A class of TIE2 inhibitors with cyclic structures and their applications

Abstract

This invention relates to a class of TIE2 inhibitors with cyclic structures and their applications. The cyclic TIE2 inhibitors have the structure shown in formula (I). The compounds of this invention exhibit high selectivity for TIE2 inhibition across a broad kinase spectrum. They demonstrate good antiproliferative activity in BaF3-FL-L914F cells that highly express TIE2 protein and can be used to treat disorders or diseases mediated by TEK gene abnormalities.

Description

Technical Field

[0001] This invention belongs to the field of biotechnology, specifically relating to a class of TIE2 inhibitors with cyclic structures, as well as their pharmaceutical combinations and applications. The TIE2 inhibitors of this invention can be used in the preparation of medicaments for the prevention and / or treatment of diseases, particularly in the preparation of medicaments for the prevention and / or treatment of disorders or diseases mediated by TEK gene abnormalities, including but not limited to vascular malformations related to TEK gene mutations. Background Technology

[0002] The ANG-TIE pathway is the second confirmed vascular tissue-specific receptor tyrosine kinase system after the VEGF receptor family. It is crucial in embryonic angiogenesis and maturation and plays a key role in maintaining adult vascular homeostasis. The TIE angiogenesis (ANGPT) family includes two receptors (TIE1 and TIE2) and three ligands (ANGPT1, ANGPT2, and ANGPT4). TIE2 is a tyrosine kinase with both immunoglobulin-like and EGF-like domains 2, primarily expressed in vascular endothelial cells, hematopoietic stem cells, and pro-angiogenic monocytes. The TIE2 protein is a single-pass transmembrane molecule with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Upon ligand binding, TIE2 protein is phosphorylated and activated, mediating the activation of downstream signaling pathways such as PI3K / MAPK / DOK-R, thereby participating in the regulation of endothelial cell migration, survival, and maintenance. The ANG-TIE pathway plays an important role in stabilizing immature endothelial cell networks, recruiting pericytes, and maintaining vascular integrity, and promotes tumor angiogenesis in tumorigenesis and development.

[0003] Venous malformations (VMs) are abnormal venous structures resulting from malformation of veins. They are characterized by enlarged venous channels formed by endothelial cells surrounded by sparsely and irregularly distributed vascular smooth muscle cells. The clinical presentation of venous malformations varies, ranging from isolated dilated cutaneous veins or localized cavernous masses to mixed cases involving multiple tissues and organs.

[0004] Venous malformations are among the most common congenital vascular malformations. They are present at birth and most are detectable, while a small percentage are discovered in early childhood or adolescence. The head, neck, and maxillofacial region are the most common sites, followed by the limbs and trunk. Their growth rate is generally synchronized with body growth, and they do not regress spontaneously. There is no gender difference in incidence. The main clinical symptoms are localized intravascular coagulation, swelling, and pain. If the lesion is located in the eyelids, lips, tongue, floor of the mouth, or pharyngeal wall, it often affects appearance and can cause corresponding visual, swallowing, speech, and respiratory dysfunctions. Severe cases can be life-threatening. Traditional treatments include endovascular sclerotherapy, surgery, laser therapy, and electrochemical therapy. However, for extensive, diffuse, and large lesions, these methods suffer from problems such as excessive treatment frequency, low efficiency (a single treatment can only improve a small area of ​​the lesion, requiring multiple treatments), high risks (massive bleeding, severe infection, and neurovascular damage, etc.), and even inability to treat the condition (involvement of all deep and superficial tissues in one or both limbs). Therefore, effective drug therapy is urgently needed to compensate for the shortcomings and deficiencies of traditional treatments.

[0005] Venous malformations are classified into common venous malformations (including single and multiple venous malformations), familial mucocutaneous venous malformations (VMCM), blue rubber nevus syndrome (BRBNS), globular venous malformations (GVM), cavernous venous malformations (CCM), and verrucous venous malformations (VVM), among which 90% of patients have common venous malformations. Genetic or somatic variations in TIE2, such as G833D, Q837H, Y897S / H / C, L914F, R915C, R918C / H, and K1100N, have been identified as being associated with the pathogenesis of hereditary or sporadic venous malformations. TEK mutation-related venous malformations include single venous malformations (TEK L914F somatic mutation), multiple venous malformations (TEK R915C chimeric mutation combined with TEK Y897C somatic mutation), VMCM (TEK R849W germline mutation combined with TEK Y1108 somatic mutation), and BRBNS (TEKT1105NT1106P somatic double mutation). Among these, the TEK L914F somatic mutation is the most common (accounting for approximately 60%). These mutations are located in the intracellular tyrosine kinase domain, leading to TIE2 receptor autophosphorylation activation in the absence of ligands, which in turn activates downstream signaling pathways such as the PI3K / AKT and MAPK / ERK pathways, resulting in endothelial cell growth dysregulation and venous malformations. Therefore, selective small molecule inhibitors of TIE2 represent a novel targeted therapy for venous malformations caused by abnormal TIE2 activation.

[0006] Besides vascular endothelial cells, TIE2 protein is also overexpressed in various solid tumor cells and tumor-infiltrating macrophages, participating in promoting angiogenesis, tumor growth, and recurrence after chemotherapy. Therefore, targeting TIE2 small molecule inhibitors is also a potential treatment for various tumors. Summary of the Invention

[0007] Based on this, the present invention provides compounds of formulas (I)-(VI) that can be used as highly selective TIE2 inhibitors for the prevention and / or treatment of disorders or diseases mediated by TEK gene abnormalities, particularly vascular malformations related to TEK gene mutations.

[0008] Specifically, the technical solution of the present invention is as follows:

[0009] In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:

[0010]

[0011] in,

[0012] Ring A is a 5-10 membered heteroaryl group substituted with m R1 atoms and containing at least one N atom;

[0013] Ring B is: C replaced by n R2s. 6-10 Aryl or 5-6 quinone heteroaryl;

[0014] The ring C is: a 5-7 membered heteroaryl group or a 4-12 membered heterocyclic alkyl group containing at least one N atom and q R4 substituted;

[0015] L1 is: bond, ethynyl group or trans vinylene;

[0016] L2 is selected from: -O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene-O-, -OC 1-6 Alkylene-NR a -、-OC 1-6 Alkylene -C(=O)NH-, -OC 3-6 Cycloalkylene-, -O-4-7-membered heterocycloalkylene-; wherein, the alkylene, cycloalkylene, and heterocycloalkylene are each optionally C 1-6 Alkyl or C 3-6 Cycloalkyl substitution; or

[0017] L2 together with ring C forms C 5-7 Cycloalkyl or 4-12 membered heterocyclic alkyl;

[0018] R a -Re -C(=O)R c -S(=O)R c -S(=O)2R c -C(=O)NHR d -CH2C(=O)NHR d ;

[0019] M is O or S; Q1, Q2, and Q3 are each individually C or N;

[0020] R1 is selected from: halogen, -CN, -NHR b -C(=O)OR c -R c -OR d -SR d -C(=O)NR d R d ';

[0021] R b For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or 4-12-membered heterocycloalkyl; and each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally surrounded by deuterium, oxo group, halogen, or OR. e NR d R e C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic alkyl substitutions;

[0022] R2 is selected from: halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl;

[0023] R3 is selected from: halogen, -CN, -NR a 'R d -C(=O)R c -C(=O)OR c -C(=O)NR d R d ', optionally subjected to halogens, OH, NR a 'R d Or the following groups substituted with 3-7 membered heterocyclic alkyl groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heteroaryl, or 4-7-membered heterocycloalkyl;

[0024] R4 is selected from: halogens, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -NR a 'R d-C(=O)R f -S(=O)R c -S(=O)2R c , Oxide group, -C(=O)NHR d -CH2C(=O)NHR d The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally further reacted with halogens, NH2, OH, or C. 1-3 Alkyl or C 1-3 Alkyl substitution;

[0025] R a 'For H, C 1-3 Alkyl or -C(=O)R c ;

[0026] R c C 1-4 Alkyl or C 3-7 cycloalkyl;

[0027] R d R d Each individually is: hydrogen, or C optionally substituted with halogen, NH2 or OH. 1-6 alkyl;

[0028] R e For hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic alkyl; wherein, the alkyl, cycloalkyl, or heterocyclic alkyl may optionally be further reacted with halogen, NH2, OH, or C. 1-3 Alkyl or C 1-3 Alkyl substitution;

[0029] R f To be optionally subjected to OH, CN, halogen, C 1-3 Alkyl or NR a 'R d The following groups are substituted: C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, wherein R a '、R d As defined above;

[0030] m can be 0, 1, 2, or 3; when m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl;

[0031] n is 0, 1, or 2;

[0032] q and p can each be 0, 1, 2 or 3 at will;

[0033] The heteroaryl and heterocyclic alkyl groups contain 1-3 heteroatoms selected from N, O and S.

[0034] In one specific embodiment of the present invention, in general formula (I),

[0035] Ring A is a 5-10 membered heteroaryl group optionally substituted with m R1 atoms and containing at least one N atom;

[0036] Ring B is: C replaced by n R2s. 6-10 Aryl or 5-6 quinone heteroaryl;

[0037] The ring C is a 4-12 membered heterocyclic alkyl group optionally substituted with q R4 atoms and containing at least one N atom;

[0038] L1 is: bond, ethynyl group or trans vinylene;

[0039] L2 is selected from: -O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene-O-, -OC 1-6 Alkylene-NR a -、-OC 1-6 Alkylene-C(O)NH-, -OC 3-6 Cycloalkylene-, -O-4-7-membered heterocycloalkylene-; wherein, the alkylene, cycloalkylene, and heterocycloalkylene are each optionally C 1-6 Alkyl or C 3-6 Cycloalkyl substitution; or

[0040] L2 together with ring C forms C 5-7 Cycloalkyl or 4-12 membered heterocyclic alkyl;

[0041] R a -R e -C(=O)R c -S(=O)R c -S(=O)2R c -C(=O)NHR d -CH2C(=O)NHR d ;

[0042] M is O or S; Q1, Q2, and Q3 are each individually C or N;

[0043] R1 is selected from: halogen, CN, C 1-6 Alkyl, C 3-6 cycloalkyl, NHR b ;

[0044] R2 is selected from: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0045] R3 is selected from: halogen, C 3-6 Cycloalkyl groups, optionally selected from halogens, OH, NR a 'R d 3-7 membered heterocyclic alkyl-substituted C 1-6 Alkyl, 4-7 membered heteroaryl, or 4-7 membered heterocyclic alkyl;

[0046] R4 is selected from: halogens, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -NHR a '、C(=O)R f S(=O)R c S(=O)2R c C(=O)NHR d CH2C(=O)NHR d The alkyl, cycloalkyl, or heterocycloalkyl groups may optionally be further reacted with halogen, NH2, OH, or C. 1-3 Alkyl substitution;

[0047] Among them, R b For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or 4-12-membered heterocycloalkyl; and each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally replaced by deuterium, halogen, OH, or NR. d R e C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic alkyl substitutions;

[0048] R a 'For H, C 1-3 Alkyl or -C(=O)R c ;R c C 1-4 Alkyl or C 3-7 cycloalkyl;

[0049] R d R d Each individually is: hydrogen, or C optionally substituted with halogen, NH2 or OH. 1-6 alkyl;

[0050] R e For hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl; wherein, the alkyl, cycloalkyl, or heterocyclic alkyl may optionally be further reacted with halogen, OH, NH2, or C. 1-3 Alkyl substitution;

[0051] R fTo be optionally subjected to OH, CN, halogen, C 1-3 The following groups are substituted with alkyl or NH2: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-12 membered heterocyclic alkyl;

[0052] m is 1 or 2; when m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl;

[0053] n is 0, 1, or 2;

[0054] q is 1 or 2;

[0055] p is 0, 1, or 2;

[0056] The heteroaryl and heterocyclic alkyl groups contain 1-3 heteroatoms selected from N, O and S.

[0057] In a preferred embodiment, in formula (I), ring A is selected from: Preferably, ring A is selected from

[0058] Among them, ring A is replaced by m R1s;

[0059] Preferably, R1 is selected from: halogen, CN, NHR b C, optionally replaced by halogen, NH2 or OH 1-6 Alkyl or C 3-6 cycloalkyl; wherein, R b The definition is as stated in equation (I);

[0060] More preferably, R1 is selected from: F, Cl, -CN, -C 1-4 Alkyl, -CF3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, -(CH2)2NH2, -(CH2)3NH2, -NH2, -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NHCH(CH3)2, -NH( CH2)2OH, -NH(CH2)3OH, -NHCF3, -NHCH2CHF2, -NHCH2CF3, -NHCD3, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)2N(CH3)2, -NH(CH2)3N(CH3)2,

[0061] More preferably, R1 is selected from: F, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -(CH2)3CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NHCF3, -NHCH2CHF2, -NHCH2CF3, -NHCD3, -CF3, -CHF2, -CH2CHF2, -CH2CF3, -(CH2)2NH2, -(CH2)3NH2,

[0062]

[0063] In a preferred embodiment, in formula (I), m is 0, 1, or 2. When m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 Cycloalkyl or 4-7 membered heterocyclic alkyl.

[0064] In a preferred embodiment, in equation (I), the ring BC=M structure is selected from: Preferably, the ring BC=M structure is selected from In this case, each ring B is arbitrarily replaced by n R2s, where n is 0 or 1;

[0065] More preferably, R2 is selected from: halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl; more preferably, R2 is selected from: methyl, ethyl, cyclopropyl.

[0066] In a preferred embodiment, in formula (I), Q1, Q2, and Q3 are all C.

[0067] In a preferred embodiment, in formula (I), Q1 and Q3 are both C, and Q2 is N.

[0068] In a preferred embodiment, in formula (I), R3 is selected from: halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, -CF2-cyclopropyl, -C 1-4 Alkyl groups -OH, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)3N(CH3)2, -NH(CH2)2OH, -CH2NH-C 3-6 Cycloalkyl, -CH2-4-7-membered heterocycloalkyl, -C(=O)-C 1-4 Alkyl group, -C(=O)OC1-4 Alkyl group, -C(O)NH2, -C(O)NH-C 1-4 Alkyl, 4-7 membered heterocyclic alkyl; wherein the heterocyclic alkyl is optionally C 1-4 Alkyl substitution;

[0069] More preferably, R3 is selected from: halogen, -CN, -NH2, C 1-6 Alkyl (e.g., methyl, ethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 1-6 Haloalkyl groups (e.g., -CF3, -CHF2, -CHF2, -CF2CH3, -CF2CH2CH3, -CH2CHF2, -CH2CF3), -C 1-4 Alkyl-OH (e.g., -CH(CH3)2OH), -C(=O)NH2, -CF2-cyclopropyl,

[0070] In a preferred embodiment, p is 1 or 2 in formula (I).

