °C and stirred for 5 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 = 1:5) to give a yellow solid compound 8-d (7 mg, yield 59%). MS m / z 356.1 [M+Na] + .

[0139] Compound 8-d (7 mg, 0.08 mmol) was dissolved in dioxane (1 mL), followed by the addition of water (0.2 mL) and a 4 M dioxane hydrochloride solution (1 mL). The mixture was heated to 50 °C and stirred for 30 minutes. The solution was then concentrated under reduced pressure to obtain crude compound 8-e (6 mg, 100% yield).

[0140] Compounds 1-e (6 mg, 0.024 mmol) and 8-e (6 mg, 0.022 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (9 mg, 0.072 mmol), N-methylmorpholine (7 mg, 0.072 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (11 mg, 0.03 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 compound 8 (4 mg, yield 36%) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 513.8 [M+H] + .

[0141] Example 9: Preparation of Compound 9

[0142] Compound 9-a was synthesized following the synthetic route described in Example 8. Compound 1-e (20 mg, 0.078 mmol) and compound 9-a (22 mg, 0.080 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (61 mg, 0.47 mmol), N-methylmorpholine (48 mg, 0.47 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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:ammonia = 10:1:0.2) to give a white solid compound 9 (10 mg, yield 25%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 512.9 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.57-11.47(m,1H),8.61-8.48(m,2H),7.57-7.28(m,1H),7.23-7.06(m,1H),5.78- 4.72(m,2H),3.62-3.41(m,5H),3.29-2.66(m,5H),2.39-2.27(m,4H),2.20-2.09(m,6H),1.54-1.44(m,3H).

[0143] Example 10: Preparation of Compound 10

[0144] Compound 10-a (100 mg, 0.327 mmol) and N-methylpiperazine (49 mg, 0.491 mmol) were dissolved in acetonitrile (3 mL), and then diisopropylethylamine (127 mg, 0.981 mmol) was added. The mixture was reacted at 75 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 10-b (73 mg, yield 72%).

[0145] Compound 10-b (73 mg, 0.235 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (114 mg, 1.18 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for half an hour, and the reaction solution was concentrated under reduced pressure after the reaction was completed. The crude product was dissolved in dichloromethane, and then diisopropylethylamine (305 mg, 2.35 mmol) was added. After stirring for 10 minutes, the mixture was evaporated to dryness under reduced pressure to obtain crude product 10-c, which was directly used in the next reaction step.

[0146] Compound 10-c (47 mg, 0.224 mmol) and methyl 5-fluoropyrimidine-2-carboxylate (35 mg, 0.224 mmol) were dissolved in acetonitrile (3 mL), and then diisopropylethylamine (87 mg, 0.672 mmol) was added. The mixture was reacted at 80 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 10-d (33 mg, yield 42%). MS m / z 346.2 [M+H] + .

[0147] Compound 10-d (33 mg, 0.095 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of a solution of lithium hydroxide (4.58 mg, 0.191 mmol) and water (0.2 mL). The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting crude product 10-e was used directly in the next reaction step.

[0148] Compound 10-e (26 mg, 0.078 mmol) was dissolved in acetonitrile (1 mL), and then compound 1-e (20 mg, 0.078 mmol), N,N-diisopropylethylamine (30 mg, 0.234 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (44 mg, 0.117 mmol) were added sequentially. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia) to obtain solid compound 10 (21.78 mg, yield 49%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.58-11.43(m,1H),8.60-8.49(m,2H),7.56-7.28(m,1H),7.22-7.06(m,1H),5.78-4.71(m,2H),3.6 4-3.56(m,1H),3.49-3.38(m,8H),3.29-3.23(m,1H),2.95-2.68(m,4H),2.41-2.23(m,8H),2.14(s,3H),1.54-1.45(m,3H). MS m / z 568.0[M+H] + .

[0149] Example 11: Preparation of Compound 11

[0150] Compound 11-a (150 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen protection. 60% sodium hydroxide (40 mg, 0.99 mmol) was added at 0°C, and the mixture was slowly heated to room temperature with stirring for 2 hours. Then, methyl iodide (141 mg, 0.99 mmol) was added, and the mixture was heated to 80°C with stirring for another 2 hours. The mixture was cooled to room temperature, 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 = 2:1) to give a colorless oily compound 11-b (90 mg, yield 57%). MS m / z 242.3 [M+H] + .

[0151] Compound 11-b (90 mg, 0.37 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give crude trifluoroacetate of 11-c (89 mg, 100% yield). MS m / z 142.2 [M+H] + .

[0152] Crude compound 11-c (89 mg, 0.37 mmol) and methyl 5-fluoropyrimidine-2-carboxylate (116 mg, 0.74 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (287 mg, 2.22 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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 = 1:1) to give a yellow solid compound 11-d (80 mg, yield 77%). MS m / z 278.2 [M+H] + .

[0153] Compound 11-d (40 mg, 0.14 mmol) was dissolved in methanol (2 mL), followed by the addition of water (0.5 mL) and lithium hydroxide (13 mg, 0.56 mmol). The mixture was heated to 60°C and stirred for 30 minutes. After cooling to room temperature, 2 M hydrochloric acid was added dropwise until the pH of the system was around 4. The solution was then concentrated under reduced pressure to obtain crude compound 1-1e (38 mg, 100% yield).

[0154] Compound 1-e (30 mg, 0.12 mmol) and compound 11-e (38 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (78 mg, 0.60 mmol), N-methylmorpholine (61 mg, 0.60 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 compound 11 (21 mg, 36% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 521.8 [M+Na] + . 1 H NMR(500MHz,DMSO-d6)δ11.57-11.45(m,1H),8.62-8.49(m,2H),7.58-7.27(m,1H),7.23-7.05(m,1H),5.78-4.73(m,2 H),3.98-3.90(m,2H),3.64-3.38(m,5H),3.25-3.19(m,3H),2.96-2.64(m,3H),2.40-2.28(m,4H),1.56-1.44(m,3H).

[0155] Example 12: Preparation of Compound 12

[0156] Compound 12 was synthesized according to the method described in Example 10, yielding a white solid compound 12 (7.56 mg, yield 23%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). In the synthesis of compound 12e, the condensation solvent was replaced with N,N-dimethylformamide. 1H NMR(500MHz,DMSO-d)δ11.57-11.44(m,1H),8.62-8.49(m,2H),7.56-7.27(m,1H),7.22-7.05(m,1H),5.77-4.76(m,2H),3.95-3.89(m,1 H),3.64-3.56(m,1H),3.50-3.39(m,7H),3.17-3.11(m,3H),3.09-3.02(m,2H),2.90-2.66(m,4H),2.40-2.24(m,4H),1.55-1.45(m,3H). MS m / z 555.0[M+H] + .

[0157] Example 13: Preparation of Compound 13

[0158] Compound 13 was synthesized according to the synthetic route of Example 8. (35 mg, yield 47%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 539.0 [M+H]+. 1 H NMR(500MHz,DMSO-d6)δ11.58-11.44(m,1H),8.60-8.49(m,2H),7.57-7. 27(m,1H),7.22-7.05(m,1H),5.76-4.74(m,2H),3.66-3.38(m,5H),3.16- 3.08(m,2H),2.95-2.64(m,3H),2.41-2.26(m,4H),2.25-2.19(m,3H),1.7 0-1.63(m,i1H),1.54-1.45(m,3H),0.48-0.34(m,2H),0.32-0.25(m,2H).

[0159] Example 14: Preparation of Compound 14

[0160] Compound 1-e (120 mg, 0.47 mmol), 5-bromopyrimidine-2-carboxylic acid (95 mg, 0.47 mmol), and N,N-diisopropylethylamine (183 mg, 1.42 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (188 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with water, 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 (ethyl acetate:petroleum ether = 1:1) to give a white solid compound 14-a (183 mg, yield 88%). MS m / z 438.7 [M+H] + .

