Compound as pparg inverse agonist

Abstract

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

Description

Compounds as PPARG inverse agonists 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 a PPARG inverse agonist in the preparation of drugs for the treatment of autoimmune diseases and other related diseases. Background Technology

[0002] PPARG (peroxisome proliferator-activated receptor gamma) is a transcription factor primarily expressed in adipose tissue, the colon, macrophages, and the luminal lining of the urothelium. It is a member of the nuclear hormone receptor family and plays a crucial role in regulating lipid metabolism, insulin sensitivity, and inflammatory responses.

[0003] As a nuclear receptor, PPARG's activity depends on ligand binding. PPARG ligands include fatty acid derivatives and drugs (such as thiazolidinediones). After binding to a ligand, PPARG forms a heterodimer with another nuclear receptor, the retinoic acid X receptor (RXR). This heterodimer complex has transcriptional regulatory functions. The PPARG-RXR dimer binds to specific DNA sequences, known as PPARG response elements (PPREs), typically located in the promoter or enhancer regions of target genes. The PPARG / RXR complex interacts with nuclear receptor coactivators (such as NCOA1) or co-repressors (NCOR1 and NCOR2), which recruit additional transcriptional regulatory proteins, including histone acetyltransferases and histone deacetylases, the mediator complex (MED1), and basic transcriptional elements, to regulate the transcription of target genes, thereby regulating lipid synthesis and metabolism, insulin signaling, and inflammatory responses.

[0004] Aberrant activation of PPARG is associated with various tumors, such as bladder cancer and pancreatic cancer. Bladder cancer is one of the top ten most common cancers worldwide. According to global cancer statistics in 2022, there are approximately 613,000 new cases of bladder cancer annually, resulting in about 220,000 deaths. Bladder cancer is far more common in men than women, with an incidence rate approximately 3 to 4 times higher in men than in women. Pathologically, bladder cancer is classified into non-muscle invasive and muscle-invasive bladder cancer. Local amplification of PPARG leads to overexpression of PPARG and its target genes; overexpression of PPARG has been detected in 12-17% of muscle-invasive bladder cancers and 10% of non-muscle-invasive bladder cancers. Furthermore, based on molecular characteristics and gene mutations, bladder cancer can be classified into luminal subtypes, basal subtypes, and transitional subtypes. Lumen-type muscularly invasive bladder cancer is often associated with higher PPARG activity. Furthermore, gain-of-function mutations in RXR can also lead to aberrant activation of downstream target genes of PPARG. Currently, there are no marketed inhibitors of PPARG; therefore, developing molecules that can regulate PPARG activity is of great significance. Summary of the Invention

[0005] The purpose of this invention is to provide a novel class of PPARG inverse agonists.

[0006] 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:

[0007] E——D——B——A

[0008] (I)

[0009] In formula (I):

[0010] A is selected from substituted or unsubstituted aryl or heteroaryl groups;

[0011] B is selected from chemical bonds, -C(O)NR 1 -、-NR 1 C(O)-、-S(O2)NR 1 - or -NR 1 S(O2)-; where R 1 Selected from hydrogen or C 1-4 alkyl;

[0012] D is selected from substituted or unsubstituted aryl or heteroaryl groups; or D is selected from formula (Ia):

[0013] In equation (Ia), "---" indicates the connection site between formula (Ia) and B or A (when B is selected from chemical bonds) in formula (I); "---" indicates the connection site between formula (Ia) and E in formula (I);

[0014] E is selected from formula (Ib) or formula (Ic):

[0015] In equations (Ib) and (Ic), Indicates a carbon-carbon double bond or a carbon-carbon triple bond; Indicates a carbon-carbon single bond or a carbon-carbon double bond; The connection point between equation (Ib) or equation (Ic) and D in equation (I);

[0016] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, S(O)2R g’ ;R g’ Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups;

[0017] Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c Among them, 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 c Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl;

[0018] R 4 Selected from hydrogen, halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8Cycloalkyl, 3- to 9-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 R 4 The 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)2NRd R d NR d S(O)2R g , or NR d S(O)2NR d R d ; or the R 4 The cycloalkyl or heterocyclic group in the R group is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, 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 24 Alkyne, CN, OR f SR f NR c R c C(O)R g S(O)2R g 、or = M;R f The definitions are as described above; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in R is optionally substituted with =M; c The definition is as described above; M is selected from CR h R i , where R h Ri and each are independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0019] 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 ;R c and Rf The definition is as described above; 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;

[0020] R p and R q Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, CN, OR f SR f , or NR c R c ;R c and R f The definition is as described above; or R p and R q 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 p and R q Together with the carbon atoms it is connected to, it forms =O;

[0021] X is selected from N, C, or CR. e ;R e Selected from hydrogen, halogen, or C 1-4 alkyl;

[0022] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c 、or CN;R c and R f The definition is as described above; or two Rs 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0023] 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 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)ORf 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 NR d S(O)2NR d R d =O; or the heteroatom N or S in the heterocyclic group is optionally oxidized; 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;

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

[0025] b is selected from 0, 1, or 2;

[0026] p is selected from 0, 1, 2, or 3;

[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 3-6 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;

[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 equivalent to equation (II):

[0032] A is selected from aryl or heteroaryl;

[0033] Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d’ R d’ NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g p(O)R d R d Among them, each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c ;

[0034] m is selected from 0, 1, 2, 3, or 4;

[0035] R c R d Rf R g The definitions of the remaining groups in formula (II) are as described above.

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

[0037] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0038] R 8 The definitions of m are as described above;

[0039] The definitions of the remaining groups in formula (III) are as described above.

[0040] In another preferred embodiment, equation (I) is equivalent to equation (IV):

[0041] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0042] R 8 The definitions of m are as described above;

[0043] The definitions of the remaining groups in formula (IV) are as described above.

[0044] In another preferred embodiment, equation (I) is equivalent to equation (V):

[0045] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0046] R 8 The definition is as described in claim 2;

[0047] The definitions of the remaining groups in formula (V) are as described in claim 1.

[0048] In another preferred embodiment, equation (I) is equivalent to equation (VI):

[0049] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0050] R 8 The definition is as described in claim 2;

[0051] The definitions of the remaining groups in formula (VI) are as described in claim 1.

[0052] In another preferred embodiment, equation (I) is equation (VIIa), equation (VIIb), or equation (VIIc):

[0053] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0054] R 8 The definition of m is as described in claim 2;

[0055] The definitions of the remaining groups in formulas (VIIa), (VIIb), and (VIIc) are as described in claim 1.

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

[0057] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0058] Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g P(O)R d R d ;

[0059] Each R 3 Each independently selects hydrogen, halogen, and C.1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c ;

[0060] Each R 5 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c Or CN; or an R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0061] 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 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The alkyl, 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 gNR 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 NR d S(O)2NR d R d =O; or the heteroatom N or S in the heterocyclic group is optionally oxidized; 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 ;

[0062] The above 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, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c Each R fEach 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 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl;

[0063] m is selected from 0, 1, 2, 3, or 4;

[0064] p is selected from 0, 1, 2, or 3;

[0065] s is selected from 0, 1, 2, 3, or 4.

[0066] In another preferred embodiment, equation (I) is equivalent to equation (IX):

[0067] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0068] R 8 R 3 R 6 R 7 The definition is as described above.

[0069] In another preferred embodiment, equation (I) is equation (X):

[0070] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0071] R 8 R 3 R 6 R d The definition is as described above.

[0072] In another preferred embodiment, equation (I) is equivalent to equation (XI):

[0073] A, R 8 The definition of m is as described in claim 2;

[0074] D is selected from substituted or unsubstituted aryl or heteroaryl groups;

[0075] The definitions of the remaining groups in formula (XI) are as described above.

[0076] In another preferred embodiment, equation (I) is equation (XIIa) or equation (XIIb):

[0077] A, R 8 The definitions of m are as described above;

[0078] D is selected from substituted or unsubstituted aryl or heteroaryl groups;

[0079] The definitions of the remaining groups in formulas (XIIa) and (XIIb) are as described above.

[0080] In another preferred embodiment, equation (I) is equation (XIIIa) or equation (XIIIb):

[0081] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0082] R 8 The definition is as described above;

[0083] The definitions of the remaining groups in formulas (XIIa) and (XIIb) are as described above.

[0084] In another preferred embodiment, in equation (V):

[0085] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0086] Each R 8 Each is independently selected from halogens, CN, NO2, C(O)R g C(O)OR f S(O)2R g S(O)R g P(O)R d R d ;

[0087] Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, CN, OR f SR f NR c R c ;

[0088] R4 Selected from hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The R 4 The 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 ; or the R 4 The cycloalkyl or heterocyclic group in the cycloalkyl group is optionally substituted with =M;

[0089] The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, 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 2-4 alkenyl, C 2-4 alkynyl group, C3 -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;

[0090] Each of the above M's is independently selected from CR. h R i , where R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl.

[0091] In another preferred embodiment, equation (V) is equation (XIV):

[0092] R 8 R 3 R 4 The definition is as described above.

[0093] On the other hand, a compound with the structure shown in formula (XV), or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate is provided:

[0094] Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl;

[0095] Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g P(O)R d R d ;

[0096] Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c ;

[0097] Each R 5 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c 、or CN; or two R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S;

[0098] R 9 Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The R 9 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 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 NR d S(O)2NR d R d =O; the above-mentioned cycloalkyl and heterocyclic groups are optionally substituted with =O; or the heteroatoms N or S in the above-mentioned heterocyclic groups are optionally oxidized;

[0099] The above R c Each is independently selected from hydrogen and C. 1-4 Alkyl, C1-4 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, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c 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 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl;

[0100] m is selected from 0, 1, 2, 3, or 4;

[0101] p is selected from 0, 1, 2, or 3;

[0102] s is selected from 0, 1, 2, 3, or 4.

[0103] In another preferred embodiment, the compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, is selected from one of the following:

[0104]

[0105] Wherein, each R is selected from: This indicates the site where the substituent R is attached to other parts of the compound;

[0106] This indicates that the configuration of the connected carbon-carbon double bond is uncertain, including both "Z-configuration" and "E-configuration";

[0107] The asterisk (*) indicates a chiral center, which includes both R- and S-configurations.

[0108] 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.

[0109] A third aspect of the invention provides the use of the compound described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof, for the preparation of a pharmaceutical composition for treating diseases, conditions, or symptoms associated with PPARG activity or expression levels.

[0110] In another preferred embodiment, the disease, symptom, or condition is selected from the group consisting of: bladder cancer, urothelial carcinoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colon cancer, thyroid cancer, melanoma, liver cancer, rectal cancer, pharyngeal cancer, breast cancer, prostate cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, endometrial cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, myeloma, and various solid tumors and hematologic malignancies. Detailed Implementation

[0111] Through long-term and in-depth research, the inventors unexpectedly discovered a novel class of PPARG inverse agonists, 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 PPARGs. Based on the above findings, the inventors completed this invention.

[0112] the term

[0113] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0114] 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.