[0071] In a preferred embodiment, in formula (I), ring C is a 4-9 membered heterocyclic alkyl group containing at least one N atom, optionally substituted with q R4 atoms, where q is 0 or 1.

[0072] In a preferred embodiment, in formula (I), the L2-ring C structure is selected from:

[0073]

[0074] Each ring C is arbitrarily replaced by q R4s; q is 0 or 1;

[0075] R4 is selected from: F, =O, optionally coated with OH or C. 1-4 Alkyl-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic alkyl, -NH2, -NH-C 1-4 Alkyl, -SO2R c , -CH2CONHCH3, -CONHCH3, -C(O)R f ;R f To be optionally subjected to F, OH, CN, NH2, C 1-3 Alkyl-substituted: C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-12-membered heterocycloalkyl; R c C 1-4 Alkyl or C 3-6 Cycloalkyl; more preferably, R4 is selected from: F, =O, C 1-4 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), C1-4 Alkyl groups -OH (e.g., -CH2CH2OH, -CH(CH3)2OH), -SO2CH3, -SO2CH(CH2)2, -SO2-C 3-6 Cycloalkyl groups (e.g., -SO2-cyclopropyl), -CH2CONHCH3, -CONHCH3, -NH2, -NH-C 1-3 Alkyl, -C(=O)R f C 3-10 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, ...) ), 3-10 membered heterocyclic alkyl groups (e.g. );

[0076] R f To be optionally subjected to F, OH, NH2, CN, C 1-3 Alkyl-substituted C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-12 membered heterocyclic alkyl; preferably, R f Selected from CH3, CF3, CH2CF3, CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl

[0077] In a preferred embodiment, in formula (I), the L2-ring C structure is selected from: Where R4 and q are defined as described above; preferably, they are selected from...

[0078] In a preferred embodiment, in formula (I), the L2-ring C structure is: in,

[0079] R4' is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -NHR a '、-C(=O)R f -S(=O)R c -S(=O)2R c -C(=O)NHR d -CH2C(=O)NHR d , where R a '、R c R d R f The definitions are as described above.

[0080] In a preferred embodiment of the present invention, in formula (I), L2 is selected from: -O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene-NR a -、-OC1-6 Alkylene-C(O)NH-, -OC 3-6 Cycloalkylene-, -O-4-7-membered heterocycloalkylene-; wherein, the alkylene, cycloalkylene, and heterocycloalkylene are each optionally C 1-6 Alkyl or C 3-6 Cycloalkyl substitution, R a The definitions are as described above;

[0081] More preferably, L2 is selected from: -O-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -OCH(CH3)CH2-, -OCH2CH(CH3)-, -OCH2C(CH3)2-, -OC(CH3)2CH2-, -OCH(CH2CH3)CH2-, -OCH2CONH-, -OCH(CH2CH2CH3)CH2-, -O(CH2)2NR a More preferably, it is selected from -O-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -O(CH2)2N(CH3)- (for example) ),

[0082] In one specific embodiment of the invention, a compound of formula (II) is provided, including its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:

[0083]

[0084] Among them, variables R1, R2, R3, R4, m, n, p, q, Q1, Q2, Q3, L2, ring A, ring B, and ring C are defined as in equation (I).

[0085] In one specific embodiment of the invention, a compound of formula (III) is provided, including its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:

[0086]

[0087] Where X is C or N, and the other variables R1, R2, R3, R4, m, n, p, q, Q2, L2, ring A, and ring C are as described in equation (I).

[0088] In a preferred embodiment, in the compound of formula (III), R4 is selected from: R f -NH2, -NH-C 1-4 Alkyl, -C(=O)R f -S(=O)R c -S(=O)2R c-C(=O)NHR d -CH2C(=O)NHR d R f To be optionally coated with OH, CN, halogen or C 1-3 Alkyl-substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 5-7 membered heterocyclic alkyl; R c C 1-4 Alkyl or C 3-7 cycloalkyl; R d For: hydrogen, or C optionally substituted with halogen or OH 1-6 alkyl.

[0089] In one specific embodiment of the invention, a compound of formula (IV) is provided, including its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:

[0090]

[0091] Where X is C or N, and Q2 is C or N (e.g., both X and Q2 are C; or both X and Q2 are N; or X is C and Q2 is N; or X is N and Q2 is C); each R g R h R g '、R h 'Each is independent for H and C' 1-4 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl groups, and other variables R1, R2, R3, R4, m, p, and cycloA as described in formula (I);

[0092] Preferably, ring A is selected from More preferably, selected from Where m is 0, 1 or 2, and R1 is as described in equation (I).

[0093] In a preferred embodiment, in formula (IV), R1 is selected from: F, -CH3, -CH2CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NH(CH2)2OH, -NH(CH2)3OH, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)3N(CH3)2, -NHCD3, -NHCH2CHF2, -NHCH2CF3,

[0094]

[0095] In a preferred embodiment, in formula (IV), R2 is selected from: F, C 1-6Alkyl (e.g., methyl, ethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl).

[0096] In a preferred embodiment, in formula (IV), R3 is selected from: halogens (e.g., F), CN, C 1-6 Alkyl (e.g., methyl, ethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), -CF3, -CHF2, -CF2CH3, -CF2CH2CH3, -CF2-cyclopropyl, -C 1-4 Alkyl-OH.

[0097] In a preferred embodiment, n is 0 in equation (IV).

[0098] In one specific embodiment of the invention, a compound of formula (V) is provided, including its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:

[0099]

[0100] Where X is C or N, and each R g R h R g '、R h 'Each is independent for H and C' 1-4 Alkyl (e.g., methyl) or C 3-6 Cycloalkyl, R3' is selected from: halogen, CN, -NR a 'R d -C(=O)R c -C(=O)OR c -C(O)NR d R d ', optionally halogenated, OH or -NR a 'R d Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heteroaryl, 4-7-membered heterocycloalkyl; other variables R1, R2, m, cycloA, R a R a '、R d R c R d As described in equation (I).

[0101] In a preferred embodiment, in formula (V), R1 is selected from: -NH2, -NHCH3,

[0102] In a preferred embodiment, n is 0 in equation (V).

[0103] In a preferred embodiment, in formula (V), R3' is selected from: -CF3, -CHF2, C 3-6 Cycloalkyl, -CF2CH3, -CF2CH2CH3, -CH2CHF2, -CH2CF3, -CF2-cyclopropyl.

[0104] In one specific embodiment of the invention, a compound of formula (VI) is provided, including its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt:

[0105]

[0106] In equation (VI), R i Selected from H, C 1-3 Alkyl groups and -C(=O)R c The other variables, namely rings A, R1, R2, R3, m, n, p, X, and Q2, are defined as shown in equation (I).

[0107] In one embodiment of the present invention, the compound of formula (I) is selected from the following compounds:

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] In another aspect, the present invention provides a method for preparing the compounds disclosed herein, an intermediate for preparing the compounds disclosed herein, and a method thereof.

[0119] In another aspect, the present invention provides a composition comprising at least one of the compounds of the present invention, its stereoisomers, hydrates, solvates, or pharmaceutically acceptable salts.

[0120] In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention, or a stereoisomer thereof, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

[0121] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0122] In another aspect, the present invention provides pharmaceutical combination products comprising at least one compound of the present invention, or a stereoisomer thereof, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and one or more other active agents.

[0123] In another aspect, the present invention provides the use of the compounds of formulas (I)-(VI), their stereoisomers, hydrates, solvates or pharmaceutically acceptable salts, or the above-described compositions or pharmaceutical compositions, or the above-described pharmaceutical combination products, in the preparation of a medicament or TIE2 inhibitor for the prevention, treatment or relief of disorders or diseases mediated by TEK gene abnormalities (including but not limited to vascular malformations related to TEK gene mutations) in patients.

[0124] On the other hand, the present invention provides a method for preventing, treating, or alleviating disorders or diseases caused by one or more abnormalities of the TEK gene, the method comprising administering to an individual in need of such treatment an effective amount of a compound of formula (I)-(VI), or a stereoisomer thereof, hydrate, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0125] In some embodiments of the present invention, the impairment or disease includes, but is not limited to, vascular malformations related to TEK gene mutations. For example, in addition to vascular endothelial cells, TIE2 protein is also overexpressed in various solid tumor cells and tumor-infiltrating macrophages, participating in promoting angiogenesis, tumor growth, and recurrence after chemotherapy. Therefore, the TIE2-targeting small molecule inhibitor of the present invention is also a potential treatment for various tumors.

[0126] In specific embodiments, the compounds of the present invention exhibit good cell proliferation inhibition at the cellular level, preferably at an IC50 concentration of ≤200 nM. 50 Value, more preferably ≤50nM IC 50 value.

[0127] It should be understood that, within the scope of this invention, the technical features defined in the various technical solutions 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. Due to space limitations, these will not be elaborated upon here. It can also be understood that each individual element of the implementation scheme is its own independent implementation scheme.

[0128] Terminology Explanation

[0129] In this disclosure, unless otherwise expressly stated, the terms used herein have the meanings defined below. Terms not expressly defined in this disclosure have the general meanings commonly understood by those skilled in the art.

[0130] When the group has a wavy line When the wavy line is used, it indicates the connection position between the group and the rest of the molecule.

[0131] As used herein, “heteroatom” refers to a nitrogen (N), oxygen (O), or sulfur (S) atom, particularly nitrogen or oxygen, which may be substituted or unsubstituted, including their oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, a C1-C4 alkyl group, or a nitrogen-protecting group (such as benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Any heteroatom having an unsatisfied valence bond is considered to have a hydrogen atom sufficient to satisfy the valence bond, unless otherwise indicated.

[0132] As used herein, "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine. Fluorine and chlorine are preferred halogens as substituents.

[0133] As used herein, "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon group. Alkyl groups preferably contain 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. "C" 1-6 "Alkyl" refers to an alkyl group having 1-6 carbon atoms. 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

[0134] As used herein, “alkoxy” refers to an alkyl-O- group, where alkyl is as defined above. “C 1-6"Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, hexoxy, cyclopropyloxy, and cyclohexyloxy. Preferably, the alkoxy group contains 1 to 6 or 1 to 4 carbon atoms.

[0135] As used in this article, "halogenated C" 1-6 "Alkyl" refers to a C14 alkyl group substituted with one or more halogens as defined above. 1-6 Alkyl groups, such as fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, etc.

[0136] As used herein, "cycloalkyl" refers to a hydrocarbon group of 3-12 carbon atoms in a saturated or unsaturated monocyclic, bicyclic, or tricyclic form. Cycloalkyl groups preferably contain 3-8 ring carbon atoms, for example, 3-8, 3-7, or 4-7 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include borneol, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptane, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, etc. Exemplary tricyclic hydrocarbon groups include adamantyl, etc.

[0137] As used herein, "aryl" refers to a group having 6-18 carbon atoms and at least one aromatic ring in the ring moiety of an aromatic hydrocarbon ring system. Preferably, the aryl group is C64-C ... 6-12 Aryl or C 6-10 Aryl groups. Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, or anthracene, etc.

[0138] As used herein, "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or fused polycyclic aromatic ring containing 1-6 heteroatoms selected from N, O, or S. Preferably, the heteroaryl contains 1-3, 1-4, or 1-5 heteroatoms selected from N, O, or S. The heteroaryl is preferably a 5-12 membered heteroaryl or a 5-10 membered heteroaryl, more preferably a 5-7 membered or a 5-6 membered heteroaryl. Preferably, the heteroaryl group includes, but is not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, indolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxolinyl, tetrahydroquinolinyl, oxazolopyridyl, imidazopyridyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, and azainzolyl.

[0139] As used herein, "heterocycle" refers to a fully saturated or partially saturated, aromatic or non-aromatic cyclic group, such as a 4-7 membered monocyclic, 7-12 membered bicyclic, or 10-15 membered tricyclic ring system, preferably a 4-12 membered monocyclic or bicyclic heterocycle, wherein the ring system contains at least one heteroatom on a ring containing at least one carbon atom. Each ring of the heterocycle containing heteroatoms may contain 1-3, 1-4, 1-5, or 1-6, preferably 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms, wherein nitrogen and sulfur heteroatoms may optionally be oxidized, for example, sulfur heteroatoms may form -S(O)- or -S(O)2- structures.

[0140] Exemplary monocyclic heterocycles include fully saturated, partially saturated, or aromatic pyrrolidines, pyrroles, pyrazoles, oxetanes, oxecyclopentanes, oxecyclohexanes, pyrazolines, imidazoles, imidazolines, imidazolines, triazoles, thiazoles, thiadiazoles, thiazolines, isothiazolides, isothiazolides, furans, tetrahydrofurans, thiophenes, piperidines, piperazines, 2-oxopiperazines, 2-oxopiperidines, 2-oxopyrrolidines, 4-piperidinones, pyridines, pyrazines, pyrimidines, pyridazines, tetrahydropyrans, morpholines, thiomorpholines, thiomorpholine sulfoxides, thiomorpholine sulfones, 1,3-dioxolane and tetrahydro-1,1-dioxothiophene, 1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl, etc.

[0141] Exemplary bicyclic heterocycles include fully saturated, partially saturated, or aromatic indoles, dihydroindoles, indazoles, benzothiazoles, benzoxazoles, benzimidazoles, benzopyrazoles, benzotriazoles, quinolines, isoquinolines, tetrahydroisoquinolines, pyridoxazoles, pyridoimidazoles, pyridopyridines, pyridopyrazoles, etc.

[0142] "Heterocyclic alkyl" refers to a group formed by the loss of one or more hydrogen atoms from a heterocycle as defined above. The heterocyclic alkyl group may be attached to other parts of the molecule at a heteroatom or carbon atom. Preferably, the heterocyclic alkyl is a saturated or partially unsaturated non-aromatic ring of monocyclic, bicyclic, or tricyclic form having 3-20 ring atoms, such as 3-12, 3-8, or 3-6 ring atoms. More preferably, the heterocyclic alkyl is a 4-12 membered heterocyclic alkyl containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, such as a 5-7 membered heterocyclic alkyl. Examples of heterocyclic alkyl groups include, but are not limited to: ethylene oxide, aziridinyl, aziridine, oxaziridine, aziridine (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl-2-one, imidazolylone, piperidinyl, N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl, piperidinone, 1,4-dioxa-8-aza-spiro[4.5]decane-8-yl, morpholinyl, thiomorpholinyl, thiomorpholino-S-monoxide, thiomorpholino-S,S-dioxide, octahydropyrrolo[3,2-b]pyrrolidinyl, etc.

[0143] As used in this article, "oxo" refers to a radical (=O).