[0161] Compound 14-a (50 mg, 0.11 mmol), N-methylpropargylamine (16 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), cuprous iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a white solid compound 14 (23 mg, yield 47%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.53(m,1H),8.98(m,2H),7.57-7.31(m,1H),7.22-7.07(m,1H),5.79-4.67(m ,2H),3.68-3.47(m,3H),2.92-2.81(m,2H),2.73-2.66(m,1H),2.44-2.33(m,3H),1.55-1.44(m,3H). MS m / z 427.9[M+H] + .

[0162] Example 15: Preparation of Compound 15

[0163] Compound 14 (15 mg, 0.04 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (11 mg, 0.07 mmol) were dissolved in methanol (1 mL), followed by the addition of acetic acid (4 mg, 0.07 mmol) and sodium cyanoborohydride (5 mg, 0.07 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 (dichloromethane:methanol = 15:1) to give a white solid compound 15 (5 mg, yield 30%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.54(m,1H),9.02(m,2H),7.58-7.31(m,1H),7.22-7.08(m,1H),5.81-4.67(m,2H),3.73-3.67(m,2H),3.54-3.49(m, 1H),2.93-2.84(m,1H),2.74-2.67(m,1H),2.41(d,J=3.6Hz,3H),1.99 -1.95(m,1H),1.56-1.44(m,3H),0.53-0.46(m,2H),0.41-0.33(m,2H). MS m / z 467.9[M+H] + .

[0164] Example 16: Preparation of Compound 16

[0165] Compound 14-a (50 mg, 0.11 mmol), N,N-dimethylpropynamide (22 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), cuprous iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a white solid compound 16 (28 mg, yield 54%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR (500MHz, DMSO-d) δ11.54(d,J=20.5Hz,1H),9.20(d,J=15.0Hz,2H),7.57-7.29(m,1H),7.23-7.06(m,1H),5.81-4.69(m,2 H),3.57-3.49(m,1H),3.28(d,J=4.7Hz,3H),2.95(d,J=3.2Hz,3H),2.92-2.83(m,1H),2.75-2.67(m,1H),1.57-1.45(m,3H). MS m / z 455.9[M+H] + .

[0166] Example 17: Preparation of Compound 17

[0167] Compound 17-a (245 mg, 0.759 mmol) and 3-bromopyridine (100 mg, 0.632 mmol) were dissolved in 1,4-dioxane solution (2 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (28 mg, 0.038 mmol), potassium carbonate (262 mg, 1.9 mmol), and water (0.4 mL) were added sequentially. The reaction was carried out at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 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 silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 17-b (130 mg, 75% yield). MS m / z 275.1 [M+H] + .

[0168] Compound 17 was synthesized according to the method described in Example 10 to obtain a white solid compound 17 (29.47 mg, 47% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.59-11.44(m,1H),8.61-8.54(m,2H),8.51-8.41(m ,2H),7.70-7.65(m,1H),7.56-7.28(m,2H),7.22-7.06(m,1H),6.43(s,1H), 5.78-5.69(m,1H),4.82-4.72(m,1H),3.64-3.44(m,5H),3.30-2.91(m,1H), 2.91-2.84(m,1H),2.75-2.61(m,1H),2.59-2.53(m,3H),1.55-1.45(m,3H). MS m / z 554.8 [M+Na] + .

[0169] Example 18: Preparation of Compound 18

[0170] The synthesis of compound 18 was performed according to Example 10, yielding a white solid compound 18 (5.91 mg, 19% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.56-11.44(m,1H),8.63-8.48(m,2H),7.66-7.02(m,4H),6.93-6.85(m,1H),5.79-5.67(m,1H),5.54- 5.42(m,1H),4.83-4.72(m,1H),4.69-4.57(m,2H),3.53-3.40(m,7H),2.97-2.81(m,2H),2.38-2.23(m,2H),1.58-1.42(m,3H). MS m / z 535.9[M+H] + .

[0171] Example 19: Preparation of Compound 19

[0172] The synthesis of compound 19e follows the synthesis method described in Example 10.

[0173] Compound 19-e (18 mg, 0.028 mmol) was dissolved in dichloromethane (2 mL), and titanium tetrachloride solution (16 mg, 0.084 mmol) was added dropwise under nitrogen protection at -78 °C. The mixture was stirred at this temperature for 0.5 hours until the reaction was complete. The reaction solution was then extracted three times with ethyl acetate (3 × 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 thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1, 2% ammonia) to give compound 19 (2.88 mg, yield 19%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.57-11.47(m,1H),8.63-8.47(m,2H),7.58-7.01(m,2H),5.78–5.74(m,1H),5.29-5.16(m,2H),4.81–4.71(m,1 H),4.16-4.10(m,1H),3.64-3.58(m,2H),3.51-3.39(m,6H),2.95-2.84(m,1H),2.75-2.66(m,2H),2.39-2.24(m,4H),1.53–1.46(m,3H). MS m / z 540.9[M+H] + .

[0174] Example 20: Preparation of Compound 20

[0175] Compound 20-a (100 mg, 0.44 mmol) was dissolved in dichloromethane (4 mL), pyridine (174 mg, 2.20 mmol) and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were added, the temperature was lowered to 0 °C, benzoyl chloride (124 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid compound 20-b (100 mg, yield 69%). MS m / z 332.3 [M+H] + .

[0176] Compound 20-b (50 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give crude trifluoroacetate of 20-c (50 mg, 100% yield). MS m / z 232.3 [M+H] + .

[0177] The trifluoroacetate of compound 20-c (50 mg, 0.15 mmol) and compound 8-b (30 mg, 0.15 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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 = 5:1) to give a yellow solid compound 20-d (40 mg, yield 65%). MS m / z 410.2 [M+H] + .

[0178] Compound 20-d (30 mg, 0.07 mmol) was dissolved in dioxane (2 mL), and formic acid (1 mL) was added. The mixture was stirred at room temperature for 18 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 oily compound 20-e (5 mg, yield 19%).

[0179] Compound 1-e (5 mg, 0.020 mmol) and compound 20-e (5 mg, 0.014 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (9 mg, 0.07 mmol), N-methylmorpholine (7 mg, 0.07 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (11 mg, 0.028 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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 = 1:1) to give a white solid compound 20-f (3 mg, yield 36%). MS m / z 611.8 [M+Na] + .

[0180] Compound 20-f (3 mg, 0.0051 mmol) was dissolved in methanol (1 mL), followed by the addition of water (0.2 mL) and lithium hydroxide (2 mg, 0.083 mmol). The mixture was heated to 60 °C and stirred for 30 minutes. The solution was cooled to room temperature, 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 white solid, compound 20 (1.5 mg, yield 61%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 507.8 [M+Na] + .

[0181] Example 21: Preparation of compound 21

[0182] Triethylphosphonoacetate (686 mg, 3.77 mmol) was dissolved in tetrahydrofuran. Sodium hydride (150 mg, 60%) was added in portions under ice bath conditions. After stirring at room temperature for one hour, compound 21-a (400 mg, 2.51 mmol) was added and stirred at room temperature for 6 hours. After the reaction was complete, ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. 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 21-b (126 mg, yield 23%).

[0183] Compound 21-b (50 mg, 0.232 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of lithium hydroxide (11 mg, 0.464 mmol) and water (0.5 mL). The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting crude product 21-c was used directly in the next reaction step.

[0184] Compound 21-c (21 mg, 0.101 mmol) was dissolved in acetonitrile (1 mL), followed by the sequential addition of compound 1-e (13 mg, 0.051 mmol), N,N-diisopropylethylamine (20 mg, 0.153 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (29 mg, 0.077 mmol). The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain solid compound 21-d (10 mg, yield 45%). MS m / z 439.1 [M+H] + .

[0185] Compound 21-d (10 mg, 0.023 mmol) was dissolved in methanol (2 mL), and then p-toluenesulfonic acid (8 mg, 0.046 mmol) was added. The mixture was reacted at room temperature for 1 hour. 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 give compound 21 (3 mg, yield 39%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.56-11.39(m,1H),7.54-7.42(m,1H),7.24-7.11(m,1H),6.83-6.59(m,2H),5.71-5.39(m,1 H),4.80-4.24(m,1H),3.53-3.44(m,1H),3.40-3.37(m,2H),3.14-2.83(m,2H),2.83-2.68(m,2H),1.56-1.38(m,3H). MS m / z 359.9[M+Na] + .