[0115] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] "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.

[0121] "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.

[0122] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0123] 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, C2-10 Ester group, amino group.

[0124] 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.

[0125] 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).

[0126] use:

[0127] 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 PPARG.

[0128] The compound of this invention can be used as a PPARG inverse agonist.

[0129] This invention relates to a single inverse agonist of PPARG, which aims to prevent, alleviate, or cure diseases by regulating PPARG activity. The diseases referred to include, but are not limited to: bladder cancer, urothelial carcinoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colon cancer, thyroid cancer, melanoma, liver cancer, rectal cancer, pharyngeal cancer, breast cancer, prostate cancer, brain tumors, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, endometrial cancer, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, myeloma, and various solid tumors and hematological malignancies.

[0130] 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.

[0131] 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.

[0132] Pharmaceutical Compositions and Administration

[0133] Because the compounds of the present invention have excellent inhibitory activity against PPARG, 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 PPARG activity or expression levels.

[0134] 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.

[0135] "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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0145] 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.

[0146] The main advantages of this invention include:

[0147] 1. A compound as shown in Formula I is provided.

[0148] 2. A novel PPARG inverse agonist is provided, as well as its preparation and application, wherein the inverse agonist can inhibit the activity of PPARG at extremely low concentrations.

[0149] 3. A PPARG inverse agonist that is well absorbed orally is provided.

[0150] 4. A class of pharmaceutical compositions for treating diseases associated with PPARG activity is provided.

[0151] 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.

[0152] 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.

[0153] Example

[0154] abbreviation:

[0155] Boc = tert-Butoxycarbonyl

[0156] CN = cyano

[0157] DCM = dichloromethane

[0158] DIPEA = N,N-diisopropylethylamine

[0159] DMF = N,N-dimethylformamide

[0160] DMSO = dimethyl sulfoxide

[0161] EtOAc or EA = ethyl acetate

[0162] Et = Ethyl

[0163] HATU = N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea)

[0164] K4Fe(CN)6.3H2O = Potassium ferricyanide trihydrate

[0165] Me = methyl

[0166] NaBH3CN = Sodium cyanoborohydride

[0167] Ph = phenyl

[0168] Pd(PPh3)4=Tetraphenylphosphinepalladium

[0169] SOCl2 = thionyl chloride

[0170] TBDPS = tert-butyldiphenylchlorosilane

[0171] TEA = Triethylamine

[0172] TFA = Trifluoroacetic acid

[0173] THF = Tetrahydrofuran

[0174] TIPS = tert-butylisopropyldimethoxysilane

[0175] TMS = Trimethylsilyl

[0176] TBAF = Tetrabutylammonium fluoride

[0177] t-BuOLi = lithium tert-butoxide

[0178] Example 1: Preparation of compounds 1 and 2

[0179] Compound 2 was synthesized using the same method as compound 6, yielding a yellow solid, compound 2 (80 mg, yield 64%). 1 H NMR (500MHz, DMSO-d) δ11.99 (s, 1H), 8.22 (s, 1H), 8.08 (d, J=7.5Hz, 1H), 7.92 (d , J=8.1Hz, 1H), 7.11 (d, J=11.4Hz, 1H), 6.00 (s, 1H), 3.12 (br, 4H), 2.28 (br, 4H). MS m / z 447.9[M+H] + .

[0180] Compound 2 (20 mg, 0.014 mmol), sodium methanesulfonate (6 mg, 0.058 mmol), cuprous iodide (0.85 mg, 0.004 mmol), L-proline (0.5 mg, 0.004 mmol), and potassium phosphate (9 mg, 0.042 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to give a white solid product 1 (7.68 mg, yield 35%). 1H NMR (500MHz, DMSO-d) δ 12.00 (s, 1H), 8.43-8.15 (m, 3H), 7.06 (br, 1H), 6.07 (br, 1H), 3.29 (s, 3H), 3.22-2.99 (m, 4H), 2.35-2.16 (m, 4H). MS m / z 491.8[M+H] + .

[0181] Example 2: Preparation of Compound 3

[0182] The synthesis methods of compounds 3-c and 3-d are referenced in patent WO2023078252.

[0183] Compounds 3-d (20 mg, 0.067 mmol), 3-e (11 mg, 0.135 mmol), palladium dichloride bis(triphenylphosphine) (5 mg, 0.007 mmol), and cuprous iodide (3 mg, 0.013 mmol) were sequentially dissolved in N,N-dimethylformamide (1.5 mL). After adding triethylamine (20 mg, 0.202 mmol), the reaction mixture was bubbled under nitrogen for 1 minute. The mixture was stirred at 80 °C for 1 hour, quenched with water, and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow solid product 3-f (19 mg, 100% yield). MS m / z 252.0 [M+H] + .

[0184] Compounds 3-f (19 mg, 0.076 mmol) and 3-c (23 mg, 0.113 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 3 hours in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a white solid product 3-g (14 mg, yield 45%). MS m / z 436.8 [M+Na] + .

[0185] 3-g (14 mg, 0.034 mmol) of compound was dissolved in 1.5 mL of 2-methyltetrahydrofuran, and lithium tert-butoxide (5 mg, 0.067 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 6:1) to give a yellow solid product 3-h (6 mg, yield 45%). MS m / z 396.8 [M+H] + .

[0186] Compound 3-h (6 mg, 0.015 mmol), sodium methanesulfonate (2.5 mg, 0.023 mmol), cuprous iodide (1 mg, 0.006 mmol), L-proline (1 mg, 0.009 mmol), and potassium phosphate (6 mg, 0.030 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 2:1) to give a white solid product 3 (2.87 mg, yield 43%). 1 H NMR(500MHz, DMSO-d6)δ 12.30 (brs, 1H), 8.37-8.25 (m, 3H), 7.20 (s, 1H), 6.21 (s, 1H), 4.85 (dd, J=8.5 , 5.5Hz, 2H), 4.64 (dd, J=7.0, 5.6Hz, 2H), 4.32-4.24 (m, 1H), 2.54 (s, 3H)ppm. MS m / z 440.9[M+H] + .

[0187] Example 3: Preparation of Compound 4

[0188] Compound 4-a (32 mg, 0.271 mmol) and diisopropylethylamine (70 mg, 0.542 mmol) were dissolved in dichloromethane (2 mL) under ice-water bath conditions, and a dilution of acetyl chloride (26 mg, 0.325 mmol) in dichloromethane (0.5 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was used directly for the next reaction. MS m / z 124.1 [M+H] + .

[0189] The synthesis of compound 4 was performed using the same method as that for compound 3. A white solid product 4 (4.4 mg) was obtained. 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.10 (d, J=9.4Hz, 1H), 6.33 (s , 1H), 4.58 (t, J=8.7Hz, 1H), 4.39-4.28 (m, 2H), 4.04 (dd, J=9.4, 6.3Hz, 1H), 3.88-3.79 (m, 1H), 3.20 (s, 3H), 1.90 (s, 3H)ppm. MS m / z 481.8[M+H] + .

[0190] Example 4: Preparation of Compound 5

[0191] The synthesis method of compound 5-a is referenced in patent WO2023078252.

[0192] Compound 5f-1 (1 g, 3.39 mmol), zinc cyanide (295 mg, 2.79 mmol), and tetrakis(triphenylphosphine)palladium (230 mg, 0.199 mmol) were dissolved in N,N-dimethylformamide (15 mL). The mixture was heated to 100 °C for two hours under a nitrogen atmosphere. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain compound 5f-2 (410 mg, yield 52%).

[0193] Compound 5f-2 (227 mg, 1.15 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide aqueous solution (55 mg, 2.31 mmol, 1 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was evaporated under reduced pressure to obtain compound 5f-3 (218 mg, 100% yield).

[0194] Compound 5f-3 (218 mg, 1.15 mmol) was dissolved in thionyl chloride (2 mL), heated to 80 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was dried twice with ethyl acetate to obtain compound 5f (232 mg, 100% yield).

[0195] The synthesis of compound 5 was performed using the same method as compound 6, yielding a white solid compound 5 (40 mg, 30% yield). 1H NMR(500MHz, DMSO-d)δ 12.08 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 7.12 (d, J=11.5Hz, 1H), 6.10 (s, 1H), 5. 81 (s, 1H), 3.64 (s, 3H), 3.25-3.14 (m, 4H), 3.06-2.95 (m, 2H), 2.48-2.40 (m, 2H). MS m / z 470.8[M+H] + .

[0196] Example 5: Preparation of Compound 6

[0197] Compound 6-a (500 mg, 1.96 mmol) was dissolved in tetrahydrofuran / methanol / water (4 / 2 / 2 mL), and lithium hydroxide (234 mg, 9.79 mmol) was added. 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 crude product was dissolved in ethyl acetate, acidified with dilute hydrochloric acid, and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude white solid 6-b (558 mg, 100% yield).

[0198] Compound 6-b (160 mg, 0.663 mmol), a tetrahydrofuran solution of dimethylamine (2 M, 0.66 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (506 mg, 1.33 mmol) were dissolved in N,N-dimethylformamide (3 mL). Diisopropylethylamine (257 mg, 1.99 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) to give a yellow oily crude product 6-c (295 mg, 100% yield). MS m / z 291.0 [M + Na] + .

[0199] The crude compound 6-c (295 mg) 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-d (120 mg), which was directly used in the next reaction. MS m / z 169.2 [M+H] + .

[0200] Compounds 5-a (184 mg, 0.719 mmol), 6-d (120 mg, 0.719 mmol), and potassium carbonate (447 mg, 3.23 mmol) were sequentially dissolved in dimethyl sulfoxide (4 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give a yellow solid product 6-f (225 mg, yield 77%). MS m / z 405.7 [M+H] + .

[0201] Compound 6-f (225 mg, 0.557 mmol) was dissolved in ethanol / water (4 / 2 mL), and iron powder (155 mg, 2.78 mmol) and ammonium chloride (149 mg, 2.78 mmol) were added. The reaction mixture was stirred at 80 °C for 1.5 hours. After the reaction was complete, the reaction mixture was filtered and washed with methanol. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a brown oily product 6-g (203 mg, yield 97%). MS m / z 375.8 [M+H] + .

[0202] Compounds 6-g (80 mg, 0.214 mmol), 6-h (154 mg, 0.428 mmol), and tetraphenylphosphine palladium (25 mg, 0.021 mmol) were sequentially dissolved in toluene (3 mL). The reaction mixture was purged with nitrogen three times and stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with potassium fluoride solution and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain the intermediate product. The intermediate product was dissolved in 1,4-dioxane (2 mL), and an appropriate amount of dilute hydrochloric acid was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution 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 = 25:1) to give a yellow oily product 6-i (35 mg, yield 49%). MS m / z 338.0 [M+H] + .

[0203] Compounds 6-i (35 mg, 0.104 mmol) and 5f (31 mg, 0.156 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 1 hour in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a yellow oily product 6-k (30 mg, yield 58%). MS m / z 523.8 [M+Na] + .