[0144] The terms “alkylene,” “cycloalkylene,” “heterocyclic alkylene,” “ethynylene,” and “vinylene” used in this article refer to the groups formed by the loss of a hydrogen atom from the corresponding “alkyl,” “cycloalkyl,” “heterocyclic alkyl,” “ethynylene,” and “vinylene,” respectively.

[0145] As used herein, the terms “optional,” “optional,” or “optionally” mean that the substitution pattern, event, or condition described below may or may not occur, and the description includes both cases where the substitution pattern occurs and cases where the substitution pattern does not occur. For example, “optionally substituted alkyl” includes both “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0146] As used herein, the terms “substituted” or “replaced” mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the substitution does not exceed the normal valence of the given atom. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced by oxygen. Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from the reaction mixture and its chemical structure can be determined, and it can subsequently be formulated into an agent with at least practical utility. For example, where no substituent is explicitly listed, the terms “substituted” or “replaced” as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example, 1, 2, 3, or 4 substituents, which may be the same or different when an atom or group is replaced by multiple substituents.

[0147] As used herein, “compounds of the present invention”, “TIE2 inhibitor”, and “TIE2 small molecule inhibitor” can refer to the compounds represented by formulas (I)-(VI) and related specific compounds.

[0148] As used herein, "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as hydrochlorides, hydrobromates, sulfates, nitrates, phosphates, methanesulfonates, oxalates, maleates, succinates, citrates, formates, benzoates, fumarates, tartrates, salicylates, mandelates, carbonates, etc. Those skilled in the art will recognize that acid addition salts are prepared by reacting said compounds with suitable inorganic or organic acids via any of a number of known methods.

[0149] As used herein, "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, similar substances, and combinations thereof, which are well known to those skilled in the art.

[0150] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined by absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This document aims to include all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically described herein. Optically active (+)- and (-)-, (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthesis or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC).

[0151] As used herein, "solvate" refers to a form involving stoichiometric or non-stoichiometric solvent addition. If the solvent is water, the resulting solvate is a hydrate; when the solvent is ethanol, the resulting solvate is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance in which the water retains its H₂O molecular state. Such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0152] As used herein, "therapeutic effective amount" refers to the amount of the disclosed compound that can elicit an individual's biological or medical response or improve symptoms, slow or delay disease progression, or prevent disease.

[0153] As used herein, "individual" or "patient" refers to an animal. Preferably, the animal is a mammal, such as a primate (e.g., a human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, etc. In a preferred embodiment, the individual is a human being.

[0154] As used in this article, "inhibition" refers to the reduction or suppression of a specific patient, symptom, condition, or disease, or a significant decrease in biological activity or baseline activity of a process.

[0155] As used herein, in one embodiment, the term "treatment" for any disease or condition refers to improving the disease or condition (i.e., stopping or slowing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to improving at least one bodily parameter, which may not be perceptible to the patient. In yet another embodiment, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both.

[0156] Beneficial effects

[0157] The compounds of this invention are TIE2 inhibitors. They exhibit high selectivity for TIE2 inhibition across a broad kinase spectrum. They also demonstrate good antiproliferative activity in BaF3-FL-L914F cells that highly express TIE2 protein.

[0158] General synthetic route

[0159] In one embodiment, the compound of formula (I) of the present invention can be synthesized by the following general synthetic scheme, wherein the variables are as defined herein and the specific reaction conditions are the same as in the examples.

[0160] This invention utilizes synthetic routes for the synthesis of compounds. The solvents, acids, bases, coupling catalysts, and ligands described below are based on existing knowledge of organic chemistry and named reactions.

[0161] In this invention, when the name of a compound is inconsistent with its structural formula, the structural formula of the compound shall prevail.

[0162] When this invention relates to a class of compounds in which L1 is an alkyne bond, the general synthetic route is shown in synthetic routes 1-5:

[0163] Synthesis Route 1:

[0164]

[0165] The intermediate Ib is obtained by Sonogashira coupling reaction of a cyclic A compound (Ia) containing a halogenated (X) and trimethylsilylacetylene.

[0166] When L1 is an alkyne bond, the target compound can be synthesized via routes 2 to 5, depending on the changes in Q1, Q2, Q3, and ring B.

[0167] Synthesis Route 2:

[0168]

[0169]

[0170] When the cyclic C compound (II-b) is connected to the heteroaromatic ring below via a nitrogen atom: the halogen (X)-substituted heteroaromatic compound (II-a) undergoes a substitution reaction or Buchwald coupling reaction with the 'N' of the cyclic C compound (II-b) under basic conditions to give compound (II-c). When the cyclic C compound (II-b) is connected to the heteroaromatic ring below via a carbon atom: the halogen (X)-substituted heteroaromatic compound (II-a) and the alkenylboronic acid or ester of the cyclic C compound (II-b) undergo a Suzuki coupling reaction to give compound (II-c). Compound (II-c) is then subjected to transition metal-catalyzed hydrogenation (reduction reaction) to give an amino compound (II-d), which, along with a compound containing a phenolic hydroxyl group (II-e), undergoes a Mitsunobu reaction to give compound (II-f). Compound (II-h) can be obtained from compound (II-f) via intramolecular cyclization after hydrolysis, condensation, or acylation. Alternatively, it can be obtained directly through an amino-ester exchange reaction under basic conditions (such as LiHMDS) to yield the intramolecular cyclization product. Compound (II-h) and intermediate (Ib) are coupled via a Sonogashira coupling reaction to yield the target compound (II-i).

[0171] Synthesis Route 3:

[0172]

[0173] When the substituent R4 on ring C is attached to a nitrogen atom on the ring, in addition to synthetic route 2 described above, synthetic route 3 can also be used. Specifically, compound (III-f) is synthesized from the nitrogen-Boc protected intermediate (III-a), followed by Sonogashira coupling, deBoc removal (under acidic conditions), substitution or acylation (with R4-X) to obtain the target compound (III-g). Alternatively, deBoc removal (under acidic conditions), substitution or acylation (with R4-X) can be performed to obtain intermediate (III-i), which is then coupled with intermediate (Ib) via a Sonogashira coupling reaction to obtain the target compound (III-g).

[0174] Synthesis Route 4:

[0175]

[0176] Compound (II-d) and intermediate (II-j) with fluorine at the ortho position of the carboxylic acid ester undergo an amino-ester exchange reaction under basic conditions (such as LiHMDS) to give amide intermediate (II-k). This intermediate can be used to synthesize the target compound via two routes: 1) in the presence of excess DBU, it is combined with intermediate Ib via a Sonogashira coupling reaction and a cyclization reaction in one step to give the target compound (II-i); 2) under basic conditions, a cyclization reaction is first carried out to give a cyclic intermediate (II-h), which is then combined with intermediate (Ib) via a Sonogashira coupling reaction to give the target compound (II-i).

[0177] The synthesis of the target compound (II-i) with the fluorine atom in the B ring at the ortho position of the pyridine 'N' can be achieved via the following synthetic route.

[0178] Synthesis Route 5:

[0179]

[0180] Compounds (II-d) and (II-m) undergo a substitution reaction under basic conditions to give compound (II-g). Subsequent reactions are as described in synthetic route 2. Similarly, the target compound (III-g) can also be synthesized via the same route.

[0181] When this invention relates to a class of compounds in which L1 is trans-vinyl or in which L1 is absent, the general synthetic route is shown in synthetic route 6:

[0182] Synthesis Route 6:

[0183]

[0184] Compound (II-h) and the corresponding borate (ester) can be coupled via a Suzuki reaction to yield the target compounds (III-a) and (IV-a), respectively. Similarly, when R4 is substituted on a nitrogen atom of the C ring, intermediate (III-f) can be used to replace compound (II-h) in the above route, and the method of introducing the R4 substituent in synthetic route 3 can be continued. Detailed Implementation

[0185] In this application, when the chemical name and structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred from the context to be correct.

[0186] The present disclosure is 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 disclosure. Experimental methods in the following embodiments, unless specific conditions are specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0187] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0188] In each embodiment, the experimental instruments (e.g.) 1 ¹H NMR was recorded using a Varian Mercury-400 or -600 NMR spectrometer, and mass spectrometry was recorded using a Finnigan / MAT-95 (EI) and Finnigan LCQ / DECA and Micromass Ultra Q-TOF (ESI) mass spectrometers; reversed-phase preparative HPLC separation used 200-300 mesh silica gel. Chemical shifts are expressed as δ (ppm); SFC purification method: Column: Chiralpak IG 250mm*4.6mm 5um, mobile phase: Hexane-EtOH, 30℃.

[0189] The following is a list of Chinese names for reagents represented by chemical formulas or English letter abbreviations:

[0190] AcOH: Acetic acid; DCM: Dichloromethane; PE: Petroleum ether; EA: Ethyl acetate; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; TFA: Trifluoroacetic acid; TEA: Triethylamine; DIEA: N,N-Diisopropylethylamine; ACN: Acetonitrile; DBAD: Dibenzyl azodicarboxylate; KOAc: Potassium acetate; NIS: N-Iodosuccinimide; LiHMDS: Lithium hexamethyldisilane diazodicarbonyl; Pd(PPh3)4: Tetraphenylphosphine palladium; Pd(PPh3)2Cl2: Di(triphenylphosphine)palladium dichloride; Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride; DCC: 1,3-Dicyclohexylcarbodiimide; MTBE: Methyl tert-butyl ether; EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride; HOBt: 1-hydroxybenzotriazole; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; TMAD: azodicarbonamide; T3P: propylphosphoric anhydride; TBAF: tetrabutylammonium fluoride; NMI: N-methylimidazolium; TCFH: tetramethylchlorourea hexafluorophosphate; Xphos: 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl; MsCl: methanesulfonyl chloride; TBS: triethanolamine; TBS-Cl: tert-butyldimethylchlorosilane; CbzCl: benzyl chloroformate; DIBAL-H: diisobutylaluminum hydride; dioxane: 1,4-dioxane; RT: retention time; LCMS: liquid chromatography-mass spectrometry.

[0191] Synthesis of key intermediates

[0192] intermediate Int-A-1

[0193]

[0194] 5-Iodopyrimidine-2-amine (600 mg, 2.71 mmol), PdCl2(PPh3)2 (54 mg, 0.27 mmol), and CuI (192 mg, 0.27 mmol) were dissolved in a solvent (ACN / TEA = 10 / 1) (10 mL). Ethynyltrimethylsilane (588 mg, 5.97 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction solution was diluted with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel flash (PE / EA = 5 / 1) to give a yellow solid Int-A-1 (400 mg, yield: 77%). 1 H NMR (400MHz, DMSO-d6) δ8.32(s,2H),7.13(s,2H),0.21(s,9H).

[0195] By replacing Int-A-1-a in the above synthetic route with the corresponding raw materials, the following intermediates can be synthesized:

[0196]

[0197] Synthesis of intermediates Int-A-13 to Int-A-33

[0198]

[0199] Step 1

[0200] Compound A-0 (2.07 g, 10 mmol) was dissolved in NH3 / i-PrOH (150 mmol, 50 mL), and the solution was stirred at 100 °C for 12 h in a sealed tube. After cooling to room temperature, the solution was filtered, washed with PE, and air-dried to give Int-A-13-a (1.7 g, yield: 90%). LCMS (ESI) m / z = 188.0 [M+H] + .

[0201] Step 2:

[0202] Int-A-13-a (1.15 g, 6.127 mmol) was dissolved in DMF (20 mL), and ethynyltrimethylsilane (1.8 g, 18.38 mmol), Pd(PPh2)Cl2 (430 mg, 0.61 mmol), CuI (116 mg, 0.61 mmol), and TEA (1.856 g, 1838 mmol) were added. The mixture was stirred at 100 °C for 12 h. The reaction solution was purified by column chromatography to obtain Int-A-13-b (700 mg, yield: 55.7%). LCMS (ESI) m / z = 206.1 [M+H] + .

[0203] Step 3:

[0204] Int-A-13-b (410 mg, 2 mmol) and potassium carbonate (2.21 g, 16 mmol) were dissolved in methanol (25 mL) and stirred overnight at room temperature. The reaction mixture was purified by column chromatography to give Int-A-13 (160 mg, yield: 60.15%). LCMS (ESI) m / z = 134.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.22 (d, J = 7.2Hz, 1H), 6.97 (s, 2H), 4.36 (s, 1H), 2.33 (s, 3H).

[0205] By substituting the raw materials A-0 and ammonia in step 1 of the above synthetic route, the following intermediates can be synthesized:

[0206]

[0207]

[0208] Intermediate Int-A-34

[0209]

[0210] Step 1:

[0211] Compound 871014-19-6 (2.50 g, 13.44 mmol) was dissolved in DCM (50 mL), and formaldehyde aqueous solution (2.69 g, 26.88 mmol), NaBH(AcO)3 (4.27 g, 20.16 mmol), and AcOH (0.91 g, 13.44 mmol) were added. The mixture was stirred at room temperature for 12 h. A saturated NaHCO3 aqueous solution (50 mL) was added, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a crude, colorless, oily product, Int-A-34-a (1.00 g, yield: 35%). LCMS (ESI) m / z = 215.3 [M+H] + .

[0212] Step 2:

[0213] Int-A-34-a (1.00 g, 4.67 mmol) was dissolved in DCM (10 mL), and 10 mL of 4 M 1,4-dioxane hydrochloride solution was added. The mixture was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure until dry to give crude white solid Int-A-34-b (0.35 g, yield: 66%). LCMS (ESI) m / z = 115.2 [M+H] + .

[0214] Step 3:

[0215] Int-A-34-b (0.35 g, 3.07 mmol) was dissolved in isopropanol (15 mL), and compound 32779-38-7 (0.74 g, 3.07 mmol) and DIEA (1.98 g, 15.35 mmol) were added. The mixture was stirred at 70 °C for 12 h. Water (30 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give a pale yellow solid Int-A-34-c (0.35 g, yield: 36%). LCMS (ESI) m / z = 319.0 [M+H] + .

[0216] Step 4:

[0217] Int-A-34-c (0.35 g, 1.10 mmol) was dissolved in DMF (5 mL), and compound 1066-54-2 (0.32 g, 3.30 mmol), Pd(PPh)₂Cl₂ (71 mg, 0.11 mmol), CuI (20.9 mg, 0.11 mmol), and TEA (0.33 g, 3.30 mmol) were added. The mixture was stirred at 80 °C for 12 h under Ar protection. The reaction solution was purified by column chromatography (PE / EA = 1 / 100–1 / 9, DCM / MeOH = 10 / 1) to give a brown solid Int-A-34-d (0.27 g, yield: 85%). LCMS (ESI) m / z = 289.2 [M+H] + .