[0186] Example 22: Preparation of compound 22

[0187] Compound 22-a was synthesized following the synthetic route described in Example 8. Compound 1-e (26 mg, 0.10 mmol) and compound 22-a (35 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (65 mg, 0.50 mmol), N-methylmorpholine (51 mg, 0.50 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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:ammonia = 20:1:0.2) to give a white solid, compound 22 (45 mg, 77% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 588.9 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.57-11.47(m,1H),8.60-8.50(m,2H),7.56-7.21(m,6H),7.21-7.05(m,1H),5.79- 4.73(m,2H),3.66-3.38(m,7H),3.29-2.66(m,5H),2.39-2.26(m,4H),2.16-2.05(m,3H),1.56-1.43(m,3H).

[0188] Example 23: Preparation of compound 23

[0189] Compound 23-a (180 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2.0 M dimethylamine tetrahydrofuran solution (1.5 mL, 3.00 mmol), N,N-diisopropylethylamine (291 mg, 2.25 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (430 mg, 1.13 mmol) were added. 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 silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow solid compound 23-b (100 mg, 50% yield). MS m / z 269.3 [M+H]+.

[0190] Compound 23-b (100 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), and 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 crude trifluoroacetate of 23-c (99 mg, 100% yield). MS m / z 169.3 [M+H] + .

[0191] The trifluoroacetate of compound 23-c (99 mg, 0.37 mmol) and methyl 5-fluoropyrimidine-2-carboxylate (87 mg, 0.56 mmol) were dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (239 mg, 1.85 mmol) was added. The mixture was heated to 80 °C and stirred for 5 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 yellow solid compound 23-d (100 mg, yield 88%). MS m / z 305.1 [M+H] + .

[0192] Compound 23-d (45 mg, 0.15 mmol) was dissolved in methanol (4 mL), followed by the addition of water (1 mL) and lithium hydroxide (14 mg, 0.60 mmol). The mixture was heated to 60 °C and stirred for 30 minutes. The solution was concentrated under reduced pressure to obtain crude compound 23-e (44 mg, 100% yield).

[0193] Compound 23-e (44 mg, 0.15 mmol) and compound 1-e (36 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (4 mL), N-methylmorpholine (61 mg, 0.60 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (87 mg, 0.23 mmol). The mixture was stirred at room temperature for 60 minutes. 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 white solid, compound 23 (30 mg, 40% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 526.9 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.57-11.46(m,1H),8.62-8.46(m,2H),7.57-7.27(m,1H),7.22-7.06(m,1H),6.11-4.73(m,2H),3.87-3.79(m,1 H),3.68-3.45(m,5H),3.20-3.03(m,2H),3.02-2.95(m,3H),2.90-2.82(m,3H),2.75-2.60(m,2H),2.44-1.83(m,2H),1.58-1.45(m,3H).

[0194] Example 24: Preparation of compound 24

[0195] Compound 14-a (60 mg, 0.14 mmol), tert-butyl 3-ethynyl-1-azacyclobutanecarboxylate (50 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.01 mmol), cuprous iodide (5 mg, 0.03 mmol), and N,N-diisopropylethylamine (53 mg, 0.41 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid compound 24-a (61 mg, yield 82%). MS m / z 539.9 [M+H] + .

[0196] Compound 24-a (60 mg, 0.11 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 2 hours, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 10:1:0.1) to give a white solid compound 24 (10 mg, yield 20%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 439.9 [M+H] + .

[0197] Example 25: Preparation of Compound 25

[0198] Compound 24 (8 mg, 0.02 mmol) and paraformaldehyde (2 mg, 0.07 mmol) were dissolved in methanol (1 mL), and anhydrous zinc chloride (10 mg, 0.07 mmol) and sodium cyanoborohydride (5 mg, 0.07 mmol) were 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 (dichloromethane:methanol:ammonia = 10:1:0.1) to give a white solid compound 25 (3 mg, yield 36%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.53(d,J=20.8Hz,1H),8.97(d,J=17.5Hz,2H),7.57-7.30(m,1H),7.23-7.08(m,1H),5.80-4.65(m ,2H),3.69-3.59(m,2H),3.56-3.47(m,2H),3.19-3.13(m,2H),2.92-2.67(m,2H),2.27(d,J=2.5Hz,3H),1.56-1.41(m,3H). MS m / z 453.9[M+H] + .

[0199] Example 26: Preparation of Compound 26

[0200] Compound 14a (25 mg, 0.06 mmol), propyneamide (8 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give a white solid compound 26 (3 mg, yield 12%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 427.8 [M+H] + .

[0201] Example 27: Preparation of Compound 27

[0202] Compound 14-a (30 mg, 0.068 mmol), 1-(prop-2-yn-1-yl)pyrrolidine (22 mg, 0.20 mmol), bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), and triethylamine (0.5 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 90 °C for 120 min under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, 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 compound 27 (27 mg, 85% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 467.9 [M+H] + .

[0203] Example 28: Preparation of Compound 28

[0204] Compound 14-a (25 mg, 0.06 mmol), propargylamine (7 mg, 0.12 mmol), palladium dichloride (4 mg, 0.006 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1) to give compound 28 (3 mg, yield 13%) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 413.9 [M+H] + .

[0205] Example 29: Preparation of compound 29

[0206] Compound 14-a (30 mg, 0.07 mmol), N-methylprop-2-acetylamide (11 mg, 0.14 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and sodium bicarbonate (18 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (ethyl acetate) to give compound 29 (6 mg, 20% yield) as a white solid (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 441.9 [M+H] + .

[0207] Example 30: Preparation of compound 30

[0208] Compound 28 (25 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (23 mg, 0.18 mmol) and acetyl chloride (5 mg, 0.06 mmol) were 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 methanol, concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (ethyl acetate:petroleum ether = 1:1) to give a white solid compound 30 (3 mg, yield 11%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 455.8 [M+H] + .

[0209] Example 31: Preparation of compound 31

[0210] Compound 28 (25 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (23 mg, 0.18 mmol) and methanesulfonyl chloride (11 mg, 0.06 mmol) were 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 methanol, concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (ethyl acetate:petroleum ether = 1:1) to give a white solid compound 31 (2 mg, yield 7%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 513.8 [M+Na] + .

[0211] Example 32: Preparation of compound 32

[0212] 3-Bromopropyne (500 mg, 4.20 mmol) and cyclopropylamine (359 mg, 6.3 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered. A 4 M dioxane chloride solution (2 mL) was added dropwise to the filtrate, and the mixture was stirred at room temperature for 10 minutes before being concentrated under reduced pressure. The resulting crude compound 32-a was used directly in the next reaction step.

[0213] Compound 14-a (30 mg, 0.07 mmol), compound 32-a (28 mg, 0.21 mmol), palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1) to give a white solid compound 32 (12 mg, yield 39%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR (500MHz, DMSO-d) δ11.54(d,J=19.9Hz,1H),8.97(d,J=17.1Hz,2H),7.57-7.30(m,1H),7.23-7.06(m,1H),5.81-4.66(m,2H),3.64(d,J =5.1Hz,2H),3.57-3.47(m,1H),2.97-2.67(m,3H),2.38-2.31(m,1H),1.49(dd,J=33.6,6.6Hz,3H),0.47-0.39(m,2H),0.33-0.28(m,2H). MS m / z 453.9[M+H] + .

[0214] Example 33: Preparation of compound 33

[0215] Compound 14-a (30 mg, 0.068 mmol), propynyloxytrimethylsilane (26 mg, 0.20 mmol), bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), and N,N-diisopropylethylamine (0.5 mL) were dissolved in acetonitrile (2 mL) and stirred at 90 °C for 120 min under a nitrogen atmosphere. The mixture was cooled to room temperature, 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 33 (23 mg, 80% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 436.9 [M+H] + .