[0204] Compound 6-k (20 mg, 0.034 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (6 mg, 0.080 mmol) was added. The reaction mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give a yellow solid product 6 (3.40 mg, yield 18%). 1 H NMR(500MHz, CD3OD)δ 8.93 (s, 1H), 8.19 (s, 1H), 7.14 (d, J = 11.4Hz, 1H), 6.35 (s, 1H), 5.99 (s, 1H), 3.34-3.31 (m, 2H), 3 .27 (t, J=5.5Hz, 2H), 3.11 (s, 3H), 2.98 (s, 3H), 2.64 (t, J=5.5Hz, 2H), 2.48 (t, J=5.4Hz, 2H) ppm. MS m / z 483.9[M+H] + .

[0205] Example 6: Preparation of Compound 7

[0206] The synthesis method of compound 7-c is the same as that of compound 3-h.

[0207] Compound 7-c (64 mg, 0.155 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 0.78 mL) was added. 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:ethyl acetate = 4:1) to give a pale yellow solid product 7-d (51 mg, 97% yield). MS m / z 340.8 [M+H] + .

[0208] Compounds 7-d (35 mg, 0.103 mmol), 7-e (51 mg, 0.154 mmol), cuprous iodide (4 mg, 0.021 mmol), 1,10-phenanthroline (7 mg, 0.041 mmol), and sodium bicarbonate (17 mg, 0.205 mmol) were dissolved in dichloromethane (3 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and stirred at room temperature for 30 minutes. The resulting mixture was extracted with dichloromethane (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: ethyl acetate = 8:1) to give a white solid product 7 (20 mg, yield 48%). 1 H NMR (500MHz, CD3OD) δ 8.06 (d, J=2.0Hz, 1H), 7.94 (dd, J=8.4, 2.0Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.21 (dd, J=9.8, 1.2Hz, 1H), 6.31 (s, 1H) ppm. MS m / z 408.8[M+H] + .

[0209] Example 7: Preparation of compounds 8 and 9

[0210] Compound 7 (10 mg, 0.024 mmol), sodium methanesulfonate (4 mg, 0.037 mmol), cuprous iodide (1 mg, 0.005 mmol), L-proline (1 mg, 0.010 mmol), and potassium phosphate (13 mg, 0.061 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and adjusted to acid with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to give a white solid product 8 (0.97 mg, yield 9%). MS m / z 452.7 [M+H] + .

[0211] Yellow solid product 9 (6.6 mg, yield 60%). 1H NMR (500MHz, CD3OD) δ8.36 (d, J=8.3Hz, 1H), 8.21 (dd, J=8.3, 1.6Hz, 1H), 8.14 (d, JJ=5.3Hz, 1H ), 7.20-7.14(m, 1H), 6.36(d, J=4.4Hz, 1H), 3.29-3.28(m, 1H), 3.21(s, 3H), 2.65(s, 3H)ppm, MS m / z 532.7[M+H] + .

[0212] Example 8: Preparation of compounds 10 and 11

[0213] The synthesis method of compound 11-e is the same as that of compound 3.

[0214] Compound 11-e (10 mg, 0.018 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1, 2% ammonia) to give a yellow solid product 11 (5 mg, yield 61%). MS m / z 439.9 [M+H] + .

[0215] Compound 11 (2.5 mg, 0.006 mmol), paraformaldehyde (2 mg, 0.057 mmol), sodium cyanoborohydride (1 mg, 0.011 mmol), and zinc chloride (2 mg, 0.011 mmol) were dissolved in methanol (1.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (dichloromethane:methanol = 8:1, 2% ammonia) to give a white solid product 10 (1.06 mg, yield 41%). MS m / z 453.8 [M+H] + .

[0216] Example 9: Preparation of Compound 12

[0217] Compound 12 was synthesized using the same method as compound 3, yielding a white solid compound 12 (9.55 mg, 35% yield). 1H NMR(500MHz, DMSO-d)δ 8.36 (d, J=8.3Hz, 1H), 8.20 (dd, J=8.3, 1.7Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.09 (d, J=9.8Hz, 1H), 6.32 (brs, 1H), 3.95 ( ddd, J=11.5, 5.7, 3.6Hz, 2H), 3.65-3.49 (m, 2H), 3.20 (s, 3H), 3.09-2.96 (m, 1H), 2.01-1.87 (m, 2H), 1.82-1.72 (m, 2H). MS m / z 468.8[M+H] + .

[0218] Example 10: Preparation of Compound 13

[0219] The synthesis of compound 13 was performed using the same method as that used for compound 6. A yellow solid product 13 (5.26 mg, 17% yield) was obtained. 1 H NMR (500MHz, CD3OD) δ8.93 (s, 1H), 8.19 (s, 1H), 7.14 (d, J=11.4Hz, 1H), 6.35 (s, 1H), 5.98 (s, 1H), 3.69-3.6 5(m, 4H), 3.65-3.60(m, 4H), 3.34-3.31(m, 2H), 3.29-3.25(m, 2H), 2.66-2.61(m, 2H), 2.50-2.45(m, 2H)ppm. MS m / z 525.9[M+H] + .

[0220] Example 11: Preparation of Compound 14

[0221] The synthesis of compound 14 was performed following the method described for compound 6. A yellow solid, product 14 (2.30 mg, 11% yield), was obtained. MS m / z 509.9 [M+H] + .

[0222] Example 12: Preparation of Compound 15

[0223] Compound 15 (4 mg, 0.008 mmol), sodium methanesulfonate (1.5 mg, 0.013 mmol), cuprous iodide (1 mg, 0.005 mmol), L-proline (1 mg, 0.010 mmol), and potassium phosphate (4 mg, 0.020 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and adjusted to acid with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give a yellow solid product 15 (1.6 mg, yield 37%). MS m / z 527.9 [M+H] + .

[0224] Example 13: Preparation of Compound 16

[0225] The synthesis of compound 16 was performed using the same method as compound 6. The final product was a yellow solid, product 16 (1.3 mg). MS m / z 508.9 [M+H] + .

[0226] Example 14: Preparation of Compound 17

[0227] Compound 16 (10 mg, 0.020 mmol), sodium methanesulfonate (3 mg, 0.029 mmol), cuprous iodide (1 mg, 0.005 mmol), L-proline (1 mg, 0.010 mmol), and potassium phosphate (10 mg, 0.049 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to give a yellow solid product 17 (6.08 mg, yield 56%). 1H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.18 (dd, J=8.3, 1.6Hz, 1H), 8.11 (d, J =1.4Hz, 1H), 7.08 (d, J = 11.7Hz, 1H), 6.28 (s, 1H), 5.99 (s, 1H), 3.54 (t, J = 6.7Hz, 2H ), 3.46 (t, J=6.9Hz, 2H), 3.35-3.32 (m, 2H), 3.27 (t, J=5.4Hz, 2H), 3.19 (s, 3H), 2.8 7 (t, J=5.5Hz, 2H), 2.49 (t, J=5.5Hz, 2H), 2.02-1.96 (m, 2H), 1.95-1.89 (m, 2H)ppm. MS m / z 553.0[M+H] + .

[0228] Example 15: Preparation of compounds 18 and 19

[0229] Compound 18-a (500 mg, 1.47 mmol) was dissolved in methanol / water (5 / 2 mL), and lithium hydroxide (105 mg, 4.40 mmol) was added. The reaction mixture was stirred at 60 °C for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate, acidified with dilute hydrochloric acid, and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 3:1) to give a white solid product 18-b (470 mg, yield 98%).

[0230] Compound 18-b (470 mg, 1.44 mmol) was dissolved in thionyl chloride (4 mL), and the reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate and concentrated under reduced pressure (twice) to obtain a yellow oily crude product 18-c (500 mg), which was directly used in the next step of the reaction.

[0231] Compounds 18-e (200 mg, 1.17 mmol) (synthetic method according to patent WO2023078252) and 18-c (500 mg, 1.46 mmol) were sequentially dissolved in ethyl acetate (4 mL). The reaction mixture was stirred at 80 °C for 1 hour in a sealed tube. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give a white solid product 18-f (520 mg, yield 93%). MS m / z 503.5 [M+Na] + .

[0232] Compound 18-f (520 mg, 1.08 mmol), dimethylphosphine oxide (93 mg, 1.19 mmol), tris(dibenzylacetone)dipalladium (99 mg, 0.108 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (125 mg, 0.216 mmol), and potassium phosphate (345 mg, 1.62 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was purged with nitrogen three times and stirred at 110 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a dark oily crude product 18-g (300 mg, yield 64%). MS m / z 453.7 [M+Na] + .

[0233] Compound 18-g (70 mg, 0.163 mmol) was dissolved in 2-methyltetrahydrofuran (3 mL), and lithium tert-butoxide (26 mg, 0.325 mmol) was added. The reaction mixture was stirred at 125 °C for 6 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid product 19 (42 mg, yield 63%). 1 H NMR (500MHz, CD3OD) δ7.95-7.80 (m, 3H), 7.06 (d, J=9.4Hz, 1H), 7.01-6.92 (m, 1H), 6.25 (s, 1H), 1.76 (s, 3H), 1.73 (s, 3H)ppm. MS m / z 413.7[M+H] + .

[0234] The synthesis method of compound 18 is based on patent WO2023078252. A white solid product 18 (2.8 mg, yield 17%) was obtained. 1 H NMR (500MHz, CD3OD) δ 8.18-8.01 (m, 3H), 7.07 (d, J = 9.5Hz, 1H), 7.02-6.93 (m, 1H), 6.28 (s, 1H), 1.80 (s, 3H), 1.78 (s, 3H) ppm. MS m / z 358.8[M+H] + .

[0235] Example 16: Preparation of Compound 20

[0236] Compounds 20-a (111 mg, 1.01 mmol), 3-d (150 mg, 0.505 mmol), palladium dichloride bis(triphenylphosphine) (35 mg, 0.050 mmol), and cuprous iodide (19 mg, 0.101 mmol) were sequentially dissolved in N,N-dimethylformamide (4 mL). Triethylamine (153 mg, 1.51 mmol) was added, and the reaction mixture was bubbled under nitrogen for 1 minute. After stirring at 80 °C for 1 hour, the reaction was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid product 20-b (132 mg, 94% yield). MS m / z 280.1 [M+H] + .

[0237] Compounds 20-b (63 mg, 0.226 mmol) and 5f (91 mg, 0.451 mmol) were dissolved sequentially in ethyl acetate (3 mL). The reaction mixture was stirred at 80 °C for 2 hours in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily product 20-c (36 mg, yield 36%). MS m / z 465.8 [M+Na] + .

[0238] Compound 20-c (36 mg, 0.081 mmol) was dissolved in 1.5 mL of 2-methyltetrahydrofuran, and lithium tert-butoxide (19 mg, 0.243 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 20 (2.2 mg, yield 12%). MS m / z 425.8 [M+H] + .