[0218] Step 5:

[0219] Int-A-34-d (0.35 g, 0.94 mmol) was dissolved in MeOH (5 mL), and K₂CO₃ (0.39 g, 2.81 mmol) was added. The mixture was stirred at room temperature for 5 h. Water (30 mL) was added, and the mixture was extracted with DCM / MeOH (10 / 1). The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9, DCM / MeOH = 10 / 1) to give a brown solid Int-A-34 (0.17 g, yield: 84%). LCMS (ESI) m / z = 217.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.38(s,2H),8.02-8.01(m,1H),4.24(s,1H),2.88-2.81(m,1H),2.24-2.20(m,2H),2.10(s,6H),2.08-2.04(m,3H).

[0220] Referring to the synthesis of intermediate Int-A-34, the following intermediates can be synthesized:

[0221]

[0222] Intermediate Int-A-37

[0223]

[0224] Step 1:

[0225] Compounds 398489-26-4 (1.0 g, 5.41 mmol) and 123-75-1 (383 mg, 5.41 mmol) were dissolved in 20 mL of DCM; sodium borohydride acetate (2.29 g, 10.82 mmol) and 0.5 mL of acetic acid were added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water. The mixture was extracted with DCM / MeOH (20 / 1), and the organic phase was dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to give crude Int-A-37-a, which was used directly in the next step.

[0226] Step 2:

[0227] Crude Int-A-37-a was dissolved in methanol (15 mL), and then a hydrochloric acid / dioxane solution (4 M, 5 mL) was added. The mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated to obtain crude Int-A-37-b.

[0228] Step 3:

[0229] Int-A-37-b (crude), compound 32779-38-7 (2.29 g, 5.41 mmol), and DIEA (3.49 g, 27.05 mmol) were dissolved in isopropanol (20 mL) and reacted overnight at 70 °C. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography (DCM / MeOH (15 / 1)) to give Int-A-37-c (250 mg, overall yield of 13.4% in 3 steps). LCMS (ESI) m / z = 345.1 [M+H] + .

[0230] Step 4:

[0231] Int-A-37 (yellow solid) was synthesized using the same method as intermediate Int-A-34. LCMS(ESI): m / z 243.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 2H), 7.98 (d, J = 6.8Hz, 1H), 4.44-4.35 (m, 1H), 4.23 (s, 1H),2.85(s,1H),2.38(brs,4H),2.26-2.20(m,2H),2.08-2.01(m,2H),1.69(brs,4H).

[0232] Referring to the synthesis of intermediate Int-A-37, the following intermediates can be synthesized:

[0233]

[0234]

[0235] intermediate Int-B-1

[0236]

[0237] Step 1:

[0238] Compound 1 (57.0 g, 176.5 mmol) and DCC (37.09 g, 180.3 mmol) were dissolved in DCM (500 mL). Compound 2 (34.06 g, 176.5 mmol) was added under ice bath conditions. The mixture was stirred overnight at room temperature, filtered, and the filter cake was washed with DCM (100 mL). The filtrate was concentrated to dryness, and MTBE (300 mL) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with MTBE. The filtrate was concentrated to give a colorless oily substance 3 (87.0 g, yield: 99%). LCMS (ESI) m / z = 521.3 [M + Na] + .

[0239] Step 2:

[0240] Compound 3 (87.0 g, 174.3 mmol) was dissolved in DCM (240 mL), and TFA (120 mL) was slowly added. The mixture was stirred at room temperature for 12 h, and then concentrated to dryness to give crude, pale yellow oil 4 (87.0 g, yield: 97%). LCMS (ESI) m / z = 610.1 [M+H] + .

[0241] Step 3:

[0242] Crude product 4 (87.0 g, 170 mmol) was dissolved in isopropanol (250 mL), stirred at 80 °C for 1 h, concentrated, and water (200 mL) was added. The pH was adjusted to 8-9 with 15% NaOH aqueous solution, extracted with DCM, dried over anhydrous Na₂SO₄, concentrated, and slurried in PE / EA (5 / 1, 500 mL). Filtration yielded white solid 5 (45.76 g, yield: 77%). LCMS (ESI) m / z = 353.2 [M+H] + .

[0243] Step 4:

[0244] LiAlH4 (11.86 g, 312.0 mmol) was dissolved in THF (300 mL). A THF (300 mL) solution containing compound 5 (45.76 g, 130 mmol) was slowly added dropwise under ice bath conditions. The addition was completed after 1 hour, and the temperature was slowly raised to 65 °C with stirring for 1 hour. After cooling to room temperature, water (11.86 g), 15% NaOH aqueous solution (11.86 g), and water (35.58 g) were slowly added under ice bath conditions. A large amount of solid precipitate formed. The precipitate was removed by filtration, washed with THF (100 mL), concentrated, and then HCl aqueous solution (2 M, 200 mL) was added. The solution was washed with EA, and the pH was adjusted to 11–12 with 15% NaOH aqueous solution. The mixture was extracted with DCM, dried over anhydrous Na2SO4, concentrated, and slurried in PE / EA (5 / 1, 300 mL). The mixture was filtered to obtain a white solid 6 (20.0 g, yield: 70%). LCMS(ESI)m / z=221.2[M+H] + .

[0245] Step 5:

[0246] Compound 6 (20.0 g, 90.9 mmol) was dissolved in DCM (200 mL), and TEA (18.36 g, 181.8 mmol) and Boc₂O (29.73 g, 136.4 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was diluted with water, extracted with DCM, and the organic phase was dried over anhydrous Na₂SO₄. The solution was concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to give a colorless oily substance 7 (26.0 g, yield: 89%). LCMS (ESI) m / z = 321.2 [M+H] + .

[0247] Step 6:

[0248] Compound 7 (26.0 g, 81.3 mmol) was dissolved in MeOH (200 mL), and Pd(OH)₂ / C (2.60 g) was added. The mixture was stirred at 50 °C for 12 h under hydrogen atmosphere. The solid was removed by filtration, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give a colorless oily substance, Int-B-1 (18.0 g, yield: 96%). LCMS (ESI) m / z = 231.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ4.38(brs,1H),4.09(brs,1H),3.94(s,1H),3.62(d,J=12.6Hz,1H),3.93-3.32(m,2H), 2.78-2.72(m,3H),2.58(dd,J=12.6,4.2Hz,1H),2.58(td,J=4.2,12.6Hz,1H),1.81-1.73(m,2H),1.37(s,9H).

[0249] intermediate Int-B-2

[0250]

[0251] Step 1:

[0252] Compound 1 (16.0 g, 45.54 mmol) was dissolved in DMF (100 mL), and K2CO was added under ice bath conditions. 3( 13.7 g (99.07 mmol) and MeI (10.6 g, 74.3 mmol) were stirred at room temperature for 12 h, water (500 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give a yellow solid 2 (8.50 g, yield: 55%). LCMS (ESI) m / z = 360.2 [M + Na] + .

[0253] Step 2:

[0254] Compound 2 (4.50 g, 13.4 mmol) was dissolved in THF (100 mL), and LiHMDS (66.8 mL, 66.8 mmol) was slowly added dropwise at -78 °C. After 1 h, MeI (7.58 g, 53.4 mmol) was slowly added, and the mixture was stirred at room temperature for 3 h. A saturated NH4Cl aqueous solution (100 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to give a yellow solid 3 (4.20 g, yield: 86%). LCMS (ESI) m / z = 388.2 [M + Na]. + .

[0255] Step 3:

[0256] Compound 3 (4.20 g, 11.5 mmol) was dissolved in ACN (60 mL) and water (1.2 mL). TEA (11.6 g, 115.1 mmol) and LiBr (2.97 g, 34.5 mmol) were added under ice bath conditions. The mixture was stirred at room temperature for 3 days. Water (50 mL) was added, and the pH was adjusted to 3-5 with 2 M HCl aqueous solution. Extraction was performed using EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude white solid 4 (3.50 g, yield: 87%). LCMS (ESI) m / z = 374.2 [M + Na]. + .

[0257] Step 4:

[0258] Compound 4 (3.50 g, 9.97 mmol) and DCC (2.10 g, 10.2 mmol) were dissolved in DCM (50 mL). Compound 5 (1.92 g, 9.97 mmol) was added under ice bath conditions. The mixture was stirred overnight at room temperature. The white solid was removed by filtration. The filter cake was washed with DCM (20 mL). The filtrate was concentrated to dryness. MTBE (300 mL) was added and stirred for 30 minutes. The white solid was removed by filtration. The filter cake was washed with MTBE (100 mL) and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give white solid 6 (2.60 g, yield: 50%). LCMS (ESI) m / z = 549.3 [M + Na] + .

[0259] Step 5:

[0260] Compound 6 (2.60 g, 4.94 mmol) was dissolved in DCM (20 mL), and TFA (10 mL) was slowly added. The mixture was stirred at room temperature for 3 h, and then concentrated to dryness to give crude, pale yellow oil 7 (2.10 g, yield: 99%). LCMS (ESI) m / z = 427.4 [M+H] + .

[0261] Step 6:

[0262] Crude product 7 (2.10 g, 4.93 mmol) was dissolved in isopropanol (30 mL), stirred at 80 °C for 1 h, the reaction solution was concentrated, water (20 mL) was added, the pH was adjusted to 8–9 with 15% NaOH, extracted with DCM, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to give white solid 8 (1.80 g, yield: 96%). LCMS (ESI) m / z = 381.3 [M+H] + .

[0263] Step 7:

[0264] LiAlH 4( 0.43 g (11.4 mmol) was dissolved in 20 mL of THF. A 20 mL solution of THF containing compound 8 (1.80 g, 4.74 mmol) was slowly added dropwise under ice bath conditions. The mixture was brought to room temperature and stirred at 65°C for 1 h. After cooling to room temperature, water (0.43 g), 15% NaOH aqueous solution (0.43 g), and water (1.30 g) were slowly added under ice bath conditions. A large amount of solid precipitate formed. The precipitate was removed by filtration, washed with 20 mL of THF, concentrated, and then washed with 2 M HCl aqueous solution (20 mL). The solution was washed with EA, and the pH was adjusted to 11–12 with 15% NaOH aqueous solution. Extraction was performed using DCM, and the organic phase was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to give a white solid 9 (1.10 g, yield: 94%). LCMS(ESI)m / z = 249.3[M+H] + .

[0265] Step 8:

[0266] Compound 9 (1.10 g, 4.44 mmol) was dissolved in DCM (20 mL), and TEA (0.90 g, 8.87 mmol) and Boc₂O (1.45 g, 6.65 mmol) were added. The mixture was stirred at room temperature for 12 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM. The organic phase was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give a colorless oily substance 10 (1.10 g, yield: 71%). LCMS (ESI) m / z = 349.2 [M + H] + .

[0267] Step 9:

[0268] Compound 10 (1.10 g, 3.16 mmol) was dissolved in MeOH (20 mL), and Pd(OH)₂ / C (0.11 g) was added under an argon atmosphere. After the addition was complete, the mixture was stirred at 50 °C for 12 h under a hydrogen atmosphere. The solid was removed by filtration, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure until dry to give a colorless oily Int-B-2 (0.70 g, yield: 66%). LCMS (ESI) m / z = 259.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ4.03-3.74(m,2H),3.44-3.38(m,1H),3.17-2.78(m,5H),2.45-2.37(m,2H),1.39(s,9H),0.93-0.78(m,6H).

[0269] intermediate S-Int-B-3

[0270]

[0271] Step 1:

[0272] Int-B-1 (2.3 g, 10 mmol) was dissolved in DCM (50 mL), and then TEA (2.02 g, 20 mmol) was added. Cb2Cl (1.87 g, 11 mmol) was added dropwise under ice bath conditions, and the reaction was allowed to proceed overnight after slowly raising the temperature to room temperature. After adding water, the mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain Int-B-3-a (2.4 g, yield: 66%).

[0273] Step 2:

[0274] Oxaloyl chloride (6.8 g, 53.5 mmol) was dissolved in DCM (120 mL), cooled to -78 °C, and then DMSO (8.35 g, 107 mmol) was slowly added dropwise, keeping the temperature below -60 °C. After the addition was complete, the mixture was stirred for 0.5 h. Then, Int-B-3-a (13 g, 35 mmol) was slowly added dropwise in DCM, again keeping the temperature below -60 °C. After the addition was complete, the mixture was stirred for 1 h. Then, TEA (17.6 g, 175 mmol) was added dropwise, and after the addition was complete, the mixture was stirred for 1 h, keeping the temperature below -60 °C. The reaction was quenched with water at approximately -10 °C. The mixture was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain Int-B-3-b (10 g, yield: 77%).

[0275] Step 3:

[0276] Int-B-3-b (3.2 g, 8.84 mmol) was dissolved in THF (50 mL), cooled to -78 °C, and then a THF solution of methyl magnesium chloride (88 mL, 88 mmol) was slowly added dropwise. After stirring for 1 h, the reaction was quenched with an aqueous solution of saturated ammonium chloride. The mixture was filtered, and the filter cake was washed with EA. The filtrate was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (PE:EA = 0–50%) to give R-Int-B-3-c and S-Int-B-3-c as white solids (1.00 g, yield: 30%). S-Int-B-3:LCMS(ESI) m / z = 379.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ4.19-4.25(m,1H),5.10-5.17(m,2H),3.77-4.29(m,5 H),2.87-3.03(m,3H),2.04(brs,1H),1.47-1.65(m,2H),0.56-1.64(m,3H).

[0277] Step 4:

[0278] S-Int-B-3-c (1.00 g, 2.65 mmol) was dissolved in MeOH (20 mL), and Pd / C (60 mg) was added. The mixture was stirred at 50 °C for 12 h under a hydrogen atmosphere. The solid was removed by filtration, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure until dry to obtain a white solid S-Int-B-3 (0.58 g, yield: 90%). LCMS (ESI) m / z = 245.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ4.03-3.74(m,2H),3.90-3.96(m,2H),3.10-3.16(m,1H),2.85-2.98(m,4 H),2.14-2.17(m,1H),1.96-2.02(m,2H),1.64(m,1H),1.47(s,9H),1.19-1.21(d,J=6.0Hz,3H).

[0279] intermediate Int-B-4

[0280]

[0281] Step 1:

[0282] Compound 1 (57.0 g, 176.5 mmol) and DCC (37.09 g, 180.3 mmol) were dissolved in DCM (500 mL). Compound 2 (34.06 g, 176.5 mmol) was added under ice bath conditions, and the mixture was stirred overnight at room temperature. The white solid was removed by filtration. The filter cake was washed with DCM (100 mL), and the filtrate was concentrated to dryness. MTBE (300 mL) was added, and the mixture was stirred for 30 minutes. The white solid was removed by filtration, and the filter cake was washed with MTBE. The filtrate was concentrated to give a colorless oily substance 3 (87.0 g, yield: 99%). LCMS (ESI) m / z = 413.3 [M+H] + .