[0216] Example 34: Preparation of compound 34

[0217] A solution of ethylaminetetrahydrofuran (2M, 3 mL) was diluted with tetrahydrofuran (5 mL), and then 3-bromopropyne (500 mg, 4.20 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered. A solution of dioxane chloride (4M, 2 mL) was added dropwise to the filtrate, and the mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The resulting crude compound 34-a was used directly in the next step of the reaction.

[0218] Compound 14-a (30 mg, 0.07 mmol), compound 34-a (25 mg, 0.21 mmol), palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1) to give a white solid compound 34 (9 mg, yield 30%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.54(d,J=19.9Hz,1H),8.97(d,J=17.0Hz,2H),7.58-7.30(m,2H),7.23-7.06(m,1H),5.82-4.66(m ,2H),3.67(d,J=4.1Hz,2H),3.53-3.47(m,1H),2.90-2.83(m,1H),2.76-2.63(m,3H),1.57-1.44(m,3H),1.12-1.00(m,3H). MS m / z 441.9[M+H] + .

[0219] Example 35: Preparation of compound 35

[0220] 4-Bromobutyne (500 mg, 3.76 mmol) and methylamine hydrochloride (381 mg, 5.64 mmol) were dissolved in tetrahydrofuran (10 mL), and then anhydrous potassium carbonate (1.56 g, 11.28 mmol) was added. The reaction mixture was heated and stirred overnight at 60 °C. The reaction mixture was filtered, and the filter cake was washed with tetrahydrofuran. The filtrate was added dropwise with dioxane chloride solution (4 M, 2 mL), stirred at room temperature for 10 minutes, and then concentrated under reduced pressure. The resulting crude compound 35-a was used directly in the next reaction.

[0221] Compound 14-a (30 mg, 0.07 mmol), compound 35-a (25 mg, 0.21 mmol), palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C under nitrogen for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1) to give a white solid compound 35 (8 mg, yield 27%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 441.8 [M+H] + .

[0222] Example 36: Preparation of compound 36

[0223] Compound 14-a (50 mg, 0.11 mmol), but-3-yn-1-amine (15 mg, 0.22 mmol), bis(triphenylphosphine)palladium dichloride (8 mg, 0.01 mmol), cuprous iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were dissolved in acetonitrile (2 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol:ammonia = 15:1:0.1) to give a white solid compound 36 (28 mg, yield 57%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.64–11.45(m,1H),8.97(d,J=17.0Hz,2H),7.58-7.30(m,1H),7.23-7.07(m,1H),5.8 1-4.64(m,2H),3.56-3.47(m,3H),2.93-2.79(m,3H),2.74-2.68(m,1H),2.64-2.57(m,2H),1.58-1.45(m,3H). MS m / z 427.9[M+H] + .

[0224] Example 37: Preparation of compound 37

[0225] Compound 36 (15 mg, 0.04 mmol) and paraformaldehyde (2 mg, 0.07 mmol) were dissolved in methanol (1 mL), and anhydrous zinc chloride (14 mg, 0.11 mmol) and sodium cyanoborohydride (7 mg, 0.11 mmol) were 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 (dichloromethane:methanol:ammonia = 10:1:0.1) to give a white solid compound 37 (4 mg, yield 26%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO) δ11.53(d,J=19.9Hz,1H),8.93(d,J=17.7Hz,2H),7.59-7.30(m,1H),7.21-7.07(m,1H),5.80-4.64(m, 2H),3.54-3.47(m,1H),2.92-2.82(m,1H),2.74-2.62(m,3H),2.56-2.54(m,2H),2.21(d,J=3.4Hz,6H),1.56-1.43(m,3H). MS m / z 456.0[M+H] + .

[0226] Example 38: Preparation of compound 38

[0227] Compound 38-a (200 mg, 1.4 mmol), the hydrochloride salt of compound 38-b (153 mg, 1.4 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (537 mg, 2.8 mmol) were dissolved in pyridine (2 mL) and 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 oily compound 38-c (50 mg, yield 18%). MS m / z 198.1 [M+H] + .

[0228] Compound 14-a (35 mg, 0.08 mmol), compound 38-c (50 mg, 0.25 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), cesium fluoride (61 mg, 0.40 mmol), and sodium bicarbonate (23 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred overnight at 70°C under a nitrogen atmosphere. The solution was cooled to room temperature, 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 white solid compound 38 (18 mg, yield 47%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 483.8 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.60-11.49(m,1H),9.26-9.11(m,2H),7.60-7. 28(m,1H),7.24-7.06(m,1H),5.96-5.88(m,1H),5.80-4.73(m,1H),4.60- 4.46(m,2H),4.25-4.14(m,1H),4.07-3.97(m,1H),3.77-3.67(m,1H),3. 59-3.46(m,2H),2.96-2.87(m,1H),2.73-2.66(m,1H),1.57-1.42(m,3H).

[0229] Example 39: Preparation of compound 39

[0230] Compound 14-a (50 mg, 0.11 mmol), compound 39-a (34 mg, 0.17 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (8 mg, 0.01 mmol), cuprous iodide (4 mg, 0.02 mmol), and sodium bicarbonate (29 mg, 0.34 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 39-b (42 mg, 66% yield). MS m / z 558.9 [M+H] + .

[0231] Compound 39-b (11 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 0.05 mL) was added dropwise. 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 a white solid compound 39 (2 mg, yield 25%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.54(d,J=20.0Hz,1H),8.97(d,J=17.3Hz,2H),7.58-7.29(m,1H),7.22-7.08(m,1H),5.79-5.74(m,1H),5.32(t,J =4.7Hz,1H),5.08(dd,J=11.3,6.0Hz,1H),4.80-4.65(m,1H),4.51-4.43(m,1H),3.57-3.48(m,3H),2.89-2.68(m,2H),1.55-1.43(m,3H). MS m / z 444.9[M+H] + .

[0232] Example 40: Preparation of Compound 40

[0233] Compound 40-a (synthesis reference: ACS Infectious Diseases, 2020, vol. 6, #1, p. 80–90). Compound 14-a (30 mg, 0.068 mmol), compound 40-a (22 mg, 0.20 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), and sodium bicarbonate (23 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred overnight at 70°C under nitrogen atmosphere. The solution was cooled to room temperature, 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 white solid compound 40 (8 mg, yield 25%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 469.8 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ11.57-11.49(m,1H),9.07-8.95(m,2H),7.60-7.31(m,1H),7.23-7.06(m,1H),5.80-5.69(m,1H),5.41-5.31(m,1 H),4.79-4.66(m,1H),4.25-4.15(m,1H),3.57-3.50(m,4H),3.07-2.96(m,2H),2.92-2.81(m,2H),2.75-2.67(m,1H),1.57-1.44(m,3H).

[0234] Example 41: Preparation of compound 41

[0235] Compound 41-a (360 mg, 1.93 mmol), propargyl acid (135 mg, 1.93 mmol), and N,N-diisopropylethylamine (747 mg, 5.79 mmol) were dissolved in dichloromethane (5 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (770 mg, 2.03 mmol) were added. 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 silica gel column chromatography to give compound 41-b (91 mg, yield 20%).

[0236] Compound 14-a (30 mg, 0.07 mmol), compound 41-b (33 mg, 0.14 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and sodium bicarbonate (18 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was heated and stirred at 80 °C for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 41-c (19 mg, 46% yield). MS m / z 596.9 [M+H] + .

[0237] Compound 41-c (19 mg, 0.03 mmol) was dissolved in methanol (1 mL), and then p-toluenesulfonic acid (8 mg, 0.05 mmol) was added. The reaction mixture was heated and stirred overnight at 50 °C. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 41 (6 mg, yield 38%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.54(d,J=20.2Hz,1H),9.18(d,J=14.9Hz,2H),7.62- 7.28(m,1H),7.23-7.07(m,1H),5.84-5.68(m,1H),4.82-4.69(m,1H),4.45-4. 36(m,1H),4.13-4.06(m,1H),4.00-3.92(m,1H),3.66(dd,J=9.7,4.7Hz,1H),3 .57-3.49(m,2H),2.92-2.70(m,2H),2.23(d,J=2.9Hz,3H),1.55-1.42(m,3H). MS m / z 496.8 [M+H] + .