[0239] Example 17: Preparation of Compound 21

[0240] Compound 20 (8 mg, 0.019 mmol), sodium methanesulfonate (3 mg, 0.023 mmol), cuprous iodide (1 mg, 0.006 mmol), L-proline (1 mg, 0.009 mmol), and potassium phosphate (8 mg, 0.038 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 21 (6 mg, yield 68%). 1 H NMR (500MHz, CD3OD) δ9.38 (s, 1H), 8.26 (s, 1H), 7.14 (d, J=9.2Hz, 1H), 6.43 (s, 1H), 3.98-3.92 (m, 2H), 3.64-3.55(m, 2H), 3.33(s, 3H), 3.07-2.99(m, 1H), 2.00-1.94(m, 2H), 1.81-1.72(m, 2H)ppm. MS m / z 469.9[M+H] + .

[0241] Example 18: Preparation of Compound 22

[0242] Compounds 22-a (47 mg, 0.19 mmol, method as per 20-b) and 5f (23 mg, 0.113 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 3 hours in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a white solid product 22-b (11 mg, yield 14%). MS m / z 438.1 [M+Na] + .

[0243] Compound 22-b (11 mg, 0.027 mmol) was dissolved in 1.5 mL of 2-methyltetrahydrofuran, and lithium tert-butoxide (4 mg, 0.054 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 6:1) to give a yellow solid product 22 (2.9 mg, yield 29%). 1H NMR (500MHz, DMSO-d) δ12.38 (s, 1H), 9.10 (s, 1H), 8.48 (s, 1H), 7.21 (s, 1H), 6.22 (s, 1 H), 5.76-5.73 (m, 1H), 5.65-5.62 (m, 1H), 5.37 (t, J=5.9Hz, 1H), 4.07 (d, J=5.6Hz, 2H). MS m / z 397.8[M+H] + .

[0244] Example 19: Preparation of Compound 23

[0245] The synthesis of compound 23 was performed using the same method as that for compound 20. The final product was a white solid, product 23 (21.70 mg). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.09 (d , J=9.4Hz, 1H), 6.32 (s, 1H), 3.20 (s, 3H), 3.02-2.93 (m, 1H), 2.21-2.10 (m, 2H), 2.06-1.85 (m, 6H)ppm. MS m / z 502.9[M+H] + .

[0246] Example 20: Preparation of compounds 24 and 30

[0247] Compounds 23-b (45 mg, 0.144 mmol) and 5f (58 mg, 0.287 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 1 hour in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to give a yellow solid product 24-a (34 mg, yield 50%). MS m / z 477.8 [M+H] + .

[0248] Compound 24-a (34 mg, 0.071 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (17 mg, 0.213 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 24 (17 mg, yield 52%).1 H NMR (500MHz, DMSO-d6) δ12.38 (br, 1H), 9.05 (s, 1H), 8.43 (s, 1H), 7.23 (d, J=9.9Hz, 1H), 6. 32(s, 1H), 3.06-2.98(m, 1H), 2.14-2.04(m, 2H), 2.01-1.92(m, 4H), 1.84-1.71(m, 2H)ppm. MS m / z 459.8[M+H] + .

[0249] Compound 24-a (22 mg, 0.046 mmol) was dissolved in 1.5 mL of 2-methyltetrahydrofuran, and lithium tert-butoxide (11 mg, 0.138 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete, methanol was added to the reaction mixture, and then the acid was adjusted with dilute hydrochloric acid. After stirring at room temperature for 5 minutes, the mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid product 30 (11 mg, yield 52%). 1 H NMR (500MHz, DMSO-d6) δ12.33 (s, 1H), 9.02 (s, 1H), 8.29 (s, 1H), 7.31-7.10 (m, 1H), 6.32 -6.03 (m, 1H), 3.93 (s, 3H), 3.10-2.95 (m, 1H), 2.16-1.90 (m, 6H), 1.82-1.71 (m, 2H)ppm. MS m / z 492.8[M+H] + .

[0250] Example 21: Preparation of Compound 25

[0251] The synthesis of compound 25 was performed using the same method as that for compound 20. The final product was a white solid, product 25 (15.70 mg). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.06 (d , J=9.6Hz, 1H), 6.31 (s, 1H), 3.19 (s, 3H), 1.62-1.56 (m, 1H), 1.00-0.95 (m, 2H), 0.85-0.80 (m, 2H)ppm. MS m / z 424.9[M+H] + .

[0252] Example 22: Preparation of Compound 26

[0253] The synthesis of compound 26 was performed using the same method as that for compound 20. The final product was a white solid, product 26 (4.4 mg). 1 H NMR (500MHz, DMSO-d6) δ12.64 (br, 1H), 8.37-8.22 (m, 3H), 7.40-7.24 (m, 1H), 6.23 (s, 1H), 3.69 (t, J=6.6Hz, 2H), 3.39 (t, J=6.8Hz, 2H), 3.36 (s, 3H), 1.96-1.84 (m, 4H)ppm. MS m / z 481.8[M+H] + .

[0254] Example 23: Preparation of Compound 27

[0255] Compounds 3-d (100 mg, 0.33 mmol), 27-a (84 mg, 0.68 mmol), palladium dichloride bis(triphenylphosphine) (23 mg, 0.033 mmol), and cuprous iodide (12 mg, 0.066 mmol) were sequentially dissolved in N,N-dimethylformamide (2 mL). After adding triethylamine (100 mg, 0.99 mmol), the reaction mixture was bubbled under nitrogen for 1 minute. The mixture was stirred at 80 °C for 1 hour, quenched with water, and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give a yellow solid product 27-b (102 mg, 100% yield). MS m / z 294.1 [M+H] + .

[0256] Compounds 27-b (50 mg, 0.17 mmol) and 5f (51 mg, 0.25 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 3 hours in a sealed tube. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid product 27-c (9 mg, yield 12%). MS m / z 480.1 [M+Na] + .

[0257] Compound 27-c (9 mg, 0.02 mmol) was dissolved in 1.5 mL of 2-methyltetrahydrofuran, and lithium tert-butoxide (3 mg, 0.04 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate = 6:1) to give a yellow solid product 27 (3 mg, yield 34%). 1 H NMR (500MHz, DMSO-d) δ12.34 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 7.20 (s, 1H), 6.20 (s, 1H), 3.92-3.83 ( m, 2H), 3.32-3.29 (m, 2H), 2.55-2.52 (m, 2H), 1.85-1.77 (m, 1H), 1.75-1.68 (m, 2H), 1.42-1.35 (m, 2H). MS m / z 439.8[M+H] + .

[0258] Example 24: Preparation of Compound 28

[0259] The synthesis of compound 28 was performed using the same method as that for compound 20. The final product was a yellow solid, product 28 (13.8 mg). 1 H NMR (500MHz, DMSO-d6) δ 12.37 (s, 1H), 8.47-8.16 (m, 3H), 7.63-7.57 (m, 2H), 7.51-7.46 (m, 3H), 7.26 (s, 1H), 6.24 (s, 1H), 3.39 (s, 3H) ppm. MS m / z 460.9[M+H] + .

[0260] Example 25: Preparation of Compound 29

[0261] Compound SM-0 (200 mg, 2.86 mmol), morpholine (373 mg, 4.28 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.63 g, 4.28 mmol) were dissolved in N,N-dimethylformamide (5 mL). Diisopropylethylamine (738 mg, 5.71 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 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 9:1) to give a yellow oily crude product 29-a (410 mg, 100% yield). MS m / z 140.1 [M+H] + .

[0262] The synthesis of compound 29 was performed using the same method as that for compound 20. The final product was a yellow solid, product 29 (5.3 mg). 1 H NMR (500MHz, CD3OD) δ 8.92 (s, 1H), 8.18 (s, 1H), 7.22 (d, J=9.9Hz, 1H), 6.43 (s, 1H), 3.94-3.89 (m, 2H), 3.80-3.76 (m, 2H), 3.75-3.65 (m, 4H)ppm. MS m / z 454.8[M+H] + .

[0263] Example 26: Preparation of Compound 31

[0264] The synthesis of compound 31 was performed using the same method as that used for compound 20. The final product was a white solid, product 31 (4.0 mg). 1 H NMR (500MHz, CD3OD) δ8.36 (d, J=8.3Hz, 1H), 8.20 (dd, J=8.3, 1.6Hz, 1H), 8.14 (d, J=1.4Hz, 1H), 7.16 (d , J=9.5Hz, 1H), 6.36 (s, 1H), 3.94-3.89 (m, 2H), 3.79-3.76 (m, 2H), 3.72-3.67 (m, 4H), 3.20 (s, 3H)ppm. MS m / z 497.8[M+H] + .

[0265] Example 27: Preparation of Compound 32

[0266] The synthesis of compound 32 was performed following the method described for compound 20. The final product was a yellow solid, 32 (2.36 mg). MS m / z 426.0 [M+H] + .

[0267] Example 28: Preparation of Compound 33

[0268] The synthesis of compound 33 was performed following the method described for compound 20. The final product was a pale yellow solid, 33 (1.24 mg). MS m / z 468.0 [M+H] + .

[0269] Example 29: Preparation of compounds 34 and 35

[0270] The synthesis of compounds 34 and 35 was performed using the same method as that used for compound 20.

[0271] Compound 34 (26 mg, yield 49.17%). 1 H NMR (500MHz, CD3OD) δ 8.94 (s, 1H), 8.20 (s, 1H), 7.13 (d, J=11.5Hz, 1H), 6.34 (br., 1H), 3.22 (t, J=5.3Hz, 4H), 2.40-2.31 (m, 4H). MS m / z 449.0[M+H] + .

[0272] Compound 35 (7.4 mg, yield 42%) 1 H NMR (500MHz, DMSO-d) δ12.09 (s, 1H), 9.30 (s, 1H), 8.46 (s, 1H), 7.60 (s, 1H), 6.99 (s, 1H), 3.38 (s, 3H), 3.26-3.08 (m, 4H), 2.35-2.23 (m, 4H). . MS m / z 493.0[M+H] + .

[0273] Example 30: Preparation of compounds 36 and 37

[0274] The synthesis of compounds 36 and 37 followed the same method as that used for compound 20, and the synthetic route is shown above.

[0275] Compound 36 (12 mg, yield 41%). MS m / z 497.1 [M+H] + .

[0276] Compound 37 (1.1 mg, 10% yield). MS m / z 541.1 [M+H]+ .

[0277] Example 31: Preparation of compound 38

[0278] The synthesis of compound 38 was performed using the same method as that used for compound 20. The final product was a white solid, 38 (3.50 mg). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.2, 1.5Hz, 1H), 8.12 (d, J=1.2Hz, 1H), 7.1 1(d, J=9.6Hz, 1H), 6.33(s, 1H), 3.78-3.72(m, 4H), 3.67(s, 2H), 3.20(s, 3H), 2.74-2.67(m, 4H)ppm. MS m / z 484.0[M+H] + .