[0283] Step 2:

[0284] TFA (120 mL) was slowly added to compound 3 (87.0 g, 174.3 mmol) in DCM (240 mL), and the mixture was stirred at room temperature for 12 h. The solution was concentrated to dryness to give crude, pale yellow oil 4 (87.0 g, yield: 97.3%). LCMS (ESI) m / z = 413.3 [M+H] + .

[0285] Step 3:

[0286] Crude product 4 (87.0 g, 170 mmol) was dissolved in isopropanol (250 mL) and stirred at 80 °C for 1 h. The reaction solution was concentrated, water (200 mL) was added, and the pH was adjusted to 8–9 with 15% NaOH aqueous solution. Extraction was performed using DCM, and the product was dried over anhydrous Na₂SO₄. The solution was concentrated, slurried in PE / EA (5 / 1, 500 mL), and filtered to obtain white solid 5 (45.76 g, yield: 76.5%). LCMS (ESI) m / z = 367.2 [M+H] + .

[0287] Step 4:

[0288] LiAlH4 (11.86 g, 312.0 mmol) was dissolved in THF (300 mL). A THF (300 mL) solution containing compound 5 (45.76 g, 130 mmol) was slowly added dropwise under ice bath conditions. The addition was completed after 1 hour, and the mixture was allowed to return to room temperature. The mixture was then stirred at 65°C for 1 hour. After cooling to room temperature, water (11.86 g), 15% NaOH aqueous solution (11.86 g), and water (35.58 g) were slowly added under ice bath conditions. A large amount of solid precipitate formed. The precipitate was removed by filtration, washed with THF (100 mL), concentrated, and then HCl aqueous solution (2 M, 200 mL) was added. The mixture was washed with EA, and the pH was adjusted to 11-12 with 15% NaOH aqueous solution. The mixture was extracted with DCM, dried over anhydrous Na2SO4, concentrated, and slurried in PE / EA (5 / 1, 300 mL). The mixture was filtered to obtain a white solid 6 (20.0 g, yield: 69.9%). LCMS(ESI)m / z = 235.3[M+H] + .

[0289] Step 5:

[0290] Compound 6 (20.0 g, 90.9 mmol) was dissolved in DCM (200 mL), and TEA (18.36 g, 181.8 mmol) and Boc₂O (29.73 g, 136.4 mmol) were added. The mixture was stirred at room temperature for 12 h. Water (200 mL) was added to the reaction solution, and the mixture was extracted with DCM. The organic phase was dried over anhydrous Na₂SO₄, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to give a colorless oily substance 7 (26.0 g, yield: 89.4%). LCMS (ESI) m / z = 335.3 M + H⁺ + .

[0291] Step 6:

[0292] Compound 7 (26.0 g, 81.3 mmol) was dissolved in MeOH (200 mL), and Pd(OH)₂ / C (2.60 g) was added under Ar protection. The mixture was stirred at 50 °C for 12 h under H₂ atmosphere. The solid was removed by filtration, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure until dry to give a colorless oily compound Int-B-4 (18.0 g, yield: 96.3%). LCMS (ESI) m / z = 245.3 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ3.82 (s, 1H), 3.62 (d, J = 13.4Hz, 1H), 3.39 (t, J = 6.6Hz, 2H), 2.91 (dd, J = 8.0, 5.5Hz,1H),2.74(m,3H),2.58(m,1H),2.40(m,1H),1.74-1.66(m,1H),1.62-1.48(m,2H),1.38(s,9H).

[0293] intermediate Int-C-1

[0294]

[0295] Step 1:

[0296] Compound 1 (2.33 g, 10 mmol) and vinyl borate (4.62 g, 30 mmol) were dissolved in 1,4-dioxane (60 mL) and water (15 mL). Pd(PPh3)4 (1.154 g, 1 mmol) and K3PO4 (4.24 g, 20 mmol) were added, and the mixture was stirred at 100 °C for 12 h. After filtration, the mixture was washed with EA, concentrated, and purified by column chromatography to give compound 2 (1.5 g, yield: 83%). LCMS (ESI) m / z = 181.1 [M+H] + .

[0297] Step 2:

[0298] Compound 2 (1.5 g, 8.33 mmol) was dissolved in methanol (40 mL), and Pd / C (150 mg) was added under argon protection. The mixture was stirred at room temperature for 12 h under H2 atmosphere, filtered, and the filtrate was concentrated to give a white solid 3 (1.4 g, yield: 92%). LCMS (ESI) m / z = 383.1 [M+H] + .

[0299] Step 3:

[0300] Compound 3 (1.3 g, 7.22 mmol) was dissolved in sulfuric acid (10 mL), and NIS (1.71 g, 7.58 mmol) was added under ice bath conditions, with stirring for 2 h. The reaction was quenched with an ice-water solution of saturated sodium sulfite, extracted with EA, and the organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography to give Int-C-1 (2 g, yield: 89%). LCMS (ESI) m / z = 309.1 [M+H] + .

[0301] intermediate Int-C-2

[0302]

[0303] Step 1:

[0304] Compound 1 (6 g, 39 mmol), 50 mL of methanol, and concentrated sulfuric acid (193 mg, 1.97 mmol) were heated under reflux for 24 h. The reaction solution was concentrated, and the residue was purified by column chromatography to give compound 2 (6.2 g, yield: 95%).

[0305] Step 2:

[0306] Compound 2 (1.6 g) was dissolved in 20 mL of methanol, and NaI (1.73 g) and NaOH (0.46 mg) were added. The reaction solution was cooled to 0 °C, and 7.5% sodium hypochlorite solution (11.5 g) was added dropwise. The reaction was carried out at 0 °C for 4 h. The pH was adjusted to 5-6 with 1 M hydrochloric acid, and 30 mL of saturated sodium thiosulfate aqueous solution was added. The mixture was stirred for 0.5 h. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by column chromatography to give compound 3 (2.2 g, yield: 78%). 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.89(d,J=2.2Hz,1H),7.76(d,J=2.0Hz,1H),3.91(s,3H),2.17(s,3H).

[0307] Example 1: Synthesis of Compound A-1

[0308]

[0309] Step 1:

[0310] A-1-0 (2.0 g, 9.6 mmol), compound 4606-65-9 (1.1 g, 9.6 mmol), and NaHCO3 (2.0 g, 23.8 mmol) were added to THF (35 mL), and the mixture was stirred at 70 °C for 3 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude A-1-a (2.3 g, yellow solid, 80% yield). LCMS (ESI): m / z = 305.1 [M+H] + .

[0311] Step 2 :

[0312] A-1-a (2.0 g) and Pd / C (0.2 g) were added to MeOH (20 mL) and stirred overnight at 30 °C under a hydrogen atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography to obtain A-1-b (1.4 g, orange oil, 80% yield). LCMS (ESI): m / z = 275 [M+H] + .

[0313] Step 3:

[0314] A-1-b (274 mg, 1 mmol), compound 4068-75-1 (278 mg, 1 mmol), DEAD (348 mg, 2 mmol), and PPh3 (524 mg, 2 mmol) were dissolved in THF (4 mL) and stirred at room temperature for 2 h. The reaction mixture was then diluted with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography (PE / EA = 10 / 1-1 / 1) to give A-1-c (500 mg, yield 394%, yellow oil). LCMS (ESI): m / z = 535 [M+H] + .

[0315] Step 4:

[0316] A-1-c (500 mg, 1 mmol) and LiOH-H2O (84 mg, 2 mmol) were dissolved in MeOH / THF / H2O (4 mL / 4 mL / 2 mL), and reacted at 40 °C for 2 h. The pH of the reaction solution was adjusted to approximately 5 with 2N HCl, and the mixture was extracted with DCM. The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain A-1-d (380 mg, yield 73%, yellow oil). LCMS (ESI): m / z = 521 [M+H] + .

[0317] Step 5:

[0318] A-1-d (300 mg) and T3P (1.5 mL) were dissolved in pyridine (4 mL) and reacted at 40 °C for 2 h. The reaction mixture was then added to 2N HCl (10 mL), extracted with DCM, and the organic phase was concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain A-1-e (150 mg, yield 51%). LCMS (ESI): m / z = 503 [M+H] + .

[0319] Step 6:

[0320] Add A-1-e (47mg, 0.1mmol), Int-A-1 (24mg, 0.2mmol), CuI (6mg, 0.03mmol), Pd(PPh3)2Cl 2( 5 mg (0.07 mmol) and DBU (0.5 mL) were dissolved in ACN / TEA (2.5 mL / 1 mL), and stirred at 80 °C for 2 h under nitrogen protection. The solution was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified to obtain A-1 (2.9 mg, yield 6%). LCMS (ESI): m / z = 494 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.46(s,2H),8.37(s,1H),7.87(s,1H),7.70(d,J=7.6Hz,1H),7.53-7.41(m,2H),7.33(d,J=7.4Hz,1H), 7.15(s,2H),4.52-4.58(m,2H),3.54-3.57(m,1H),3.06-3.19(d,J=13. 0Hz,2H),2.60-2.63(d,J=11.8Hz,1H),2.35(m,1H),1.68-1.88(m,4H).

[0321] Example 2 Synthesis of compound A-2

[0322]

[0323] Step 1:

[0324] A-2-1 (3.0 g, 15 mmol) and A-2-2 (1.20 g, 18 mmol) were dissolved in DCM (20 mL), and sodium borohydride acetate (4.5 g, 21.2 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain A-2-a (crude product). LCMS (ESI): m / z = 245.1 [M+H] + .

[0325] Step 2:

[0326] A-2-a (7 g) was dissolved in DCM (30 mL), and TFA (25 mL) was added. The mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain crude A-2-b (2.17 g). LCMS (ESI): m / z = 144.1 [M+H] + .

[0327] Step 3:

[0328] A-2-b (2 g, 13.8 mmol, crude), A-2-3 (1.94 g, 9.28 mmol), and K₂CO₃ (3.8 g, 27.5 mmol) were added to THF (25 mL), and the mixture was stirred at 80 °C for 3.5 h. The reaction solution was then extracted with saturated ammonium chloride aqueous solution using EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 1 / 1 to 100% EA) to obtain A-2-c (3.3 g, brown oil, crude). LCMS (ESI): m / z = 334.1 [M+H] + .

[0329] Step 4:

[0330] A-2-c (1 g, 2.99 mmol), Boc₂O (980 mg, 4.49 mmol), and potassium carbonate (454 mg, 3.28 mmol) were added to THF (20 mL) under ice bath conditions and stirred overnight at room temperature. The reaction mixture was then extracted with saturated ammonium chloride solution using EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give A-2-d (1.32 g, yellow oil, crude product). LCMS (ESI): m / z = 434.1 [M+H] + .

[0331] Step 5:

[0332] Add 1.3 g of A-2-d to 20 mL of MeOH, then add 130 mg of Pd / C. Stir overnight at 35 °C under a hydrogen atmosphere (1 atm). Filter the reaction mixture, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE / EA = 3 / 1) to obtain A-2-e, a yellow oil (500 mg, yield: 34%). LCMS (ESI): m / z = 404.2 [M+H] + .

[0333] Step 6:

[0334] A-2-e (220 mg, 0.545 mmol), A-2-4 (228 mg, 0.82 mmol), TMAD (235 mg, 1.37 mmol), and n-Bu3P (276 mg, 1.37 mmol) were dissolved in THF (8 mL) and stirred at 60 °C for 5 h. The reaction mixture was then extracted with saturated ammonium chloride aqueous solution using EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1) to obtain A-2-f, a yellow solid (230 mg, yield 44%). LCMS (ESI): m / z = 664.1 [M+H] + .

[0335] Step 7:

[0336] A-2-f (230 mg, 0.35 mmol) and LiOH-H2O (44 mg, 1 mmol) were dissolved in MeOH / H2O / THF (1 mL / 1 mL / 3 mL) and stirred overnight at 35 °C. The reaction solution was concentrated under reduced pressure, diluted with DCM, and the pH was adjusted to 3 at 0 °C with 1 N dilute hydrochloric acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude A-2-g, a yellow solid (220 mg, 99% yield). LCMS (ESI): m / z = 650.1 [M+H] + .

[0337] Step 8:

[0338] A-2-g (100 mg, 0.15 mmol) and T3P (0.75 mL, 0.375 mmol) were dissolved sequentially in pyridine (6 mL) and stirred at 40 °C for 6 h. The solution was diluted with saturated ammonium chloride aqueous solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 2 / 1) to obtain A-2-h, a yellow oil (70 mg, 60% yield). LCMS (ESI): m / z = 632.1 [M+H] + .

[0339] Step 9:

[0340] A-2-h (70 mg, 0.11 mmol), Int-A-1 (53 mg, 0.44 mmol), CuI (2.5 mg, 0.011 mmol), Pd(PPh3)2Cl2 (8 mg, 0.011 mmol), and DBU (0.5 mL) were added to ACN / TEA (5 mL / 1 mL), and stirred at 85 °C for 8 h under a nitrogen atmosphere. A saturated ammonium chloride aqueous solution was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The purified solution yielded a white solid A-2-i (27 mg, 39% yield). LCMS (ESI): m / z = 623.3 [M+H] + .

[0341] Step 10:

[0342] A-2-i (27 mg) was dissolved in 1,4-dioxane (2 mL), and HCl (3.5 mL, 4 mol / L dioxane solution) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was then concentrated under reduced pressure to give a yellow solid A-2 (24.9 mg, 100% yield). LCMS (ESI): m / z = 523.1 [M+H] + .

[0343] Example 3 Synthesis of compound A-3

[0344]

[0345] Step 1:

[0346] Compound 367-86-2 (500 mg, 1.44 mmol), compound 1030377-21-9 (465 mg, 2.15 mmol), and K2CO3 (593 mg, 4.30 mmol) were added to 10 mL of THF. The mixture was stirred at 70 °C for 3 h, concentrated under reduced pressure, and the crude product was purified by column chromatography to give A-3-a, a yellow solid (560 mg, 96% yield). LCMS (ESI): m / z = 406.2 [M+H] + .

[0347] Step 2:

[0348] A-3-a (560 mg, 1.38 mmol) and Pd / C (230 mg) were added to MeOH (10 mL), and stirred for 5 h at room temperature under hydrogen protection. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain A-3-b, a colorless oil (500 mg, yield: 95%). LCMS (ESI): m / z = 376.2 [M+H] + .

[0349] Step 3:

[0350] A-3-b (400 mg, 1.06 mmol), compound 4068-75-1 (297 mg, 1.06 mmol), DBAD (369 mg, 2.12 mmol), PPh3 (556 mg, 2.12 mmol), and toluene (20 mL) were reacted overnight at 90 °C. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Further purification yielded A-3-c (200 mg, 24% yield). LCMS (ESI): m / z = 636.1 [M+H] + .