[0238] Example 42: Preparation of compound 42

[0239] Compound 42-a (300 mg, 1.74 mmol), propargyl acid (122 mg, 1.74 mmol), and N,N-diisopropylethylamine (673 mg, 5.22 mmol) were dissolved in dichloromethane (5 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (695 mg, 1.83 mmol) were added. 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 silica gel column chromatography to give compound 42-b (42 mg, yield 11%).

[0240] Compound 14-a (30 mg, 0.07 mmol), compound 42-b (31 mg, 0.14 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.01 mmol), and sodium bicarbonate (18 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2 mL). The reaction mixture was heated and stirred at 80 °C for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 42-c (17 mg, 43% yield). MS m / z 582.9 [M+H] + .

[0241] Compound 42-c (17 mg, 0.03 mmol) was dissolved in methanol (1 mL), and p-toluenesulfonic acid (8 mg, 0.05 mmol) was added. The reaction mixture was heated and stirred overnight at 50 °C. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 42 (5 mg, yield 36%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.54(d,J=20.1Hz,1H),9.22-9.08(m,2H),7.59-7 .31(m,2H),7.25-7.05(m,1H),5.81-5.74(m,1H),4.82-4.68(m,1H),4.47 -4.38(m,1H),4.18-4.09(m,1H),3.94-3.86(m,1H),3.82-3.73(m,1H),3. 62-3.56(m,1H),3.55-3.49(m,2H),2.91-2.64(m,2H),1.56-1.44(m,3H). MS m / z 482.8[M+H] + .

[0242] Example 43: Preparation of compound 43

[0243] Compound 14-a (50 mg, 0.11 mmol), compound 43-a (50 mg, 0.44 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), and sodium bicarbonate (23 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred overnight at 70°C under nitrogen atmosphere. The solution was cooled to room temperature, 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 white solid compound 43 (15 mg, yield 28%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 471.9 [M+H] + .

[0244] Example 44: Preparation of compound 44

[0245] Compound 44-a (390 mg, 1.68 mmol) was dissolved in dichloromethane (4 mL) under ice-water bath conditions, and a solution of diisobutylaluminum hydride in n-hexane (1 M, 3.51 mL) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with ice water. After stirring at room temperature for 30 minutes, the mixture was filtered through diatomaceous earth and washed. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a colorless oily product 44-b (256 mg, yield 75%). MS m / z 227.1 [M + Na] + .

[0246] Compound 44-b (256 mg, 1.25 mmol) was dissolved in dichloromethane (4 mL) under ice-water bath conditions, followed by the sequential addition of diisopropylethylamine (324 mg, 2.51 mmol) and methanesulfonyl chloride (215 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a colorless oily product 44-c (220 mg, yield 62%).

[0247] Compound 44-c (220 mg, 0.779 mmol) was dissolved in dichloromethane (4 mL) under ice-water bath conditions, followed by the sequential addition of diisopropylethylamine (151 mg, 1.17 mmol) and pyrrolidine (83 mg, 1.17 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia) to give a colorless oily product 44-d (182 mg, yield 91%). MS m / z 258.2 [M+H] + .

[0248] Compound 44-d (120 mg, 0.466 mmol) was dissolved in dichloromethane (5 mL) under ice-water bath conditions. Titanium tetrachloride (265 mg, 1.40 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with saturated sodium bicarbonate solution. The resulting mixture was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 12:1, 2% ammonia) to give a colorless oily product 44-e (29 mg, yield 37%). MS m / z 168.2 [M+H] + .

[0249] Compound 44-e (25 mg, 0.149 mmol), compound 44-f (47 mg, 0.299 mmol), and cesium carbonate (146 mg, 0.448 mmol) were dissolved in acetonitrile (3 mL), and the reaction mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 18:1, 2% ammonia) to give a colorless oily product 44-g (12 mg, yield 26%). MS m / z 304.1 [M+H] + .

[0250] Compound 44-g (12 mg, 0.040 mmol) was dissolved in methanol / water (2 / 0.5 mL), and lithium hydroxide (3 mg, 0.119 mmol) was added. The reaction solution was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a white solid crude product 44-h, which was directly used in the next reaction. MS m / z 290.1 ​​[M+H] + .

[0251] Compound 44-h (12 mg, 0.041 mmol), compound 1-e (12 mg, 0.048 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (31 mg, 0.082 mmol) were dissolved in N,N-dimethylformamide (2 mL). Diisopropylethylamine (11 mg, 0.082 mmol) was added, and 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 = 16:1, 2% ammonia) to give a white solid product 44 (7.20 mg, yield 34%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d6)δ11.57–11.48(m,1H),8.63–8.52(m,2H),7.57–7.26(m,1H),7.21–7.07(m,1H),5.79–4.65(m,3H),3.54–3 .46(m,1H),3.30–3.20(m,4H),3.03–2.96(m,2H),2.90–2.68(m,4H),2.49–2.47(m,3H),1.73–1.65(m,4H),1.56–1.41(m,3H)ppm. MS m / z 525.9[M+H] + .

[0252] Example 45: Preparation of compound 45

[0253] Compound 14a (20 mg, 0.05 mmol), compound 45-a (11 mg, 0.09 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 45 (9 mg, 41% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.54(d,J=20.3Hz,1H),9.19(d,J=15.1Hz,2H),7.58-7.30(m,1H),7.22-7.05(m,1H),5.81-5.73(m,1H),4.81-4 .70(m,1H),3.72(dd,J=12.1,6.0Hz,2H),3.57-3.49(m,1H),3.42-3.37(m,2H),2.94-2.69(m,2H),1.97-1.81(m,4H),1.57-1.44(m,3H). MS m / z 481.8[M+H] + .

[0254] Example 46: Preparation of Compound 46

[0255] Compound 14-a (20 mg, 0.05 mmol), compound 46-a (12 mg, 0.09 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 46 (4 mg, 18% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR (500MHz, DMSO-d) δ11.54(d,J=20.4Hz,1H),9.12(d,J=16.5Hz,2H),7.58-7.28(m,1H),7.21-7.09(m,1H),5.82-5.72(m,1H),4. 81-4.64(m,1H),4.13-4.05(m,1H),3.56-3.49(m,1H),2.91-2.70(m,3H),1.88-1.81(m,2H),1.71-1.62(m,2H),1.57-1.43(m,7H). MS m / z 495.8[M+H] + .

[0256] Example 47: Preparation of Compound 47

[0257] Compound 14-a (20 mg, 0.05 mmol), compound 47-a (13 mg, 0.09 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 47 (8 mg, 35% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.54(d,J=21.4Hz,1H),9.21(d,J=15.0Hz,2H),7.60-7.29(m,1H),7.24-7.07(m,1H),5.83-5.68(m,1H),4. 84-4.64(m,1H),3.89-3.77(m,2H),3.71-3.65(m,2H),3.65-3.54(m,4H),3.53-3.48(m,1H),2.93-2.69(m,2H),1.58-1.44(m,3H). MS m / z 519.8[M+Na] + .

[0258] Example 48: Preparation of Compound 48

[0259] Compound 48-a (100 mg, 1.01 mmol), compound 38-a (143 mg, 1.01 mmol), and N,N-diisopropylethylamine (391 mg, 3.03 mmol) were dissolved in dichloromethane (3 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (403 mg, 1.06 mmol) were added. 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 silica gel column chromatography to give compound 48-b (88 mg, yield 58%).

[0260] Compound 14-a (10 mg, 0.02 mmol), compound 48-b (18 mg, 0.05 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (2 mg, 0.002 mmol), cuprous iodide (1 mg, 0.005 mmol), and sodium bicarbonate (7 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 48 (3 mg, 26% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 509.8 [M+Na] + .