[0279] Example 32: Preparation of compound 39

[0280] The synthesis of compound 39 was performed using the same method as that used for compound 20. The final product was a white solid, 39 (14.40 mg). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.7Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.07 (d, J=9.3Hz , 1H), 6.31(s, 1H), 3.41-3.33(m, 1H), 3.20(s, 3H), 2.45-2.37(m, 2H), 2.31-2.22(m, 2H), 2.09-1.96(m, 2H)ppm. MS m / z 439.0[M+H] + .

[0281] Example 33: Preparation of Compound 40

[0282] The synthesis of compound 40 was performed using the same method as that used for compound 20. The final product was a white solid, product 40 (18.0 mg). 1H NMR (500MHz, CD3OD) δ8.35 (d, J=8.2Hz, 1H), 8.19 (d, J=8.3Hz, 1H), 8.12 (s, 1H), 7.07 (d, J=9.5Hz, 1H), 6.31 (s, 1H ), 3.20 (s, 3H), 2.78-2.71 (m, 1H), 1.95-1.87 (m, 2H), 1.86-1.76 (m, 2H), 1.65-1.55 (m, 3H), 1.48-1.39 (m, 3H)ppm. MSm / z 467.0[M+H] + .

[0283] Example 34: Preparation of Compound 41

[0284] The synthesis of compound 41-e was performed following the method described for compound 20. A yellow solid intermediate (51 mg) was finally obtained. MS m / z 541.0 [M+H] + .

[0285] Compound 41-e (20 mg, 0.037 mmol), 3-iodopyridine (15 mg, 0.074 mmol), palladium dichloride (3 mg, 0.004 mmol), cuprous iodide (2 mg, 0.008 mmol), and cesium fluoride (34 mg, 0.222 mmol) were sequentially dissolved in N,N-dimethylformamide (2.5 mL). The reaction mixture was bubbled under nitrogen for 1 minute and then stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 41 (4.68 mg, yield 27%). 1 H NMR (500MHz, DMSO-d6) δ12.44(brs, 1H), 8.81(s, 1H), 8.65(d, J=4.3Hz, 1H), 8.39-8.25(m , 3H), 8.05 (d, J=7.9Hz, 1H), 7.56-7.46 (m, 1H), 7.30 (s, 1H), 6.27 (s, 1H), 3.37 (s, 3H)ppm. MS m / z 461.9[M+H] + .

[0286] Example 35: Preparation of Compound 42

[0287] Compound 41-e (15 mg, 0.028 mmol), 2-chloropyrimidine (6 mg, 0.055 mmol), palladium dichloride bis(triphenylphosphine) (2 mg, 0.003 mmol), and cesium fluoride (25 mg, 0.166 mmol) were sequentially dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was bubbled under nitrogen for 1 minute and then stirred at 100 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 42 (5.90 mg, yield 46%). 1 H NMR (500MHz, DMSO-d6) δ12.47 (brs, 1H), 8.90 (d, J=4.9Hz, 2H), 8.43-8.20 (m, 3H), 7.59 (t, J=4.9Hz, 1H), 7.28 (s, 1H), 6.28 (s, 1H), 3.35 (s, 3H)ppm. MS m / z 462.9[M+H] + .

[0288] Example 36: Preparation of Compound 43

[0289] Compound 41-e (16 mg, 0.029 mmol), 2-chloroquinazoline (10 mg, 0.059 mmol), palladium dichloride bis(triphenylphosphine) (2 mg, 0.003 mmol), and cesium fluoride (27 mg, 0.178 mmol) were sequentially dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was bubbled under nitrogen for 1 minute and then stirred at 100 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 18:1) to give a yellow solid product 43 (5.50 mg, yield 36%). 1 H NMR (500MHz, DMSO-d6) δ12.46 (brs, 1H), 9.70 (s, 1H), 8.39-8.28 (m, 3H), 8.24 (d, J=8.0H z, 1H), 8.14-8.07 (m, 2H), 7.88-7.83 (m, 1H), 7.31 (s, 1H), 6.32 (s, 1H), 3.38 (s, 3H)ppm. MS m / z 513.0[M+H] + .

[0290] Example 37: Preparation of Compound 44

[0291] Compound 44-a (220 mg, 1.51 mmol) was dissolved in dichloromethane (3 mL). Triethylamine (305 mg, 3.02 mmol) and acetyl chloride (118 mg, 1.51 mmol) were added under nitrogen atmosphere and ice bath. The reaction mixture was heated to room temperature and reacted for one hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain compound 44-b (180 mg, yield 79%).

[0292] Compound 44-b (84 mg, 0.56 mmol), compound 3-d (150 mg, 0.505 mmol), palladium dichloride (35 mg, 0.05 mmol), and cuprous iodide (10 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (153 mg, 1.51 mmol). The mixture was reacted at 80 °C for 2 hours under a nitrogen atmosphere. The reaction solution was then diluted with water and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain compound 44-c (56 mg, yield 35%).

[0293] Compound 44 was synthesized using the same method as compound 20. The resulting yellow compound 44 (6.15 mg, 28% yield) was obtained. 1 H NMR (500MHz, DMSO-d) δ12.27 (s, 1H), 8.44-8.18 (m, 3H), 7.16 (s, 1H), 6.19 (s, 1H), 3.82-3.61 (m, 2H), 3.34(s, 3H), 3.30-3.23(m, 2H), 3.15-2.95(m, 1H), 2.02(s, 3H), 1.93-1.78(m, 2H), 1.70-1.44(m, 2H). MS m / z 510.1[M+H] + .

[0294] Example 38: Preparation of Compound 45

[0295] Compound 45 was synthesized using the same method as compound 20, yielding a white solid compound 45 (13.9 mg, 43% yield). 1H NMR(500MHz, DMSO-d)δ 11.98 (br., 1H), 8.39-8.13 (m, 3H), 7.05 (br., 1H), 6.05 (br., 1H), 5.10 (d, J=8.7Hz, 1H), 3.87-3.75 (m, 2H), 3.54 (br, 1H), 3. 42-3.34 (m, 2H), 3.29 (s, 3H), 3.21-3.00 (m, 4H), 2.43-2.31 (m, 2H), 2.30-2.16 (m, 2H), 1.56-1.43 (m, 2H), 1.39-1.27 (m, 2H). MS m / z 540.1[M+H] + .

[0296] Example 39: Preparation of Compound 46

[0297] The synthesis of compound 46-e was performed following the synthesis of compound 3. The final product was a yellow solid, 46-e (31 mg). MS m / z 567.8 [M+H] + Compound 46-e (31 mg, 0.055 mmol) was dissolved in dichloromethane (3 mL), and difluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain crude product 46-f, which was directly used in the next reaction. MS m / z 467.8 [M+H] + .

[0298] Compound 46-f (8 mg, 0.017 mmol), paraformaldehyde (3 mg, 0.086 mmol), sodium cyanoborohydride (3 mg, 0.051 mmol), and zinc chloride (5 mg, 0.034 mmol) were dissolved in methanol (1.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 5:1, 2% ammonia) to give a yellow solid product 46 (6.3 mg, yield 76%). 1 H NMR(500MHz, CD3OD)δ 8.33 (d, J=8.3Hz, 1H), 8.14 (dd, J=8.3, 1.7Hz, 1H), 8.06 (d, J=1.5Hz, 1H), 7.10 (d, J=8.9Hz, 1H), 6.35 (s, 1H), 3.23 (s , 3H), 3.01-2.95(m, 2H), 2.94-2.88(m, 1H), 2.71-2.57(m, 2H), 2.49(s, 3H), 2.12-2.02(m, 2H), 1.94-1.82(m, 2H)ppm. MS m / z 481.9[M+H]+ .

[0299] Example 40: Preparation of Compound 47

[0300] The synthesis of compound 47 was performed using the same method as that used for compound 3. The final product was a pale yellow solid, 47 (15 mg). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.5Hz, 1H), 8.11 (d, J=1.3Hz, 1H), 7.09 (d, J=9.6Hz, 1H), 6.33 (s, 1 H), 3.54-3.46(m, 2H), 3.24-3.21(m, 2H), 3.20(s, 3H), 3.05-2.97(m, 1H), 2.86(s, 3H), 2.10-2.02(m, 2H), 1.91-1.82(m, 2H)ppm. MS m / z 545.8[M+H] + .

[0301] Example 41: Preparation of Compound 48

[0302] The synthesis of compound 48 was performed using the same method as that used for compound 3.

[0303] Compound 48 (1.24 mg, yield 11%). 1 H NMR (500MHz, MeOH-d4)δ 8.35 (d, J=8.3Hz, 1H), 8.19 (d, J=8.3Hz, 1H), 8.11 (s, 1H), 7.10-7.01 (m, 1H), 6.25 (br, 1H), 5.98 (s, 1H), 3.70 -3.57 (m, 7H), 3.35-3.30 (m, 4H), 3.29-3.24 (m, 2H), 3.21-3.14 (m, 2H), 2.68-2.59 (m, 2H), 2.54-2.45 (m, 2H). MS m / z 568.9[M+H] + .

[0304] Example 42: Preparation of compound 49

[0305] N-fluorobis(benzenesulfonamide) (922 mg, 2.93 mmol) was dissolved in tetrahydrofuran (8 mL). Under nitrogen protection at -78 °C, diisopropylaminolithium (0.9 mL, 2.0 M) was added dropwise. After stirring for one hour under this atmosphere, compound 36-d (435 mg, 1.46 mmol) was added. The reaction mixture was heated to room temperature and reacted for 2 hours. The reaction mixture was then extracted with saturated ammonium chloride aqueous solution and ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain compound 49-a (360 mg, yield 78%).

[0306] Compound 49 was synthesized using the same method as compound 36. The result was a pale yellow compound 49 (19.88 mg, 52% yield). 1 H NMR (500MHz, MeOH-d4)δ 8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.11 (d, J=1.5Hz, 1H), 7.07 (d, J=11.3Hz, 1H), 6.27 (s, 1H), 4.01-3.90 (m , 2H), 3.49(t, J=11.9Hz, 2H), 3.24-3.12(m, 8H), 2.48-2.42(m, 2H), 2.42-2.34(m, 2H), 1.90-1.78(m, 2H), 1.57-1.48(m, 2H). MS m / z 557.9[M+H] + .

[0307] Example 43: Preparation of compounds 50 and 51

[0308] Compound 51-a (330 mg, 2.50 mmol), N-bromosuccinimide (2.22 g, 12.48 mmol), and triphenylphosphine (3.27 g, 12.48 mmol) were sequentially dissolved in dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give a colorless oily product 51-b (101 mg, yield 21%).

[0309] Compounds 51-b (101 mg, 0.518 mmol) and 51-c (113 mg, 0.673 mmol) were dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (143 mg, 1.04 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow oily product 51-d (86 mg, yield 59%). MS m / z 281.9 [M+H] + .