[0351] Step 4:

[0352] A-3-c (200 mg, 0.31 mmol) and LiOH·H₂O (80 mg, 0.62 mmol) were dissolved in MeOH / THF (15 mL / 5 mL) and H₂O (7 mL), and reacted at 40 °C for 2 h. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. A-3-d (110 mg, 40% yield) was then purified to obtain the crude product. LCMS (ESI): m / z = 622.2 [M+H] + .

[0353] Step 5:

[0354] A-3-d (100 mg, 0.16 mmol) and T3P (2 mL) were dissolved in pyridine (5 mL) and reacted at 40 °C for 2 h. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. A-3-e (60 mg, yield 57%) was obtained through preparative purification. LCMS (ESI): m / z = 604.1 [M+H] + .

[0355] Step 6:

[0356] A-3-e (40 mg, 0.07 mmol), Int-A-1 (32 mg, 0.26 mmol), CuI (10 mg, 0.035 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol), and DBU (0.5 mL) were dissolved in ACN / TEA (4 mL / 1 mL) and reacted overnight at 70 °C under nitrogen protection. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, a crude product was obtained, which was then purified to give A-3-f (48 mg, 99% yield). LCMS (ESI): m / z = 595.2 [M+H] + .

[0357] Step 7:

[0358] A-3-f (48 mg) was dissolved in HCl / 1,4-dioxane (5 mL) in 1,4-dioxane (5 mL), and the reaction was carried out at room temperature for 4 h. The reaction solution was extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. A-3 (13.7 mg, yield 35%) was obtained through preparative purification. LCMS (ESI): m / z = 495.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.47(s,1H),8.45(s,2H),8.35(d,J=2.2Hz,1H),7.90(d,J= 2.3Hz,1H),7.69(dd,J=8.4,2.3Hz,1H),7.52-7.44(m,2H),7.33(d,J=8.2Hz,1H),7.15 (s,2H),4.60(t,J=8.7Hz,1H),4.52(dd,J=8.8,6.4Hz,1H),3.48(d,J=12.3Hz,1H),3.3 8-3.36(m,1H),3.10(d,J=8.3Hz,2H),2.85(dd,J=17.6,8.0Hz,2H),2.66-2.63(m,1H).

[0359] Example 4 Synthesis of compound A-4

[0360] The synthesis of compound A-4 is the same as that of compound A-3. The difference is that compound 1030377-21-9 in the synthetic route of compound A-3 is replaced with the starting materials shown in the table below.

[0361]

[0362] Example 5 Synthesis of Compound A-5

[0363]

[0364] Step 1:

[0365] A-5-a (2.5 g, 13.15 mmol) and compound 454-81-9 (3.49 g, 19.74 mmol) were dissolved in toluene (25 mL), and PPh3 (5.13 g, 19.74 mmol) and DBAD (3.43 g, 14.9 mmol) were added. The reaction mixture was reacted at 100 °C for 6 h under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography to give A-5-b, a red oil (1.34 g, yield: 37%). LCMS (ESI): m / z = 350 [M+H] + .

[0366] Step 2:

[0367] A-5-b (1.3 g, 3.72 mmol) was dissolved in THF (20 mL), and TBAF (11.1 mL, 11.14 mmol) was added at 0 °C. The reaction mixture was reacted at 0 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, then extracted with EA. The organic phase was backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography yielded A-5-c, a brown solid (590 mg, yield: 67%). LCMS (ESI): m / z = 236 [M+H] + .

[0368] Step 3:

[0369] A-5-c (560 mg, 2.38 mmol) and compound 4068-75-1 (993.7 mg, 3.57 mmol) were dissolved in toluene (15 mL), followed by the addition of PPh3 (822.1 mg, 3.57 mmol) and DBAD (936.5 mg, 3.57 mmol). The reaction mixture was reacted at 100 °C for 6 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to give A-5-d, a red oil (575 mg, yield: 52%). LCMS (ESI): m / z = 496 [M+H] + .

[0370] Step 4:

[0371] A-5-d (575 mg, 1.16 mmol) was dissolved in THF / H₂O (10 mL / 10 mL), followed by the addition of LiOH-H₂O (195.2 mg, 4.65 mmol). The reaction mixture was reacted at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 2–3 with 1 N HCl. After the product precipitated, it was filtered and washed with water to obtain A-5-e, a yellow solid (500 mg, yield: 90%). LCMS (ESI): m / z = 482 [M+H] + .

[0372] Step 5:

[0373] A-5-e (500 mg, 1.04 mmol) was dissolved in pyridine (5 mL), and then T3P (5.2 mL, 2.60 mmol, 0.5 M) was added. The reaction was carried out under nitrogen protection at 35 °C for 2 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After purification by column chromatography, A-5-f was obtained as a white solid (132 mg, yield: 28%). LCMS (ESI): m / z = 464 [M+H] + .

[0374] Step 6:

[0375] A-5-f (50 mg, 0.11 mmol) and Int-A-1 (32.1 mg, 0.27 mmol) were dissolved in acetonitrile / triethylamine (2 mL / 0.4 mL), followed by the addition of CuI (2.1 mg, 0.011 mmol) and Pd(PPh3)2Cl2 (7.6 mg, 0.011 mmol), and DBU (0.5 mL). The reaction mixture was then subjected to nitrogen protection at 70 °C for 16 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After preparative purification, A-5 was obtained as a white solid (4.0 mg, yield: 8%). LCMS (ESI): m / z = 455 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.45(s,2H),7.72(s,1H),7.48(s,3H),7.15(s, 2H), 4.45 (t, J = 5.2Hz, 2H), 4.28 (t, J = 4.6Hz, 2H), 2.31 (d, J = 13.9Hz, 2H), 1.24 (s, 2H).

[0376] Example 6 Synthesis of compound A-6

[0377]

[0378] Step 1:

[0379] Compound 98977-36-7 (0.60 g, 3.0 mmol) was dissolved in DCM (10 mL), and compound 100243-39-8 (0.26 g, 3.0 mmol), sodium borohydride acetate (0.95 g, 4.5 mmol), and acetic acid (0.27 g, 4.5 mmol) were added. The mixture was stirred at room temperature for 12 h. The mixture was washed with saturated sodium bicarbonate aqueous solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the crude product, a colorless oily substance A-6-a (0.70 g, yield: 86.7%), was concentrated. LCMS (ESI): m / z = 271.2 [M+H] + .

[0380] Step 2:

[0381] A-6-a (0.70 g, 2.60 mmol) was dissolved in DCM (5 mL), and 4 M 1,4-dioxane hydrochloride solution (3 mL) was added. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure until dry to give crude white solid A-6-b (0.54 g, yield: 85.1%). LCMS (ESI): m / z = 171.2 [M+H] + .

[0382] Step 3:

[0383] A-6-b (0.50 g, 2.21 mmol) was dissolved in THF (10 mL), and 72587-15-6 (0.54 g, 2.21 mmol) and potassium carbonate (1.53 g, 11.06 mmol) were added. The mixture was stirred at 70 °C for 3 h, and water (50 mL) was added. Extraction was performed using EA. The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a yellow solid A-6-c (0.65 g, yield: 81.6%). LCMS (ESI): m / z = 361.2 [M+H] + .

[0384] Step 4:

[0385] A-6-c (0.65 g, 1.81 mmol) was dissolved in isopropanol (20 mL), and Pd / C (0.12 g) was added under nitrogen protection. The mixture was stirred at 70 °C for 2 h under hydrogen protection, cooled to room temperature, filtered, and the filtrate was concentrated to give a white solid A-6-d (0.58 g, yield: 97.3%). LCMS (ESI): m / z = 331.2 [M+H] + .

[0386] Step 5:

[0387] A-6-d (0.16 g, 0.485 mmol) was dissolved in 10 mL of THF. Lithium bis(trimethylsilyl)amide / THF solution (1 M, 1.45 mL, 1.45 mmol) was added under ice bath conditions, and the mixture was stirred for 0.5 h. Then, 1427195-21-8 (0.14 g, 0.485 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with EA, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give a white solid A-6-e (0.14 g, yield: 48.8%). LCMS (ESI): m / z = 593.1 [M+H] + .

[0388] Step 6:

[0389] A-6-e (100 mg, 0.167 mmol), Int-A-1 (42 mg, 0.217 mmol), CuI (3.2 mg, 0.0167 mmol), Pd(PPh3)2Cl2 (7.4 mg, 0.0167 mmol), TEA (35 mg, 0.501 mmol), TBAF / THF solution (1 M, 0.17 mL), and 2 mL LDM were added and reacted at 80 °C for 16 h under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain A-6 (5 mg, yield: 5%). LCMS (ESI): m / z = 564.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.29(s,1H),8.78(d,J=1.9Hz,1H),8.44(s,3H),7.89(s,1H),7.12(d,J=4.1H z,3H),5.07(d,J=3.5Hz,1H),3.28(d,J=12.6Hz,3H),3.16(dd,J=12.3,4.8Hz,1H),3.05-2.99(m,1H),2 .85(s,1H),2.68(dd,J=11.7,3.1Hz,1H),2.50(s,3H),2.29-2.19(m,1H),2.05-1.98(m,1H),1.98-1.91 (m,1H),1.87(dt,J=13.0,9.4Hz,1H),1.83-1.77(m,1H),1.74-1.67(m,1H),1.53(dd,J=9.0,3.8Hz,2H).

[0390] Example 7 Synthesis of Compound A-7

[0391]

[0392] Step 1:

[0393] Int-B-1 (500 mg, 2.17 mmol), compound 72587-15-6 (733 mg, 3.26 mmol), and K₂CO₃ (1.20 g, 8.68 mmol) were added to THF (15 mL), stirred for 3 h at 75 °C under nitrogen protection, water was added, and the mixture was extracted with EA. The mixture was washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a yellow oily substance A-7-a (720 mg, 79%). LCMS (ESI): m / z = 421.1 [M+H] + .

[0394] Step 2:

[0395] A-7-a (720 mg, 1.71 mmol) was dissolved in MeOH (15 mL), and Pd / C (200 mg) was added. The mixture was reacted at 35 °C under H2 atmosphere for 4 h. After filtration and concentration under reduced pressure, a white oily substance A-7-b (540 mg, 81%) was obtained. LCMS (ESI): m / z = 391.2 [M+H] + .

[0396] Step 3:

[0397] A-7-b (500 mg, 1.28 mmol) and compound 625471-27-4 (359 mg, 1.28 mmol) were dissolved in THF (20 mL). LiHMDS (2.5 mL, 2.5 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 h. The solution was quenched with saturated NH4Cl aqueous solution (20 mL), extracted with EA, and the organic phase was washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give A-7-c (500 mg, yield: 61%). LCMS (ESI): m / z = 583.1 [M-100] + .

[0398] Step 4:

[0399] A-7-c (300 mg, 0.47 mmol) was dissolved in DMF (4 mL), and Int-A-1 (179 mg, 0.94 mmol), Pd(PPh)₂Cl₂ (33 mg, 0.05 mmol), CuI (9 mg, 0.047 mmol), TEA (142 mg, 1.41 mmol), and TBAF in THF (1 mL, 1 mmol) were added. The mixture was stirred at 80 °C for 2 h. The reaction solution was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain A-7-d (200 mg, yield: 68%). LCMS (ESI): m / z = 630.3 [M+H] + .

[0400] Step 5:

[0401] A-7-d (200 mg, 0.317 mmol) was dissolved in DMF (5 mL), and DBU (152 mg, 0.95 mmol) was added. The mixture was stirred at 100 °C for 2 h, quenched with water, extracted with EA, and the organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography to give A-7-e (140 mg, yield: 72%). LCMS (ESI): m / z = 610.3 [M+H] + .

[0402] Step 6:

[0403] A-7-e (140 mg, 0.23 mmol) was dissolved in DCM (10 mL), and HCl / 1,4-dioxane (1 mL, 4 mmol) was added. The mixture was stirred in an ice bath for 2 h, and then concentrated to obtain A-7-f (110 mg). LCMS (ESI): m / z = 510.3 [M+H] + .

[0404] Step 7:

[0405] A-7-f (50 mg, 0.13 mmol) was dissolved in DCM (3 mL) and methanol (2 mL), and formaldehyde aqueous solution (37% v / v, 0.3 mL) was added. NaBH(AcO)3 (80 mg, 0.38 mmol) was added under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to give a white solid A-7 (15 mg, yield: 33%). LCMS (ESI): m / z = 524.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.12(s,1H),8.45(d,3H),8.06(d,1H),7.70(d,1H), 7.28(s,1H),7.14(s,2H),4.64(s,1H),4.16(s,2H),3.37(s,4H),2.75(d,3H),2.29(d,1H).

[0406] Example 8 Synthesis of compounds A-8 and A-9

[0407] Compounds A-8 and A-9 can be synthesized by referring to the synthesis of compound A-7.

[0408]

[0409] Example 9 Synthesis of Compound A-10

[0410]

[0411] Step 1:

[0412] A-7-f (28 mg, 0.051 mmol) was dissolved in 2 mL of methanol, followed by the sequential addition of TBS-protected hydroxyacetaldehyde (8.94 mg, 0.051 mmol) and sodium cyanoborohydride (3.22 mg, 0.051 mmol). The mixture was stirred at 25 °C for 16 h. The reaction solution was filtered to remove the solid, and the organic phase was concentrated and purified by column chromatography to obtain A-10-a (20 mg, yield: 59%). LCMS (ESI): m / z = 668.4 [M+H] + .

[0413] Step 2:

[0414] A-10-a (20 mg 0.030 mmol) was dissolved in 2 THF, and 5 drops of TBAF in THF solution (1 M) were added. The mixture was stirred at 25 °C for 2 h. After concentration, the reaction solution was purified by column chromatography to obtain A-10 (4.3 mg, yield: 27%). LCMS (ESI): m / z = 554.3 [M+H) + ; 1H NMR (400MHz, DMSO-d6): δ10.33(s,1H),9.00(s,1H),8.45(s,3H),8.13-8.05(m,1H),7.73(dd,1H),7.29(d,1H),7.14(s,2H),4.70-4.65(m,1H), 4.44(t,J=5.4Hz,1H),4.18-4.04(m,2H),3.55-3.49(m,3H),3.06(d,1H) ,2.85(p,2H),2.78-2.73(m,1H),2.64(q,2H),2.59(q,1H),1.99(m,2H).

[0415] Example 10 Synthesis of compounds A-11 and A-12

[0416] Compounds A-11 and A-12 can be synthesized by referring to the synthesis of compound A-10.