[0261] Example 49: Preparation of Compound 49

[0262] Compound 49-a (100 mg, 1.06 mmol), compound 38-a (151 mg, 1.06 mmol), and N,N-diisopropylethylamine (410 mg, 3.18 mmol) were dissolved in dichloromethane (3 mL), and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (423 mg, 1.11 mmol) were added. 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 silica gel column chromatography to give compound 49-b (94 mg, yield 61%).

[0263] Compound 14-a (20 mg, 0.05 mmol), compound 49-b (14 mg, 0.09 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred at 70 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 49 (5 mg, 22% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.55(d,J=20.1Hz,1H),11.35(d,J=9.8Hz,1H),9.22(d,J=15.9Hz,2H),8.82(s,1H),8.36(s,1H),8.12-8.02(m,1 H),7.58-7.29(m,2H),7.24-7.07(m,1H),5.84-5.71(m,1H),4.81-4.69(m,1H),3.58-3.52(m,1H),2.93-2.72(m,2H),1.58-1.46(m,3H). MS m / z 504.9[M+H] + .

[0264] Example 50: Preparation of Compound 50

[0265] Compound 14-a (20 mg, 0.05 mmol), compound 50-a (13 mg, 0.09 mmol), palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 50 (9 mg, 41% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.54(d,J=20.3Hz,1H),9.00(d,J=16.4Hz,2H),7.58-7.30(m,1H),7.22-7.07(m,1H),5.87-5.70(m,1H),4 .81-4.66(m,1H),3.63(d,J=4.3Hz,2H),3.55-3.49(m,4H),2.92-2.69(m,3H),2.66-2.55(m,4H),2.24(s,3H),1.58-1.43(m,3H). MS m / z 496.8[M+H] + .

[0266] Example 51: Preparation of compound 51

[0267] Compound 14-a (20 mg, 0.05 mmol), compound 51-a (11 mg, 0.09 mmol), palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 51 (13 mg, 59% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR (500MHz, DMSO-d) δ11.54(d,J=20.1Hz,1H),9.01(d,J=16.5Hz,2H),7.58-7.31(m,1H),7.22-7.06(m,1H),5.83-5.68( m,1H),4.82-4.67(m,1H),3.70-3.56(m,6H),3.54-3.48(m,1H),2.92-2.68(m,2H),2.63-2.54(m,4H),1.57-1.43(m,3H). MS m / z 483.8[M+H] + .

[0268] Example 52: Preparation of compound 52

[0269] Compound 14-a (20 mg, 0.05 mmol), compound 52-a (10 mg, 0.09 mmol), bis(triphenylphosphine)palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to obtain compound 52 (9 mg, 43% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.54(d,J=19.4Hz,1H),9.13(d,J=17.1Hz,2H),7.68-7.61(m,2H),7.58-7.32(m,4H),7. 24-7.06(m,1H),5.82-5.73(m,1H),4.84-4.68(m,1H),3.57-3.48(m,1H),2.92-2.69(m,2H),1.62-1.43(m,3H). MS m / z 460.9[M+H] + .

[0270] Example 53: Preparation of compound 53

[0271] Compound 14-a (20 mg, 0.05 mmol), compound 53-a (11 mg, 0.09 mmol), palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 53 (12 mg, 57% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.55(d,J=19.8Hz,1H),9.29(d,J=2.3Hz,1H),9.20(s,1H),9.17(s,1H),9.11(d,J=6.3Hz,2H),7.60-7 .30(m,1H),7.23-7.06(m,1H),5.86-5.70(m,1H),4.82-4.69(m,1H),3.58-3.51(m,1H),2.92-2.69(m,2H),1.57-1.45(m,3H). MS m / z 462.8[M+H] + .

[0272] Example 54: Preparation of compound 54

[0273] Compound 14-a (20 mg, 0.05 mmol), 3-ethynyloxetane (8 mg, 0.09 mmol), bis(triphenylphosphine)palladium dichloride (4 mg, 0.005 mmol), cuprous iodide (2 mg, 0.01 mmol), and N,N-diisopropylethylamine (20 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL). The reaction mixture was heated and stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 54 (12 mg, 61% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.53(d,J=20.6Hz,1H),9.01(d,J=17.3Hz,2H),7.57-7.30(m,1H),7.24-7.07(m,1H),5. 85-5.73(m,1H),4.90-4.62(m,5H),4.53-4.24(m,1H),3.55-3.46(m,1H),2.92-2.68(m,2H),1.62-1.39(m,3H). MS m / z 462.7[M+Na] + .

[0274] Example 55: Preparation of compound 55

[0275] Compound 14-a (20 mg, 0.04 mmol), compound 55-a (22 mg, 0.09 mmol), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (3 mg, 0.004 mmol), cuprous iodide (2 mg, 0.01 mmol), and sodium bicarbonate (10 mg, 0.12 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction mixture was heated and stirred overnight at 70 °C. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 55-b (15 mg, 55% yield). MS m / z 596.9 [M+H] + .

[0276] Compound 55-b (15 mg, 0.03 mmol) was dissolved in methanol (1 mL), and then p-toluenesulfonic acid (8 mg, 0.05 mmol) was added. The reaction mixture was heated and stirred overnight at 50 °C. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography to give compound 55-c (9 mg, yield 72%). MS m / z 496.8 [M+H] + .

[0277] Compound 55-c (7 mg, 0.01 mmol), paraformaldehyde (1 mg, 0.04 mmol), and anhydrous zinc chloride (6 mg, 0.04 mmol) were dissolved in methanol (1 mL), and sodium cyanoborohydride (3 mg, 0.04 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 obtain compound 55 (4 mg, yield 72%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.54(d,J=21.3Hz,1H),9.21(d,J=14.9Hz,2H),7.58-7.30(m,1H),7.22-7.08(m,1H),5.82-5.73(m,1H),4.81-4.64(m,1H) ,3.80(dd,J=9.8,4.0Hz,2H),3.59-3.48(m,3H),2.92-2.68(m,2H),2.42- 2.38(m,2H),2.35-2.30(m,2H),2.22(d,J=2.5Hz,3H),1.55-1.43(m,3H). MS m / z 510.9[M+H] + .

[0278] Example 56: Preparation of compound 56

[0279] Compound 14-a (120 mg, 0.273 mmol), 4-(prop-2-yn-1-yl)piperazine-1-carboxylic acid tert-butyl ester (27 mg, 0.300 mmol), cuprous iodide (3 mg, 0.014 mmol), and bis(triphenylphosphine)palladium dichloride (20 mg, 0.027 mmol) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (82 mg, 0.819 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 = 3:1) to obtain a colorless liquid compound 56-a (138 mg, yield 87%).

[0280] Compound 56-a (138 mg, 0.236 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride solution (0.5 mL, 4 M) was added under ice bath conditions. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was adjusted to pH 7-9 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (3 × 20 mL). The combined organic phases were 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 = 20:1) to obtain a colorless liquid compound 56-b (83 mg, yield 73%).

[0281] Compound 56-b (18 mg, 0.037 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (11 mg, 0.111 mmol) was added under ice bath conditions. Then, a dichloromethane solution of acetyl chloride (3 mg, 0.037 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was added with water and extracted with dichloromethane (3 × 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 (dichloromethane:methanol = 20:1) to obtain a white solid compound 56 (10.86 mg, yield 55%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1H NMR(500MHz,DMSO-d)δ11.60-11.42(m,1H),9.09-8.85(m,2H),7.59-7.3 0(m,1H),7.24-7.05(m,1H),5.86-5.66(m,1H),4.82-4.64(m,1H),3.75- 3.63(m,2H),3.56-3.42(m,6H),2.94-2.79(m,2H),2.72-2.62(m,1H),2. 58-2.54(m,2H),2.07-1.96(m,3H),1.59-1.49(m,2H),1.49-1.41(m,1H). MS m / z 524.9[M+1] + .