[0310] Compound 51-d (86 mg, 0.306 mmol) and ammonium molybdate tetrahydrate (38 mg, 0.031 mmol) were dissolved in ethanol (3 mL). An aqueous solution of hydrogen peroxide (30%, 173 mg, 1.53 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with ethyl acetate and quenched with saturated sodium thiosulfate solution. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 5:1) to give a white solid product 51-e (72 mg, yield 68%). MS m / z 345.9 [M+H] + .

[0311] Compounds 51-e (52 mg, 0.150 mmol) and 51-f (36 mg, 0.181 mmol) were dissolved in tetrahydrofuran (2.5 mL) under ice-water bath conditions. A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (1 M, 0.3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give a white solid product 51-g (26 mg, yield 52%). MS m / z 351.9 [M + Na] + .

[0312] Compound 51-g (26 mg, 0.079 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a yellow oily crude product 51-h, which was directly used in the next reaction step.

[0313] Crude compounds 51-h (theoretical yield: 18 mg, 0.078 mmol), 36-h (26 mg, 0.102 mmol), and potassium carbonate (33 mg, 0.235 mmol) were sequentially dissolved in dimethyl sulfoxide (2 mL), 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 silica gel column chromatography (dichloromethane:ethyl acetate = 10:1) to give a yellow oily product 51-j (37 mg, 100% yield).

[0314] Compound 51-j (37 mg, 0.080 mmol) was dissolved in ethanol / water (3 / 0.5 mL), and iron powder (22 mg, 0.397 mmol) and ammonium chloride (21 mg, 0.397 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered and washed with methanol. The resulting filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow solid product 51-k (33 mg, yield 95%). MS m / z 434.8 [M+H] + .

[0315] Compounds 51-k (33 mg, 0.076 mmol), 51-l (55 mg, 0.152 mmol), and tetraphenylphosphine palladium (9 mg, 0.008 mmol) were sequentially dissolved in toluene (2 mL). The reaction mixture was purged with nitrogen three times and stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with potassium fluoride solution 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 to obtain the crude intermediate product. The crude intermediate product was dissolved in 1,4-dioxane (2 mL), and an appropriate amount of dilute hydrochloric acid was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow solid product 51-m (26 mg, yield 86%). MS m / z 398.9 [M+H] + .

[0316] Compounds 51-m (26 mg, 0.065 mmol) and 3-c (16 mg, 0.078 mmol) were dissolved sequentially in ethyl acetate (2 mL). The reaction mixture was stirred at 80 °C for 1 hour in a sealed tube. After the reaction was complete, the mixture 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 oily product 51-o (29 mg, yield 79%). MS m / z 561.8 [M+H] + .

[0317] Compound 51-o (29 mg, 0.052 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (16 mg, 0.206 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a yellow solid product 51-p (15 mg, yield 53%). MS m / z 543.9 [M+H] + .

[0318] Compound 51-p (15 mg, 0.028 mmol), sodium methanesulfonate (4 mg, 0.041 mmol), cuprous iodide (1 mg, 0.005 mmol), L-proline (1 mg, 0.010 mmol), and potassium phosphate (15 mg, 0.069 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give yellow solid product 51 (6.0 mg, yield 37%) and yellow solid product 50 (2.68 mg, yield 16%).

[0319] 51: 1H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.11 (d, J=1.3Hz, 1H), 7.07 (d, J=11.4Hz, 1H), 6.28 (s, 1H), 5.17 (d, J=9.0Hz, 1 H), 3.26-3.20(m, 6H), 3.19(s, 3H), 3.08-2.97(m, 2H), 2.76-2.67(m, 1H), 2. 50-2.44(m, 2H), 2.36-2.30(m, 2H), 2.07-1.89(m, 4H)ppm, MSm / z587.9[M+H] + .

[0320] 50: 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.2, 1.6Hz, 1H), 8.1 1 (d, J=1.3Hz, 1H), 7.07 (d, J=10.6Hz, 1H), 6.27 (s, 1H), 5.30 (t, J=7.5Hz, 1H) , 3.26-3.19(m, 6H), 3.18(s, 3H), 3.12-3.03(m, 1H), 2.79-2.72(m, 1H), 2.53 -2.43(m, 3H), 2.41-2.34(m, 3H), 2.34-2.28(m, 2H), 1.93-1.84(m, 1H)ppm, MS m / z 587.8 [M+H] + .

[0321] Example 44: Preparation of Compound 52

[0322] Compound 51-f (1 g, 5.02 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a yellow oily crude product 52-e, which was directly used in the next step of the reaction.

[0323] The crude compounds 52-e (theoretical yield: 498 mg, 5.02 mmol), 36-h (1.67 g, 6.53 mmol), and lithium carbonate (3.47 g, 25.12 mmol) were sequentially dissolved in dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 35 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid product 52-g (1.38 g, yield 82%). 1 H NMR (500MHz, CDCl3) δ7.69 (dd, J=11.5, 2.0Hz, 1H), 3.65 (t, J=6.0Hz, 4H), 2.63 (t, J=6.1Hz, 4H).

[0324] Compound 52-g (500 mg, 1.49 mmol) was dissolved in ethanol / water (10 / 3 mL), and iron powder (417 mg, 7.46 mmol) and ammonium chloride (399 mg, 7.46 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered and washed with methanol. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a yellow oily crude product -52-h (600 mg, 100% yield). MS m / z 305.0 [M+H] + .

[0325] Compounds 52-h (theoretical yield: 455 mg, 1.49 mmol), 51-l (700 mg, 1.94 mmol), and tetraphenylphosphine palladium (86 mg, 0.074 mmol) were sequentially dissolved in toluene (6 mL). The reaction mixture was purged with nitrogen three times and stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with potassium fluoride solution and extracted with ethyl acetate (3 x 35 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude intermediate product. The crude intermediate product was dissolved in 1,4-dioxane (5 mL), and an appropriate amount of dilute hydrochloric acid was added. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a yellow oily product 52-j (260 mg, yield 65%).

[0326] Compounds 52-j (100 mg, 0.373 mmol) and 3-c (75 mg, 0.373 mmol) were dissolved sequentially in ethyl acetate (3 mL). The reaction mixture was stirred at 80 °C for 2 hours in a sealed tube. After the reaction was complete, the mixture 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 product 52-l (79 mg, yield 49%). MS m / z 432.0 [M+H] + .

[0327] Compounds 52-l (79 mg, 0.183 mmol) and 52-c (59 mg, 0.220 mmol) were dissolved in tetrahydrofuran (3 mL) under dry ice bath conditions. A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (1 M, 0.37 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give crude product 52-m (59 mg, yield 66%). MS m / z 485.9 [M+H] + .

[0328] Compound 52-m (59 mg, 0.121 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (39 mg, 0.486 mmol) was added. The reaction mixture was stirred at 120 °C for 2 hours. After cooling to room temperature, the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a yellow solid product 52-n (19 mg, yield 33%). MS m / z 467.9 [M+H] + .

[0329] Compound 52-n (19 mg, 0.041 mmol), sodium methanesulfonate (8 mg, 0.081 mmol), cuprous iodide (1 mg, 0.005 mmol), L-proline (1 mg, 0.010 mmol), and potassium phosphate (22 mg, 0.102 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The reaction mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and acidified with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to give a yellow solid product 52 (7.38 mg, yield 36%). 1 H NMR (500MHz, CD3OD) δ8.35 (d, J=8.3Hz, 1H), 8.18 (dd, J=8.3, 1.6Hz, 1H), 8.1 0 (d, J=1.5Hz, 1H), 7.06 (d, J=11.6Hz, 1H), 6.27 (s, 1H), 5.68 (d, J=8.8Hz, 1H ), 4.91-4.88(m, 2H), 4.55-4.49(m, 2H), 4.14-4.03(m, 1H), 3.25-3.20(m, 2H) ), 3.18(s, 3H), 3.18-3.14(m, 2H), 2.40-2.35(m, 2H), 2.36-2.31(m, 2H)ppm. MS m / z 511.7 [M+H] + .

[0330] Example 45: Preparation of Compound 53

[0331] The synthesis of compound 53 was performed using the same method as that used for compound 51.

[0332] Compound 53 (39 mg, yield 63%). MS m / z 480.9 [M+H] + . 1 H NMR (500MHz, MeOD) δ8.35 (d, J=8.2Hz, 1H), 8.19 (d, J=8.2Hz, 1H), 8.11 (s, 1H), 7.09 (d, J=11.6Hz , 1H), 6.29(s, 1H), 5.42(s, 1H), 3.34(s, 4H), 3.19(s, 3H), 2.78-2.72(m, 2H), 2.60-2.55(m, 2H).

[0333] Example 46: Preparation of Compound 54

[0334] The synthesis of compound 54 was performed using the same method as that used for compound 51.

[0335] Compound 54 (15 mg, yield 45%). MS m / z 495.9 [M+H] + . 1 H NMR (500MHz, DMSO-d) δ12.00 (s, 1H), 8.38-8.18 (m, 3H), 7.21 (s, 1H), 6.10 (s, 1H), 4.64 (d, J=9.7Hz, 1H), 3.19 -3.09 (m, 7H), 2.47-2.44 (m, 2H), 2.26-2.18 (m, 2H), 1.59-1.54 (m, 1H), 0.72-0.67 (m, 2H), 0.34-0.28 (m, 2H).

[0336] Example 47: Preparation of Compound 55

[0337] Compound 55-m (33 mg, yield 52%). MS m / z 595.9 [M+H] + .

[0338] Compound 55-m (33 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL), and dilute hydrochloric acid (1 M, 1 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to give compound 55 (15 mg, 49% yield). MS m / z 55 1.8 [M+H] + . 1 H NMR (500MHz, MeOD) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.3Hz, 1H), 8.11 (d, J=0.7Hz, 1H), 7.09-7.04 (m, 1H), 6.28 (s, 1H), 5.18 (d, J=9.0Hz, 1H), 3.26-3.14 (m, 7H), 2.89-2.82 (m, 1H), 2.58-2.46 (m, 4H), 2.38-2.26 (m, 4H), 2.04-1.98 (m, 2H), 1.64-1.56 (m, 2H).

[0339] Example 48: Preparation of Compound 56

[0340] The synthesis of compound 56 was performed using the same method as that used for compound 36.

[0341] Compound 56 (4.42 mg, yield 65%). 1H NMR (500MHz, MeOH-d4) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.3, 1.6Hz, 1H), 8.11 (d, J=1.5Hz, 1H), 7.07 (d, J=11.4Hz, 1H), 6.27 (s , 1H), 5.48 (t, J=6.9Hz, 1H), 4.14 (d, J=7.0Hz, 2H), 3.27-3.20 (m, 4H), 3.18 (s, 3H), 2.47 (t, J=5.4Hz, 2H), 2.37 (t, J=5.4Hz, 2H). MS m / z 507.7[M+Na] + .