[0417]

[0418] Example 11 Synthesis of Compound A-13

[0419]

[0420] A-7-f (1.50 g, 2.95 mmol) was dissolved in DMF (20 mL), and AcOH (0.19 g, 3.24 mmol), HOBT (0.44 g, 3.24 mmol), EDCI (0.62 g, 3.24 mmol), and DIEA (0.76 g, 5.89 mmol) were added. The mixture was stirred at room temperature for 5 h, and the reaction solution was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) to obtain a white solid A-13 (1.25 g, yield: 77%). LCMS (ESI) m / z = 552.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.37-10.32(d,1H),9.11-9.07(m,1H),9.47-9. 44(m,3H),8.13(s,1H),7.74(d,1H),7.34-7.31(m,1H),7.14(s,2H),4.71 -4.45(m,2H),4.37-4.25(m,2H),3.92-3.85(m,1H),3.53-3.50(m,2H),3. 20-2.89(m,2H),2.71-2.56(m,1H),2.08-2.07(m,3H),1.88-1.67(m,1H).

[0421] Example 12 Synthesis of Compound A-14

[0422] Compound A-14 can be synthesized by referring to the synthesis of compound A-13.

[0423]

[0424] Example 13 Synthesis of Compound A-15

[0425]

[0426] Step 1:

[0427] A-7-c (1.27 g, 1.88 mmol) and DBU (571 mg, 3.76 mmol) were added to DMF (15 mL), stirred at 100 °C for 4 h under nitrogen protection, then water was added, and the mixture was extracted with EA. The mixture was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give a yellow oily product A-15-a (1.0 g, 86.0%). LCMS (ESI): m / z = 619.4 [M+H] + .

[0428] Step 2:

[0429] A-15-a (300 mg, 0.485 mmol) was dissolved in 1,4-dioxane (5 mL), and HCl / dioxane (4 mol / L, 4 mL) was added. After stirring for 4 h, the solution was concentrated to obtain a white solid A-15-b (240 mg, 95.6%). LCMS (ESI): m / z = 519.6 [M+H] + .

[0430] Step 3:

[0431] A-15-b (280 mg, 0.540 mmol) and TEA (218 mg) were added to THF (10 mL), followed by cyclopropionyl chloride (62 mg, 2.16 mmol). After stirring for 2 h, the mixture was concentrated and separated by column chromatography (DCM:MeOH = 20:1) to obtain a yellow solid A-15-c (240 mg, 75.9%). LCMS (ESI): m / z = 587.1 [M+H] + .

[0432] Step 4:

[0433] The following were added: A-15-c (100 mg, 0.170 mmol), Int-A-1 (130 mg, 0.682 mmol), X-phos (41 mg, 0.09 mmol), and Pd(ACN)2Cl. 2( 22mg (0.09mmol), K2CO 3( 71 mg (0.51 mmol) and DBU (124 mg, 0.82 mmol) were added to TEA (1 mL) / ACN (3 mL), and the mixture was stirred at 85 °C for 3 h under nitrogen protection. Water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and subjected to prep-HPLC to obtain a white solid A-15 (23.3 mg, 23.7%). LCMS (ESI): m / z = 578.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.35(d,1H),9.15-9.03(m,1H),8.54-8.36(m,3 H),8.13(d,1H),7.74(d,1H),7.33(d,1H),7.15(s,2H),4.69(d,2H),4.5 3-4.06(m,3H),3.56(d,1H),3.19(t,1H),3.09-2.99(m,1H),2.85(dd,1H ),2.61-2.53(m,1H),2.11-2.02(m,1H),1.76(dd,1H),0.87-0.68(m,4H).

[0434] Example 14 Synthesis of Compound A-16

[0435] The following compounds can be synthesized by referring to the synthesis of compound A-15.

[0436]

[0437] Example 15 Synthesis of Compound A-17

[0438]

[0439] Step 1:

[0440] A-17-a (10.0 g, 84.03 mmol) was dissolved in a saturated sodium bicarbonate aqueous solution (420 mL, 1 M), and Cbz-Cl (13 mL, 92.44 mmol, 1.212 g / mL) was added. The reaction mixture was allowed to react overnight at room temperature. The pH of the reaction solution was adjusted to 2 with 3N HCl, and the solution was extracted with EA. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude A-17-b (19.2 g, white solid), yield: 90.1%. LCMS (ESI): m / z = 271 [M+H8] + .

[0441] Step 2:

[0442] Crude product A-17-b (7.8 g, 30.71 mmol) was dissolved in n-hexane / MeOH (84 mL / 35 mL), followed by the addition of TMS-CH2N2 (20 mL, 39.92 mmol, 2.0 M in hexane). The reaction mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain crude product A-17-c (3.0 g, white solid). LCMS (ESI): m / z = 290 [M + Na] + .

[0443] Step 3:

[0444] Crude A-17-c (3.0 g, 11.19 mmol) and TBSCl (2.0 g, 13.43 mmol) were dissolved in DCM (30 mL), followed by the addition of pyrazole (1.8 g, 26.87 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was quenched with water, then extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain A-17-d (1.8 g, colorless oil). LCMS (ESI): m / z = 382 [M+H] + .

[0445] Step 4:

[0446] A-17-d (1.8 g, 4.71 mmol) was dissolved in 12 mL of THF. Under nitrogen protection, DIBAL-H (12.7 mL, 12.7 mmol, 1.0 M in THF) was added at -78 °C, and the reaction was carried out at -78 °C for 3 h. The reaction solution was quenched with 60 mL of icy dilute hydrochloric acid (1 M) aqueous solution, then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain crude A-17-e (715 mg, pale yellow oil). LCMS (ESI): m / z = 352 [M+H] +.

[0447] Step 5:

[0448] Crude A-17-e (715 mg, 2.03 mmol) and ethyl 2-aminoacetate hydrochloride (511.9 mg, 4.06 mmol) were dissolved in methanol (10 mL), followed by the addition of sodium cyanoborohydride (204.8 mg, 3.57 mmol) and acetic acid (243.8 mg, 4.06 mmol). The reaction mixture was reacted overnight at room temperature. The reaction solution was neutralized with potassium carbonate and filtered. The filtrate was concentrated and extracted with water and EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give A-17-f (209 mg, colorless oil), yield: 25%. LCMS (ESI): m / z = 425 [M+H] + .

[0449] Step 6:

[0450] A-17-f (209 mg, 0.49 mmol) was dissolved in ethanol (5 mL), followed by the addition of palladium on carbon (100 mg) and hydrogen gas. The reaction was carried out at room temperature for 8 h. The mixture was filtered and concentrated under reduced pressure to obtain crude A-17-g (167 mg, yellow oil). LCMS (ESI): m / z = 259 [M+H] + .

[0451] Step 7:

[0452] Crude A-17-g (120 mg, 0.46 mmol) and compound 72587-15-6 (157.8 mg, 0.69 mmol) were dissolved in THF (5 mL), followed by the addition of potassium carbonate (191.8 mg, 1.39 mmol). The reaction mixture was reacted at 70 °C for 4 h. After cooling, the reaction solution was quenched with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give A-17-h (81 mg, yellow-green oil), yield: 39%. LCMS (ESI): m / z = 449 [M+H] + .

[0453] Step 8:

[0454] A-17-h (81 mg, 0.18 mmol) was dissolved in ethanol (3 mL), and palladium on carbon (40 mg) was added. The reaction mixture was reacted at room temperature for 6 h under a hydrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in THF (2 mL). Then, TBAF (0.89 mL, 0.89 mmol, 1.0 M in THF) was added, and the reaction mixture was reacted at room temperature for 1 h. The reaction solution was diluted with EA, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-17-i (42 mg, colorless oil), yield: 76%. LCMS (ESI): m / z = 419 [M+H] + / 305[M+H] + .

[0455] Step 9:

[0456] A-17-i (42 mg, 0.14 mmol) and 850146-80-4 (40.2 mg, 0.14 mmol) were dissolved in THF (5 mL), followed by the addition of DBAD (63.9 mg, 0.28 mmol) and triphenylphosphine (72.2 mg, 0.28 mmol). The reaction mixture was reacted at 70 °C for 6 h under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-17-j (45 mg, pale yellow oil), yield: 56%. LCMS (ESI): m / z = 579 [M+H] + .

[0457] Step 10:

[0458] A-17-j (45 mg, 0.078 mmol) and LiOH-H2O (9.8 mg, 0.23 mmol) were dissolved in MeOH / H2O / THF (0.5 mL / 0.5 mL / 1.5 mL) and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, ice water was added, and the pH was adjusted to 2–3 with 1 N HCl. The product precipitated, filtered, and washed with water. The filter cake was dried to give A-17-k (30 mg, pale yellow solid), yield: 68%. LCMS (ESI): m / z = 565 [M+H] + / 565[M+H8] + .

[0459] Step 11:

[0460] A-17-k (30 mg, 0.053 mmol) was dissolved in ACN (4 mL), followed by the addition of NMI (21.2 mg, 0.27 mmol) and TFCH (22.3 mg, 0.080 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-17-l (18 mg, white solid), yield: 62%. LCMS (ESI): m / z = 547 [M+H] + .

[0461] Step 12:

[0462] Dissolve A-17-l (18 mg, 0.033 mmol) and Int-A-1 (25.1 mg, 0.13 mmol) in ACN (1 mL), TEA (2 mL), and DBU (0.16 mL), then add potassium carbonate (17.3 mg, 0.13 mmol), Xphos (9.4 mg, 0.020 mmol), and Pd(ACN)2Cl. 2( 0.86 mg (0.033 mmol) was added, and the reaction was carried out under nitrogen protection at 80 °C for 5 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by formic acid to give A-17 (2.5 mg, pale yellow solid), yield: 14%. LCMS (ESI): m / z = 538 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.40(s,2H),7.96(s,1H),7.86(d,J=8.6Hz,1H),7.42(s,1H),7.09(d,J=10.6Hz,3H),6.85(s,1H),4.25(dd, J=22.9,15.4Hz,3H),4.10(d,J=16.4Hz,1H),3.89-3.82(m,1H),3.79-3.7 3(m,1H),2.37(s,3H),2.04(dd,J=9.3,4.8Hz,2H),1.59(t,J=9.7Hz,1H).

[0463] Example 16 Synthesis of Compound A-18

[0464]

[0465] Step 1:

[0466] A-15-b (80 mg, 0.180 mmol), cyclopropanesulfonyl chloride (32 mg, 0.23 mmol), and TEA (62 mg, 0.62 mmol) were added to THF (5 mL), and the mixture was stirred at 50 °C for 16 h under nitrogen protection. Water was added, and the mixture was extracted with EA, washed with saturated brine, dried over the organic phase, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to obtain a white solid product A-18-a (70 mg, 73%). LCMS (ESI): m / z = 623.0 [M+H] + .

[0467] Step 2:

[0468] The following were added: A-18-a (80 mg, 0.14 mmol), Int-A-1 (75 mg, 0.391 mmol), X-phos (30 mg, 0.06 mmol), Pd(ACN)₂Cl₂ (16.6 mg, 0.06 mmol), and K₂CO₃. 3( 53 mg (0.39 mmol) and DBU (94 mg, 0.616 mmol) were added to TEA (1 mL) / ACN (4 mL), and the mixture was stirred at 85 °C for 3 h under nitrogen protection. Water was added, and the mixture was extracted with EA, washed with saturated brine, dried over the organic phase, concentrated, and subjected to prep-HPLC to obtain a white solid A-18 (9.5 mg, 11.2%). LCMS (ESI): m / z = 614.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.09(d,J=2.2Hz,1H),8.52-8.38(m,3H),8.13(d,J=2.3Hz, 1H),7.75(dd,J=8.6,2.3Hz,1H),7.33(d,J=8.8Hz,1H),7.15(s,2H),4.68(d,J=8.7Hz,1H),4.29(d d, J = 18.8, 9.2 Hz, 2H), 4.18 (d, J = 11.1 Hz, 1H), 3.79 (d, J = 13.4 Hz, 1H), 3.47 (t, J = 12.8 Hz, 2H), 3.29-3.12 (m, 2H), 2.83-2.71 (m, 2H), 2.01 (d, J = 15.0 Hz, 1H), 1.02 (d, J = 6.6 Hz, 4H). Example 17 Synthesis of Compound A-25

[0469]

[0470] Step 1:

[0471] A-7-b (50 mg, 0.13 mmol) was dissolved in THF (3 mL), and under nitrogen protection at 0 °C, NaH (36 mg, 0.90 mmol) was added and reacted for 30 min. Then, 931105-37-2 (60 mg, 0.26 mmol) was added at 0 °C, and the reaction was brought to room temperature for 2 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-25-a (67 mg, pale yellow solid), yield: 89%. LCMS (ESI): m / z = 590 [M+H] + .

[0472] Step 2:

[0473] Crude A-25-a (67 mg, 0.11 mmol) was dissolved in ACN (3 mL), followed by the addition of NMI (45.4 mg, 0.57 mmol) and TCFH (47.7 mg, 0.17 mmol). The reaction was carried out at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride aqueous solution, then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-25-b (47 mg, white solid), yield: 72%. LCMS (ESI): m / z = 572 [M+H] + .

[0474] Step 3:

[0475] In a sealed tube, A-25-b (20 mg, 0.035 mmol) and Int-A-1 (26.7 mg, 0.14 mmol) were dissolved in ACN (1 mL), TEA (2 mL), and DBU (0.16 mL). Potassium carbonate (18.3 mg, 0.13 mmol), XPhos (10.0 mg, 0.021 mmol), and Pd(ACN)₂Cl₂ (0.91 mg, 0.0035 mmol) were then added. The reaction mixture was kept in a sealed container at 80 °C for 5 h under nitrogen protection. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to obtain A-25-c (12 mg, white solid), yield: 56%. LCMS (ESI): m / z = 611.0 [M+H] + .

[0476] Step 4:

[0477] A-25-c (12 mg, 0.020 mmol) was dissolved in 1,4-dioxane (0.5 mL), followed by the addition of HCl / 1,4-dioxane (0.5 mL). The reaction mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain crude A-25-d (10 mg, colorless oil). LCMS (ESI): m / z = 511.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.72(s,1H),8.53(d,J=2.3Hz,1H),8.45(d,J=10.7Hz,3H),8.28(s,1H),7.19(s,2H) ,4.82(s,1H),4.32-4.22(m,1H),3.18-3.11(m,4H),2.93-2.82(m,2H),2.09-1.88(m,1H),1.86-1.61(m,2H),1.23(s,1H).

[0478] Step 5:

[0479] Crude A-25-d (10 mg, 0.020 mmol) and acetic anhydride (2 mg, 0.020 mmol) were dissolved in DCM (1 mL), and TEA (6 mg, 0.059 mmol) was added. The reaction mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by neutralization to give A-25 (1.0 mg, white solid), yield: 9.3%. LCMS (ESI): m / z = 553.1 [M+H] + .