[0282] Example 57: Preparation of Compound 57

[0283] Compound 56-b (15 mg, 0.031 mmol), N-methylpiperidinone (4 mg, 0.037 mmol), and zinc chloride (6 mg, 0.046 mmol) were dissolved sequentially in methanol (1 mL), followed by the addition of sodium cyanoborohydride (4 mg, 0.062 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture 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 white solid compound 57 (7.18 mg, yield 36%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.59-11.45(m,1H),9.06-8.94(m,2H),7.58-7.30(m,1H),7.25 -7.03(m,1H),5.81-5.69(m,1H),4.82-4.64(m,1H),3.66-3.56(m,2H),3.52-3.36(m,6 H),2.94-2.85(m,1H),2.81-2.74(m,2H),2.72-2.55(m,6H),2.15-2.10(m,3H),1.88-1 .78(m,2H),1.74-1.65(m,2H),1.55-1.50(m,1H),1.47-1.43(m,1H),1.42-1.32(m,2H). MS m / z 580.0[M+1] + .

[0284] Example 58: Preparation of Compound 58

[0285] Compound 56-b (15 mg, 0.031 mmol), 3-oxetane (4 mg, 0.062 mmol), and zinc chloride (6 mg, 0.046 mmol) were dissolved sequentially in methanol (1 mL), followed by the addition of sodium cyanoborohydride (4 mg, 0.062 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until completion. The reaction mixture 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 white solid compound 58 (4.02 mg, yield 24%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.66-11.40(m,1H),9.12-8.83(m,2H),7.62-7.27(m, 1H),7.25-6.97(m,1H),5.85-5.69(m,1H),4.82-4.62(m,1H),4.59-4.47(m,2 H),4.46-4.37(m,2H),3.72-3.60(m,2H),3.58-3.37(m,6H),2.93-2.77(m,1H ),2.65-2.53(m,3H),2.37-2.17(m,2H),1.58-1.51(m,2H),1.49-1.41(m,1H). MS m / z 538.9 [M+1] + .

[0286] Example 59: Preparation of compound 59

[0287] The synthesis of compound 59-c followed the same method as that used for compound 60. Compound 59-c was obtained (10 mg, yield 36%).

[0288] Compound 59-c (10 mg, 0.016 mmol) was dissolved in methanol (1 mL), and then p-toluenesulfonic acid (4 mg, 0.024 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction was monitored by TLC until completion. The reaction mixture was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 25:1) to give a white solid compound 59-d (2 mg, yield 24%).

[0289] Compound 59 was synthesized using the same method as compound 57. A white solid, compound 59 (0.55 mg, 27% yield) was obtained (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 524.9 [M+1] + .

[0290] Example 60: Preparation of Compound 60

[0291] Compound 60-b was synthesized using the same method as compound 561-b.

[0292] Compound 14-a (20 mg, 0.045 mmol), compound 60-b (10 mg, 0.055 mmol), cuprous iodide (0.9 mg, 0.004 mmol), cesium fluoride (35 mg, 0.227 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (4 mg, 0.005 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, 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 thin-layer chromatography on silica gel plates (dichloromethane:methanol = 20:1) to obtain a white solid compound 60 (4.75 mg, yield 22%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). 1 H NMR(500MHz,DMSO-d)δ11.61-11.44(m,1H),9.27-9.09(m,2H),7.59-7.28(m,1H), 7.24-7.06(m,1H),5.82-5.71(m,1H),4.81-4.68(m,1H),3.56-3.47(m,1H),3.00- 2.93(m,1H),2.93-2.88(m,3H),2.03-1.93(m,1H),1.57-1.51(m,1H),1.50-1.45( m,1H),1.27-1.18(m,3H),1.00-0.96(m,1H),0.93-0.87(m,1H),0.80-0.68(m,1H). MS m / z 482.0[M+1] + .

[0293] Example 61: Preparation of compound 61

[0294] Compound 38-a (200 mg, 1.4 mmol), the hydrochloride salt of compound 61-a (196 mg, 2.1 mmol), N,N-diisopropylethylamine (543 mg, 4.2 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (798 mg, 2.1 mmol) were dissolved in dichloromethane (2 mL) and 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 preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a pale yellow oily compound 61-b (10 mg, yield 4%). MS m / z 182.1 [M+H] + .

[0295] Compound 14-a (20 mg, 0.045 mmol), compound 61-b (10 mg, 0.055 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (5 mg, 0.007 mmol), cuprous iodide (3 mg, 0.016 mmol), cesium fluoride (61 mg, 0.40 mmol), and sodium bicarbonate (23 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred overnight at 70°C under a nitrogen atmosphere. The solution was cooled to room temperature, 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 white solid compound 61 (5 mg, yield 23%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 468.0 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.59-11.51(m,1H),9.23-9.12(m,2H),7.60-7.29(m,1H),7.23-7.07(m,1H),5.80-4.70(m,1 H),4.35-4.23(m,2H),4.06-3.93(m,2H),3.59-3.46(m,2H),2.93-2.78(m,2H),2.35-2.26(m,2H),1.57-1.42(m,3H).

[0296] Example 62: Preparation of compound 62

[0297] Compound 62-a (250 mg, 2.23 mmol), dimethylaminetetrahydrofuran solution (4.5 mL, 9.00 mmol, 2 M), N,N-diisopropylethylamine (866 mg, 6.7 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1255 mg, 3.3 mmol) were dissolved in dichloromethane (10 mL) and 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 preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 62-b (250 mg, yield 81%), a pale yellow oil. MS m / z 140.1 [M+H] + .

[0298] Compound 14-a (20 mg, 0.045 mmol), compound 62-b (20 mg, 0.14 mmol), palladium dichloride (5 mg, 0.007 mmol), and cuprous iodide (3 mg, 0.016 mmol) were dissolved in acetonitrile (2 mL), followed by the addition of 0.5 mL of triethylamine. The mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, 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 white solid, compound 62 (20 mg, 88% yield) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 498.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.59-11.48(m,1H),9.04-8.95(m,2H),7.58-7.28(m,1H),7.24-7.04(m,1 H),4.76-4.56(m,1H),3.57-3.41(m,2H),3.38-3.34(m,2H),3.06-2.66(m,6H),1.58-1.41(m,9H).

[0299] Example 63: Preparation of compound 63

[0300] Compound 63-a (250 mg, 2.55 mmol), dimethylaminetetrahydrofuran solution (2.0 mL, 4.00 mmol, 2 M), 4-dimethylaminopyridine (31 mg, 0.25 mmol), N,N-diisopropylethylamine (866 mg, 6.7 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (586 mg, 3.1 mmol) were dissolved in dichloromethane (10 mL) and 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 preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give compound 63-b (110 mg, yield 34%), a pale yellow oil. MS m / z 126.1 [M+H] + .

[0301] Compound 14-a (20 mg, 0.045 mmol), compound 63-b (20 mg, 0.16 mmol), palladium dichloride (5 mg, 0.007 mmol), and cuprous iodide (3 mg, 0.016 mmol) were dissolved in acetonitrile (2 mL), followed by the addition of 0.5 mL of triethylamine. The mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, 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 white solid compound 63 (15 mg, yield 68%) (enantiomer mixture, S / R 2:1, configuration arbitrarily specified). MS m / z 484.0 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.58-11.47(m,1H),9.00-8.86(m,2H),7.59-7.29(m,1H),7.22-7.06(m,1H),4.82-4.62(m,1 H),3.64-3.37(m,2H),3.32-3.24(m,2H),3.02-2.94(m,3H),2.87-2.82(m,3H),2.73-2.64(m,4H),1.57-1.41(m,3H).

[0302] Example 64: Inhibition of cGAS enzyme activity by the compound

[0303] 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.

[0304] Table 1: Inhibitory activity of compounds against cGAS enzyme

[0305] Example 65: Pharmacokinetics in rats

[0306] 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.

[0307] Animals: Three male SD rats, weighing 180-220g, were purchased and housed in the laboratory of the experimental animal center for 3 days before use. They 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 the compound was in a homogeneous suspension, thus preparing a drug solution of the appropriate concentration.