[0342] Example 49: Preparation of Compound 57

[0343] Compound 57 was synthesized using the same method as compound 36. Compound 57 was obtained (14 mg, yield 36%). 1 H NMR (500MHz, DMSO-d) δ8.35 (d, J=8.3Hz, 1H), 8.19 (dd, J=8.2, 1.2Hz, 1H), 8.11 (s, 1H), 7.06 (d, J=8.9Hz, 1H), 6.25 (s, 1H), 5.44 ( t, J=7.0Hz, 1H), 4.01 (d, J=7.0Hz, 2H), 3.34 (s, 3H), 3.27-3.20 (m, 4H), 3.18 (s, 3H), 2.48 (t, J=5.4Hz, 2H), 2.39 (t, J=5.4Hz, 2H). MS m / z 521.8[M+Na] + .

[0344] Example 50: Preparation of Compound 58

[0345] The hydrochloride salt of compound 58-a (800 mg, 4.17 mmol) and 2-bromo-3,4,5-trifluoronitrobenzene (1068 mg, 4.17 mmol) were dissolved in dimethyl sulfoxide (15 mL), and potassium carbonate (1153 mg, 8.34 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a yellow solid compound 58-b (1.2 g, yield 74%). MS m / z 391.1 [M+H] + .

[0346] Compound 58-b (1000 mg, 2.56 mmol) was dissolved in ethanol (20 mL), followed by the addition of iron powder (717 mg, 12.8 mmol) and ammonium chloride (1369 mg, 25.6 mmol), and then water (5 mL). The mixture was stirred at 80°C for 2 hours. After filtration, the mixture was extracted with water and ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a yellow solid compound 58-c (1.0 g, 91% yield). MS m / z 361.1 [M+H] + .

[0347] Compound 58-c (500 mg, 1.38 mmol) and tributyl(1-ethoxyethylene)tin (997 mg, 2.76 mmol) were dissolved in toluene (10 mL), and tetratetraphenylphosphine palladium (162 mg, 0.14 mmol) was added. The mixture was heated to 120 °C and stirred overnight. 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 = 5:1) to give a yellow solid compound 58-d (200 mg, yield 41%). MS m / z 353.1 [M+H] + .

[0348] Compound 58-d (200 mg, 0.57 mmol) was dissolved in dioxane (2 mL), followed by the addition of 0.5 mL of 2 M hydrochloric acid aqueous solution. 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 = 5:1) to give a yellow solid compound 58-e (120 mg, yield 65%). MS m / z 325.1 [M+H] + .

[0349] Compound 58-e (60 mg, 0.18 mmol) was dissolved in methanol (4 mL), followed by the addition of water (1 mL) and lithium hydroxide (17 mg, 0.72 mmol). The mixture was stirred at 70 °C for 3 hours. The solution was then concentrated under reduced pressure to obtain crude compound 58-f (59 mg, 100% yield).

[0350] Compound 58-f (30 mg, 0.095 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N-methylpiperazine (29 mg, 0.29 mmol), N,N-diisopropylethylamine (62 mg, 0.48 mmol), and HATU (53 mg, 0.14 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 preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 58-g (25 mg, yield 67%). MS m / z 393.1 [M+H] + .

[0351] Compound 58-g (25 mg, 0.064 mmol) and compound 3-c (19 mg, 0.096 mmol) were dissolved in ethyl acetate (2 mL) and stirred at 80 °C for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 58-h (30 mg, yield 85%). MS m / z 556.1 [M+H]+.

[0352] Compound 58-h (30 mg, 0.054 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (13 mg, 0.16 mmol) was added. The mixture was stirred overnight at 120 °C. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 58-i (20 mg, yield 69%). MS m / z 538.1 [M+H] + .

[0353] Compound 58-i (20 mg, 0.037 mmol) was dissolved in dimethyl sulfoxide (1 mL), followed by the addition of sodium methanesulfinate (11 mg, 0.11 mmol), cuprous iodide (2 mg, 0.01 mmol), L-proline (2 mg, 0.017 mmol), and potassium phosphate (23 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 58 (13 mg, 60% yield). MS m / z 58 1.9 [M+H] +. 1H NMR (500MHz, MeOD) δ8.35 (d, J=8.3Hz, 1H), 8.18 (dd, J=8.3, 1.6Hz, 1H), 8.11 (d, J=1.3Hz, 1H), 7.08 (d, J=11.5Hz, 1H), 6.28 (s, 1H), 5.98 (s, 1H), 3.71-3.59 (m, 4H), 3.34-3.31 (m, 2H), 3.26 (t, J=5.3Hz, 2H), 3.20 (s, 3H), 2.61 (t, J=5.4Hz, 2H), 2.53-2.43 (m, 6H), 2.34 (s, 3H).

[0354] Example 51: Preparation of compound 59

[0355] Compound 59-a was prepared using the same method as compound 58-g. Compound 59-a (30 mg, 0.082 mmol) and compound 59-b (36 mg, 0.16 mmol) were dissolved in dichloromethane (2 mL), followed by the addition of pyridine (0.5 mL). The temperature was lowered to approximately 0°C, and phosphorus oxychloride (63 mg, 0.41 mmol) was added. Stirring was continued at 0°C for 1 hour, followed by quenching with water, extraction with ethyl acetate, and concentration of the organic phase under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, compound 59-c (20 mg, yield 43%). MS m / z 573.1 [M+H] + .

[0356] Compound 59-c (17 mg, 0.030 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and lithium tert-butoxide (5 mg, 0.060 mmol) was added. The mixture was stirred overnight at 80 °C. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a pale yellow solid, compound 59 (IGP-19060-01) (0.3 mg, yield 1.7%). MS m / z 555.0 [M+H] + .

[0357] Example 52: Preparation of Compound 60

[0358] Compound 60 was synthesized using the same method as compound 57.

[0359] Example 53: Preparation of Compound 61

[0360] Compound 61 was synthesized using the same method as compound 57.

[0361] Example 54: Inhibition of HT1197 cell proliferation by the compound

[0362] Method A:

[0363] HT1197 cell culture conditions: MEM medium supplemented with 15% fetal bovine serum (FBS), 1% penicillin-streptomycin (PS), 1% non-essential amino acids, and 1 mM sodium pyruvate was used. The cells were cultured at 37°C in a 5% CO2 incubator. When the HT1197 cells showed good growth under a microscope, the culture flask was removed from the incubator, the medium was aspirated, the cells were rinsed with PBS, the waste liquid was discarded, and 2 mL of 0.25% Trypsin-EDTA solution was added to the flask for trypsin digestion. When the cells were loose and about to detach from the flask wall, 8 mL of complete medium was added to stop trypsin digestion, and the mixture was gently mixed. The cell suspension was transferred to a centrifuge tube using a pipette and centrifuged at 1000 rpm for 5 minutes. The supernatant in the centrifuge tube was discarded. An appropriate volume of medium was added to the centrifuge tube, and the cells were gently resuspended using EVE. TM Cell counting was performed using a Plus Automated Cell Counter. Cell suspensions were prepared and added to 96-well plates, 200 μL per well (2000 cells). The plates were incubated overnight in a CO2 incubator. Compounds were prepared as 15 mM or other concentration stock solutions using DMSO, and the compounds were diluted according to a specific concentration gradient and added to the corresponding wells using an I.DOT instrument. Blank wells contained only normal culture medium, no cells, and no DMSO; DMSO wells contained cells and 0.1% DMSO. Cells were incubated at 37°C in a 5% CO2 incubator for 7 days.

[0364] After 7 days of incubation, the culture medium was removed from the 96-well plates, the original medium was aspirated, and each well was rinsed once with 100 μL of PBS, then the waste liquid was discarded. 20 μL of 0.25% Trypsin-EDTA solution was added to each well, and the cells were observed under an inverted microscope until the cell layer dispersed. After mixing the cells by pipetting, the cells in the DMSO wells were counted. Based on the counting results, the same volume of suspension was transferred from each well to a new plate, and the culture medium was added to a final volume of 200 μL / well. The new plate was placed in a CO2 incubator for 4 hours, and after I.DOT administration, it was incubated for another 7 days at 37°C with 5% CO2 for a total of 14 days. The cell culture plate was equilibrated at room temperature for 30 minutes, the supernatant was discarded, and 60 μL of CellCounting-Lite 2.0 chemiluminescent cell viability assay reagent was added to each well. The plate was shaken for 2 minutes and allowed to react at room temperature for 30 minutes. The chemiluminescent signal was detected using a BMG instrument. The inhibition rate was calculated using the following formula: Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L). Where Ave_H is the average value of the DMSO wells, and Ave_L is the average value of the culture medium wells. The IC50 values ​​for each compound were also calculated. 50 The values ​​were analyzed using the nonlinear regression method of XLFit 5.5.0 software, with the formula: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 -X)*HillSlope)). Y represents the inhibition rate, and X represents the concentration log value of the compound. The test results for the compounds are shown in Table 1.

[0365] Method B:

[0366] HT1197 cell culture conditions: EMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (PS) was used, and the cells were cultured in a 37°C, 5% CO2 incubator. When the HT1197 cells showed good growth under a microscope, the cell culture flask was removed from the incubator, the medium was aspirated, the cells were rinsed with PBS, the waste liquid was discarded, and 5 mL of fresh trypsin was added for digestion. When the cells were loose and about to detach from the flask wall, 5 mL of complete culture medium was added to stop the trypsin digestion, and the mixture was gently stirred. The cell suspension was transferred to a centrifuge tube using a pipette and centrifuged at 1000 rpm for 5 minutes. The supernatant in the centrifuge tube was discarded. An appropriate volume of culture medium was added to the centrifuge tube, and the cells were gently resuspended using EMEM. TMCell counting was performed using a Plus Automated Cell Counter. Cell suspension was prepared and added to 96-well plates (150 μL per well, 2000 cells per well). The plates were incubated overnight in a CO2 incubator. The compound was prepared as a 10 mM or other concentration stock solution using DMSO and added using a Tecan D300E. Blank wells contained only normal culture medium, no cells, and no DMSO; DMSO wells contained cells and 0.1% DMSO. Cells were incubated at 37°C in a CO2 incubator for 7 days.

[0367] After 7 days of incubation, the culture medium was removed from the 96-well plates. 30 μL of 0.25% Trypsin-EDTA solution was added to each well. Cells were observed under an inverted microscope until the cell layer dispersed. 120 μL of intact growth medium was added, and the cells were gently pipetted into a single-cell suspension. 30 μL of the suspension was transferred from each well to a new plate, and the culture medium was added to a final volume of 150 μL / well. The new plate was placed in a CO2 incubator for 4 hours, and the compound was added using a Tecan D300E. The cells and compound were incubated for another 7 days at 37°C with 5% CO2. CellCounting-Lite 2.0 chemiluminescent cell viability assay reagent was added, shaken for 2 minutes, and allowed to react at room temperature for 30 minutes. The chemiluminescent signal was detected using a BMG instrument. The inhibition rate was calculated using the following formula: Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L), where Ave_H is the average value of the DMSO wells and Ave_L is the average value of the culture medium wells. Use GraphPad to plot the drug efficacy inhibition rate curve and calculate IC. 50 Values. The test results for the compounds are shown in Table 1.