[0308] Drug samples: Multiple structurally similar samples (with molecular weights differing by more than 2 units) are accurately weighed and administered together (cassette PK). This allows for the simultaneous screening of multiple compounds and comparison of their oral absorption rates.

[0309] Blood samples were collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after gavage administration. 30 μL of plasma sample (30 μL of blank plasma was added to both blank and internal standard blank samples) was transferred to a 1.5 mL centrifuge tube, and 300 μL of 50% methanol-acetonitrile solution containing the internal standard (100 ng / mL Tolbutamide) was added (300 μL of 50% methanol-acetonitrile solution was added to Doubleblank samples). The sample was vortexed for 5 minutes, centrifuged at 4000 rpm and 4 °C for 10 minutes, and 100 μL was added to 100 μL of water. After thorough mixing, the mixture was analyzed by LC-MS / MS.

[0310] 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 relevant software, and pharmacokinetic parameters (primarily including kinetic parameters Tmax, T1 / 2, Cmax, and AUC) were calculated using the statistical moment method. 0-24h (etc.). Table 2 shows the pharmacokinetic data of some representative compounds in rats.

[0311] Table 2: Pharmacokinetic parameters in rats

[0312] Example 66: Pharmacokinetics in Mice

[0313] 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, T1 / 2, Cmax, and AUC. 0-24h wait.

[0314] Animals: Three male C57BL / 6N mice, weighing 25-30g, were purchased and housed in the laboratory of the experimental animal center for 3 days before use. They 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 the compound was in a homogeneous suspension to prepare a drug solution of the appropriate concentration.

[0315] Drug samples: Multiple structurally similar samples (with molecular weights differing by more than 2 units) are accurately weighed and administered together (cassette PK). This allows for the simultaneous screening of multiple compounds and comparison of their oral absorption rates.

[0316] 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 sample was analyzed by LC-MS / MS.

[0317] 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 relevant software, and pharmacokinetic parameters (primarily including kinetic parameters Tmax and T2) were calculated using the statistical moment method. 1 / 2 Cmax, AUC 0-24h (etc.). Pharmacokinetic data for some representative compounds in mice are shown in Table 3.

[0318] Table 3: Pharmacokinetic parameters in mice

[0319] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound 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): "*" indicates a chiral center; A is selected from formula (Ia), formula (Ib), or formula (Ic): In equation (Ia), equation (Ib), or equation (Ic), Indicates a carbon-carbon double bond or a carbon-carbon triple bond; This indicates a carbon-carbon single bond or a carbon-carbon double bond. The site where formula (Ia), formula (Ib), or formula (Ic) connects to other segments of the compound of formula (I); R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, or CN; R 2 and R 2’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, or CN; 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, OR a SR a NR c R c 、or CN; or two R 3 Together with the carbon atoms connected thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; each R a Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; each R c Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; R 4 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, 3- to 6-membered heterocyclic, aryl, heteroaryl, OR a SR a NR c R c 、or CN;R a and R c The definition is as described above; R is selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups in R 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 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 the cycloalkyl or heterocyclic group in said R is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, (R) d’ R d’ )NC 2-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; or two R d Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、or = M; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, cyano C 1-3 Alkyl, (R) d’ R d’ )NC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in R is optionally substituted with =M; c The definitions are as described above; each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; M is selected from CR h R i ,in, R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl; R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O; X is selected from N, C, or CR. e ;R e Selected from hydrogen, halogen, or C 1-4 alkyl; Y is selected from O, S, NR b or CR b’ R b’ ;R b Selected from hydrogen or C 1-4 Alkyl groups; each R b’ Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR a SR a NR c R c 、or CN; or two R 5 Together with the carbon atoms connected to it, it forms a spirocyclic, bridged, or fused ring structure, which optionally contains 0 or 1 additional heteroatoms selected from N, O, and S; R a and R c The definition is as described above; R 6 and R 7 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, C 3-6 cycloalkyl C 1-4 Alkyl, 3- to 6-membered heterocyclic C 1-4 Alkyl, 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, 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 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 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 ;R d R f R g The definition is as described above; a is selected from 0, 1, 2, or 3; m is selected from 0, 1, 2, 3, or 4; n is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, or 2; q and r are each independently selected from 0, 1, 2, 3, or 4; s is selected from 0, 1, 2, 3, or 4; 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; 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 either equation (IIa) or equation (IIb): The definitions of each group in formulas (IIa) and (IIb) are as described in claim 1.

3. The compound according to claim 1, characterized in that, Equation (I) is either equation (IIIa) or equation (IIIb): The definitions of each group in formulas (IIIa) and (IIIb) are as described in claim 1.

4. The compound according to claim 1, characterized in that, Equation (I) is either Equation (IVa) or Equation (IVb): The definitions of each group in formulas (IVa) and (IVb) are as described in claim 1.

5. The compound according to any one of claims 2-4, characterized in that, R is selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups in R 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 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 the cycloalkyl or heterocyclic group in said R is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, R d’ R d’ NC 2- 4-alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; or two R d Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、or = M; each R f Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, cyano C 1-3 Alkyl, R d’ R d’ NC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in the R group is optionally substituted with =M; each R c Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl; M is selected from CR h R i , where R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 Alkyl; R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3- 6-cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O; 'a' can be selected from 0, 1, 2, or 3.

6. The compound according to any one of claims 2-5, characterized in that, R is selected from SR f NR d1 R d2 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 ;R d1 and R d2 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 2-4 Alkyl, hydroxyl C 2-4 Alkyl, cyano C 2-4 Alkyl, R d’ R d’ NC 2-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; provided that R d1 and R d2 Cannot be simultaneously selected from hydrogen; or R d1 and R d2 Together with the nitrogen atom attached thereto, a 3- to 8-membered ring structure is formed, which optionally contains 0 or 1 additional 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, C 2-4 alkenyl, C 2-4 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、 or = M; R c R d R d’ R f R g The definition of M is as described in claim 5.

7. The compound according to any one of claims 2-5, characterized in that, R is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group in R is 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 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 .

8. The compound according to claim 1, characterized in that, Equation (I) is either equation (Va) or equation (Vb): R d1 and R d2 The definition is as described in claim 6; R j and R k Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic, CN, OR f SR f , or NR c R c ; or R j and R k Together with the carbon atoms attached thereto, they form a 3- to 6-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S; or R j and R k Together with the carbon atoms it is connected to, it forms =O; a is selected from 1, 2, or 3; 9. The compound according to claim 1, characterized in that, Equation (I) is either Equation (VIa) or Equation (VIb): R d The definition is as described in claim 5; 10. The compound according to claim 1, characterized in that, Equation (I) is either equation (VIIa) or equation (VIIb): The definitions of each group in formulas (VIIa) and (VIIb) are as described in claim 1.

11. The compound according to claim 1, characterized in that, Equation (I) can be Equation (VIIIa), Equation (VIIIb), Equation (VIIIc), Equation (VIIId), Equation (VIIIe), or Equation (VIIIf): The definitions of each group in formulas (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), and (VIIIf) are as described in claim 1.

12. The compound according to claim 1, characterized in that, Equation (I) can be Equation (IXa), Equation (IXb), Equation (IXc), Equation (IXd), Equation (IXe), or Equation (IXf): The definitions of each group in formulas (IXa), (IXb), (IXc), (IXd), (IXe), and (IXf) are as described in claim 1.

13. The compound according to claim 1, characterized in that, Equation (I) is either equation (Xa) or equation (Xb): The definitions of each group in formulas (Xa) and (Xb) are as described in claim 1.

14. The compound according to claim 1, characterized in that, Equation (I) is either equation (XIa) or equation (XIb): t is selected from 0, 1, 2, or 3; R is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, 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 ; C in R 1-4 Alkyl, cycloalkyl, heterocyclic, aryl, or 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 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 ;R d R f R g The definition is as described in claim 1.

15. 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 racemic, R-, and S-configurations.

16. A pharmaceutical composition, characterized in that, The compound comprising any one of claims 1 to 15, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

17. Use of a compound according to any one of claims 1 to 15, 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.

18. The use as described in claim 17, 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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