[0368] Table 1: Inhibitory activity of compounds on HT1197 cell proliferation

[0369] *Inhibition efficiency (inh%) at single concentrations (11 nM or 33 nM); other data in the table are IC50 values. 50 Value (nM)

[0370] Example 55: Inhibition of RT112 cell proliferation by the compound

[0371] When RT112 cells showed good growth under a microscope, the cell culture flask was removed from the incubator, the culture medium was aspirated, and the cells were rinsed with 3 mL of trypsin. The waste liquid was discarded, and 3 mL of fresh trypsin was added to the culture flask for digestion. When the cells were loose and about to detach from the flask wall, 8 mL of complete culture medium was added to stop the trypsin digestion, and the mixture was gently stirred. The cell suspension was transferred to a centrifuge tube using a pipette and centrifuged at 1000 rpm for 5 minutes. The supernatant in the centrifuge tube was discarded. An appropriate volume of culture medium was added to the centrifuge tube, and the cells were gently resuspended and homogenized using a Vi-Cell XR cell counter. Cells were counted using a Vi-Cell XR cell counter. The cell suspension was prepared and added to 96-well plates, 200 μL per well, for 400 cells. The culture plate was placed in a CO2 incubator overnight. The compound was prepared as a 2 mM DMSO stock solution, and the compound was diluted according to a specific concentration gradient (using an HPD instrument) and added to the corresponding wells. Blank wells contained only normal culture medium, without cells or DMSO; DMSO wells contained cells and 0.5% DMSO. Cells were incubated at 37°C in a 5% CO2 incubator for 7 days.

[0372] After 7 days of incubation, the culture medium was removed from the 96-well plates, the supernatant was aspirated, and 50 μL of 0.25% Trypsin-EDTA solution was added. Cells were observed under an inverted microscope until the cell layer was dispersed. 150 μL of intact growth medium was added, and the cells were gently pipetted into the single-cell suspension. The number of cells was counted using Vi-cell XR, and the cell density was adjusted to an appropriate level. Based on the counting results, the same volume of suspension was transferred from each well to a new plate, and the culture medium was added to a final volume of 200 μL / well. The new plate was placed in a CO2 incubator for 4 hours, and the compound was added using HPD300. The cells and compound were incubated for another 7 days at 37°C with 5% CO2. The CellTiter-Glo reagent was thawed at room temperature. After the cell culture plate was equilibrated to room temperature, 100 μL of the mixed CellTiter-Glo reagent was added to each well, and the plate was shaken in the dark for 2 min, then incubated for 10 min. The RLU fluorescence signal was read using an Enspire. The inhibition rate was calculated using the following formula: Inhibition rate (%) = (1 - (compound RLU - Blank RLU) / (DMSO control RLU - Blank RLU)) × 100%. An inhibition rate curve was plotted using XLFit, and the IC50 was calculated. 50 Values. The test results for the compounds are shown in Table 2.

[0373] Table 2: Inhibitory activity of compounds on RT112 cell proliferation

[0374] Example 56: Pharmacokinetic Study in Rats

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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.). The test results for the compounds are shown in Table 3.

[0379] Table 3 Pharmacokinetic parameters in rats

[0380] FX-909 is a positive compound: It was prepared according to the method reported in WO2023078252.

[0381] 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: E——D——B——A (I) In formula (I): A is selected from substituted or unsubstituted aryl or heteroaryl groups; B is selected from chemical bonds, -C(O)NR 1 -、-NR 1 C(O)-、-S(O2)NR 1 - or -NR 1 S(O2)-; where, R 1 Selected from hydrogen or C 1-4 alkyl; D is selected from substituted or unsubstituted aryl or heteroaryl groups; or D is selected from formula (Ia): In equation (Ia), "---" indicates the connection site between formula (Ia) and B or A (when B is selected from chemical bonds) in formula (I); "---" indicates the connection site between formula (Ia) and E in formula (I); E is selected from formula (Ib) or formula (Ic): Equations (Ib) and (Ic) Indicates a carbon-carbon double bond or a carbon-carbon triple bond; Indicates a carbon-carbon single bond or a carbon-carbon double bond; The connection point between equation (Ib) or equation (Ic) and D in equation (I); R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, S(O)2R g’ ;R g’ Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic groups; Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c Among them, 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 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 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 9-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 R 4 The 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 ; or the R 4 The cycloalkyl or heterocyclic group in the R group is optionally substituted with =M; each R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, 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;R f The definitions are as described above; each R g Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; the R g The cycloalkyl or heterocyclic group in R is optionally substituted with =M; c The definition is as described above; 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 ;R c and R f The definition is as described above; 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; R p and R q Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, CN, OR f SR f , or NR c R c ;R c and R f The definition is as described above; or R p and R q 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 p and R q 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; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c 、or CN;R c and R f The definition is as described above; or two Rs 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; 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 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g NR dd 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 NR d S(O)2NR d R d Or = O; or the heteroatom N or S in the heterocyclic group is optionally oxidized; 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; b is selected from 0, 1, or 2; p is selected from 0, 1, 2, or 3; 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 equivalent to Equation (II): A is selected from aryl or heteroaryl; Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d’ R d’ NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g P(O)R d R d Among them, each R d’ Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c ; m is selected from 0, 1, 2, 3, or 4; R c R d R f R g The definitions of the remaining groups in formula (II) are as described in claim 1.

3. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (III): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition of m is as described in claim 2; The definitions of the remaining groups in formula (III) are as described in claim 1.

4. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (IV): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition of m is as described in claim 2; The definitions of the remaining groups in formula (IV) are as described in claim 1.

5. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (V): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition is as described in claim 2; The definitions of the remaining groups in formula (V) are as described in claim 1.

6. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (VI): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition is as described in claim 2; The definitions of the remaining groups in formula (VI) are as described in claim 1.

7. The compound according to claim 1, characterized in that, Equation (I) can be Equation (VIIa), Equation (VIIb), or Equation (VIIc): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition of m is as described in claim 2; The definitions of the remaining groups in formulas (VIIa), (VIIb), and (VIIc) are as described in claim 1.

8. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (VIII): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g P(O)R d R d ; Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c ; Each R 5 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c 、or CN; or two R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; 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 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, OR f SR f NR d R d C(O)R g 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 NR d S(O)2NR d R d Or = O; or the heteroatom N or S in the heterocyclic group is optionally oxidized; or R 6 and R 7 Together with the carbon atom it is attached to, it forms a 3- to 8-membered ring structure, which optionally contains 0 or 1 heteroatom selected from N, O, and S, and is optionally substituted by one or more groups selected from the group consisting of halogens, C, and N. 1-4 Alkyl, CN, OR f SR f NR d R d C(O)R g , or S(O)2R g ; The above R 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, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c 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 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; m is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, or 3; s is selected from 0, 1, 2, 3, or 4.

9. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (IX): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 R 3 R 6 R 7 The definition is as described in claim 8.

10. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (X): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 R 3 R 6 R d The definition is as described in claim 8.

11. The compound according to claim 1, characterized in that, Equation (I) is equivalent to Equation (XI): A, R 8 The definition of m is as described in claim 2; D is selected from substituted or unsubstituted aryl or heteroaryl groups; The definitions of the remaining groups in formula (XI) are as described in claim 1.

12. The compound according to claim 1, characterized in that, Equation (I) is either equation (XIIa) or equation (XIIb): A, R 8 The definition of m is as described in claim 2; D is selected from substituted or unsubstituted aryl or heteroaryl groups; The definitions of the remaining groups in formulas (XIIa) and (XIIb) are as described in claim 1.

13. The compound according to claim 1, characterized in that, Equation (I) is either equation (XIIIa) or equation (XIIIb): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; R 8 The definition is as described in claim 2; The definitions of the remaining groups in formulas (XIIa) and (XIIb) are as described in claim 1.

14. The compound according to claim 5, characterized in that, In formula (V): Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; Each R 8 Each is independently selected from halogens, CN, NO2, C(O)R g C(O)OR f S(O)2R g S(O)R g P(O)R d R d ; Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, CN, OR f SR f NR c R c ; R 4 Selected from hydrogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The R 4 The 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 ; or the R 4 The cycloalkyl or heterocyclic group in the cycloalkyl group is optionally substituted with =M; The above R d Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, 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 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 of the above M's is independently selected from CR. h R i , where R h and R i Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl.

15. The compound according to claim 5, characterized in that, Equation (V) is equivalent to equation (XIV): R 8 R 3 R 4 The definition is as described in claim 14.

16. A compound with the structure shown in formula (XV), or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate: Y is selected from N or CR t ;R t Selected from hydrogen, halogen, or C 1-4 alkyl; Each R 8 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, CN, NO2, OR f SR f NR d R d C(O)R g C(O)OR f OC(O)R g C(O)NR d R d NR d C(O)R g S(O)2R g S(O)R g S(O)2NR d R d , or NR d S(O)2R g P(O)R d R d ; Each R 3 Each independently selects hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, CN, OR f SR f NR c R c ; Each R 5 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, OR f SR f NR c R c 、or CN; or two R 5 They connect together to form a spiral ring, bridged ring, or fused ring structure, which optionally contains 0 or 1 additional heteroatom selected from N, O, and S; R 9 Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 9-membered heterocyclic, aryl, heteroaryl, CN, C(O)R g C(O)OR f C(O)NR d R d S(O)2R g or S(O)2NR d R d The R 9 The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of halogens, C, cycloalkyls, heterocyclics, aryl groups, and heteroaryl groups. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, aryl, heteroaryl, CN, 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 NR d S(O)2NR d R d =O; the above-mentioned cycloalkyl and heterocyclic groups are optionally substituted with =O; or the heteroatoms N or S in the above-mentioned heterocyclic groups are optionally oxidized; The above 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, 3- to 6-membered heterocyclic, aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroaryl C 1-4 Alkyl; 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 , or NR c R c 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 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic, aryl, or heteroaryl; m is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, or 3; s is selected from 0, 1, 2, 3, or 4.

17. The compound of claims 1 and 16, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, selected from the group consisting of: in, Each R is selected from: This indicates the site where the substituent R is attached to other parts of the compound; This indicates that the configuration of the connected carbon-carbon double bond is uncertain, including both "Z-configuration" and "E-configuration"; "*" indicates a chiral center, which includes R- and S-configurations.

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

19. Use of a compound according to any one of claims 1 to 17, 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 PPARG activity or expression levels.

20. The use as described in claim 19, characterized in that, The diseases, symptoms, or conditions described are selected from the following group: bladder cancer, urothelial carcinoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colon cancer, thyroid cancer, melanoma, liver cancer, rectal cancer, pharyngeal cancer, breast cancer, prostate cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, endometrial cancer, esophageal cancer, kidney cancer, skin cancer, stomach cancer, myeloid leukemia, lymphoid leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, myeloma, and various solid tumors and hematologic malignancies.

Images