[0480] Example 18 Synthesis of compounds A-26 to A28, A-30, A-33 to A35, A37, A39 to A42, A52 to A59

[0481] The following compounds can be synthesized by referring to the synthesis of compound A-25.

[0482]

[0483]

[0484] Example 19 Synthesis of compounds A-32, A-36, and A-38

[0485] Following the synthesis of compound A-18, compounds A-32, A-36, and A-38 can be synthesized.

[0486]

[0487] Example 20 Synthesis of Compound A-43

[0488]

[0489] Step 1:

[0490] A-25-b (183 mg, 0.32 mmol) was stirred in 3N hydrochloric acid-methanol for 8 h. The concentrated product was dissolved in DCM (5 mL) / MeOH (5 mL), and oxetane-3-one (92 mg, 1.27 mmol) and acetic acid (0.3 mL) were added. The mixture was stirred at 0 °C under nitrogen protection for 10 min, and then NaBH3CN (60 mg, 0.96 mmol) was added. The reaction was carried out at room temperature for 16 h. Water was added, and the mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a pale yellow solid (130 mg, 77%). LCMS (ESI): m / z = 529.1 [M+H] + .

[0491] Step 2:

[0492] Add A-43-a (45 mg, 0.09 mmol), Int-A-1 (65 mg, 0.34 mmol), and Pd(ACN)2Cl 2( 11mg, 0.04mmol), X-Phos (20mg, 0.04mmol), K2CO 3( 35 mg (0.26 mmol) and DBU (62 mg, 0.41 mmol) were added to ACN (3 mL) / TEA (1 mL), and the mixture was sealed and stirred at 85 °C for 3 h under nitrogen protection. After cooling, water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and subjected to prep-HPLC to obtain a yellow solid A-43 (12.0 mg, 25%). LCMS (ESI): m / z = 567.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 9.02 (s, 1H), 8.55 (d, J = 2.4Hz, 1H), 8.50-8. 43(m,3H),8.37(d,J=2.3Hz,1H),7.21(s,2H),4.96(d,J=10.2Hz,1H),4.56(dq,J= 20.4,6.5Hz,4H),4.08(ddd,J=19.8,17.5,8.7Hz,3H),3.05(d,J=11.0Hz,1H),2.8 0(dt,J=24.4,11.9Hz,3H),2.70-2.59(m,1H),2.54(s,2H),1.66(d,J=13.8Hz,1H).

[0493] Synthesis of Compounds A-44, A-49, A-50, and A-51 in Example 21

[0494] Referring to the synthesis of reference compound A-43, compounds A-44, A-49, A-50, and A-51 can be synthesized.

[0495]

[0496] Synthesis of Compound A-45 in Example 22

[0497]

[0498] Dissolve crude A-25-d (10 mg, 0.020 mmol) and paraformaldehyde (2.3 mg, 0.023 mmol) in DCM (1 mL), then add sodium cyanoborohydride (1.8 mg, 0.029 mmol) and acetic acid (1 drop), and react for 4 h. Concentrate the reaction solution under reduced pressure. The residue is purified by neutral preparative chromatography to obtain A-45 (1.1 mg, white solid), yield: 11%. LCMS (ESI): m / z = 525.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.85 (s, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.47 (s, 2H), 8.45 (d, J = 1.1 Hz, 1H), 8.32 (d, J = 1.4 Hz, 1H), 7.20 (s, 2H), 2.92 - 2.78 (m, 5H), 2.35 (s, 3H), 2.10 - 1.96 (m, 4H), 1.51 - 1.39 (m, 2H).

[0499] Synthesis of Compounds A-46, A-47, and A-48 in Example 23

[0500] Referring to the synthesis of reference compound A-43, compounds A-46, A-47, and A-48 can be synthesized.

[0501]

[0502] Synthesis of Compound A-60 in Example 24

[0503]

[0504] Step 1:

[0505] S-Int-B-3 (0.90 g, 3.69 mmol) was dissolved in THF (30 mL), and 72587-15-6 (0.83 g, 3.69 mmol) and K₂CO₃ (1.02 g, 7.38 mmol) were added. The mixture was heated under reflux for 3 h. Water (130 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated. The residue was subjected to column chromatography to give A-60-a (1 g, yield: 63%). LCMS (ESI) m / z = 335.1 [M-99] + .

[0506] Step 2:

[0507] A-60-a (1 g, 2.30 mmol) was dissolved in MeOH (20 mL), and Pd / C (0.11 g) was added. The mixture was stirred at room temperature for 12 h under hydrogen atmosphere. The solid was removed by filtration, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure until dry to obtain A-60-b (0.80 g, yield: 86%). LCMS (ESI) m / z = 405.3 [M+H] + .

[0508] Step 3:

[0509] A-60-b (0.8 g, 1.98 mmol) and 78686-83-6 (0.76 g, 2.57 mmol) were dissolved in THF (10 mL), and LiHMDS (6 mL, 6 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 h. The solution was quenched with NH4Cl aqueous solution (20 mL), extracted with EA, and the organic phase was washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography to give a white solid A-60-c (0.8 g, yield: 60.4%). LCMS (ESI) m / z = 570.0 [M-99] + .

[0510] Step 4:

[0511] A-60-c (0.8 g, 1.19 mmol) was dissolved in DMF (8 mL), and DBU (0.73 g, 2.38 mmol) was added. The mixture was stirred at 120 °C for 3 h. The reaction solution was purified by column chromatography to give a white solid A-60-d (0.68 g, yield: 89%). LCMS (ESI) m / z = 634.1 [M+H] + .

[0512] Step 5:

[0513] A-60-d (0.68 g, 1.07 mmol) was dissolved in DCM (10 mL), and 4 M 1,4-dioxane hydrochloride solution (3 mL) was added. The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure until dry to give crude white solid A-60-e (600 mg, yield: 98%). LCMS (ESI) m / z = 534.1 [M+H] + .

[0514] Step 6:

[0515] A-60-e (200 mg, 0.35 mmol) was dissolved in DCM (10 mL). TEA (136 mg, 1.04 mmol) and cyclobutylformyl chloride (62 mg, 0.53 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added, and the mixture was extracted with DCM. The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The reaction mixture was purified by column chromatography to give a white solid A-60-f (200 mg, yield: 92%). LCMS (ESI) m / z = 616.1 [M+H] + .

[0516] Step 7:

[0517] A-60-f (100 mg, 0.16 mmol) was dissolved in DMF (2 mL), and Int-A-15 (56 mg, 0.24 mmol), Pd(PPh)₂Cl₂ (12 mg, 0.016 mmol), CuI (3 mg, 0.016 mmol), DBU (74 mg, 0.49 mmol), and TBAF in THF (0.25 mL, 0.25 mmol) were added. The mixture was microwaved at 100 °C for 1 h under Ar protection. The reaction solution was purified by column chromatography (PE / EA = 1 / 100 to 1 / 9 to DCM / MeOH = 10 / 1) and reverse-phase preparation (ACN / H₂O = 5 / 95 to 95 / 5, 0.1% aqueous solution of NH₄HCO₃) to obtain a white solid A-60 (45 mg, yield: 46%). LCMS (ESI) m / z = 647.4 [M+H] +.10.07(d,1H),9.11(m,1H),8.55(dd,4H),8.36(dd,1H),7.95(d,1H),5.61(d,1 H),4.75(dd,1H),4.34-3.75(m,2H),3.51-3.42(m,1H),3.38(m,2H),3.29(m,1H) ,3.20-2.98(m,2H),2.78(m,1H),2.63(m,1H),2.34-2.09(m,4H),1.96(m,1H),1. 79(m,1H),1.76-1.54(m,2H),1.52(m,2H),0.77-0.68(m,2H),0.58-0.48(m,2H).

[0518] Example 25 Synthesis of compounds A-61 to A-74

[0519] By referring to the synthesis of compound A-60, compounds A-61 to A-74 can be synthesized.

[0520]

[0521]

[0522] Example 26 Synthesis of Compound B-1

[0523]

[0524] Step 1:

[0525] B-1-a (2.7 g, 6.27 mmol), cyclopropylboronic acid (1.08 g, 12.5 mmol), Pd(dppf)Cl2-DCM (910 mg, 1.25 mmol), and K2CO3 (2.5 g, 18.8 mmol) were added to 1,4-dioxane (20 mL) / H2O (4 mL), stirred at 90 °C for 4 h, cooled, and then water was added. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, and purified by column chromatography to obtain a yellow oily substance, B-1-b (1.8 g, 72%). LCMS (ESI): m / z = 393.2 [M+H] + .

[0526] Step 2:

[0527] B-1-b (1.8 g, 4.58 mmol) was dissolved in MeOH (20 mL), and Pd / C (300 mg) was added. The mixture was reacted at 35 °C under a H2 atmosphere for 5 h. After filtration and concentration under reduced pressure, a white oily substance, B-1-c (1.2 g, 72%), was obtained. LCMS (ESI): m / z = 363.2 [M+H]+ .

[0528] Step 3:

[0529] B-1-c (300 mg, 0.83 mmol) was added to THF (20 mL) under nitrogen protection. NaH (140 mg, 5.78 mmol) was added at 0 °C, and the mixture was stirred for 1 h. Compound 931105-37-2 (386 mg, 1.66 mmol) was then added, and the reaction was carried out at 25 °C for 10 h. The reaction was quenched with ice water, extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a blue solid B-1-d (140 mg, 19%). LCMS (ESI): m / z = 562.5 [M+H] + .

[0530] Step 4:

[0531] B-1-d (130 mg, 0.23 mmol) and NMI (95 mg, 1.15 mmol) were dissolved in ACN (3 mL) and reacted at 25 °C for 10 min. TCFH (100 mg, 0.34 mmol) was added, and the reaction was continued at 25 °C for 2 h. Water was added, and the mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a yellow solid B-1-e (55 mg, 50%). LCMS (ESI): m / z = 488.4 [M-56+H] + .

[0532] Step 5:

[0533] B-1-e (55 mg, 0.085 mmol), Int-A-1 (97 mg, 0.51 mmol), X-Phos (20 mg, 0.043 mmol), K₂CO₃ (35 mg, 0.255 mmol), and DBU (93 mg, 0.612 mmol) were added to ACN (3 mL) / TEA (2 mL). The mixture was stirred at 85 °C for 3 h under nitrogen protection, cooled, and then extracted with EA. The extract was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and subjected to Prep-HPLC to obtain a pale yellow solid B-1-f (50 mg, 90%). LCMS (ESI): m / z = 583.3 [M+H] + .

[0534] Step 6:

[0535] B-1-f (50 mg, 0.085 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of HCl / 1,4-dioxane (2 mL) and reaction at 35 °C for 4 h. The reaction solution was concentrated to obtain a white solid B-1 (4.5 mg, 12%). LCMS (ESI): m / z = 483.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 8.53 (d, J = 2.3Hz, 1H), 8.46 (s, 2H), 8.43-8 .33(m,2H),8.22-8.10(m,1H),7.93(d,J=2.2Hz,1H),7.19(s,2H),5.01(brs,1H) ,4.23(t,J=11.1Hz,1H),3.71(t,J=6.7Hz,1H),3.20-3.13(m,3H),3.04-2.90(m, 3H),2.89-2.56(m,2H),1.94-1.86(m,2H),1.00-0.96(m,2H),0.67-0.64(m,2H).

[0536] Example 27 Synthesis of compounds B-2 and B-3

[0537] Following the synthesis of compound B-1, compounds B-2 and B-3 can be synthesized.

[0538]

[0539] Example 28 Synthesis of compounds B-4 to B-9

[0540] By referring to the synthesis of compound A-45, compounds B-4 to B-9 can be synthesized.

[0541]

[0542] Example 29 Synthesis of compounds B-10 and B-11

[0543] Following the synthesis of compound A-43, compounds B-10 and B-11 can be synthesized.

[0544]

[0545] Example 30 Synthesis of compounds B-12 and B-13

[0546] Following the synthesis of compound A-25, compounds B-12 and B-13 can be synthesized.

[0547]

[0548]

[0549] Example 31 Synthesis of compound B-14

[0550]

[0551] Step 1:

[0552] B-14-a (105 mg, 0.24 mmol), cyclobutylformyl chloride (50 mg, 0.48 mmol), and TEA (120 mg, 1.18 mmol) were added to 8 mL of THF and stirred at 30 °C for 3 h. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography (PE:EA = 2:1) to give a pale yellow solid B-14-b (85 mg, 68.5%). LCMS (ESI): m / z = 526.1 [M+H] + .

[0553] Step 2:

[0554] B-14-b (85 mg, 0.16 mmol), Int-A-1 (122 mg, 0.64 mmol), Pd(ACN)₂Cl₂ (20 mg, 0.08 mmol), X-phos (38 mg, 0.08 mmol), DBU (115 mg, 0.77 mmol), and K₂CO₃ (66 mg, 0.48 mmol) were added to ACN (5 mL) / TEA (2 mL). The mixture was stirred at 85 °C under nitrogen protection for 4 h, then water was added. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, and concentrated. Prep-HPLC yielded a pale yellow solid B-14 (12.2 mg, 13.4%). LCMS (ESI): m / z = 565.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.13(d,1H),8.61-8.42(m,4H),8.42-8.35(m,1H),7.98-7.9 1(m,1H),7.19(s,2H),5.18-5.01(m,1H),4.54(m,1H),4.27(m,1H),4.12-3.72(m,1H), 3.43(d,2H),3.15(m,1H),3.05(s,2H),2.88(d,1H),2.46-2.39(m,1H),2.30-2.22(m, 1H),2.14(dd,J=16.0,8.4Hz,3H),1.94(m,2H),1.74(d,2H),0.98(m,2H),0.66(d,2H).

[0555] Example 32 Synthesis of Compound B-15

[0556]

[0557] Dissolve B-15-a (synthesized in the same way as B-14-b) (45 mg, 0.08 mmol) in DMF (6 mL), add Int-A-1 (24 mg, 0.13 mmol), and Pd(PPh)2Cl. 2( 6 mg (0.08 mmol), CuI (2 mg, 0.08 mmol), and DBU (38 mg, 0.25 mmol) were added and stirred at 120 °C for 24 h. The reaction mixture was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain B-15 (10 mg, yield: 21%). LCMS (ESI) m / z = 579.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.15(d,1H),8.57-8.49(m,2H),8.47(s,2H),8.41-8 .36(m,1H),7.94(m,1H),7.20(s,2H),5.10(d,1H),4.76-4.40(m,1H),4.40-3 .94(m,3H),3.44(m,1H),3.17(d,2H),3.05(d,2H),2.88(m,1H),2.41(d,1H), 1.95(m,1H),1.79(m,3H),1.70-1.47(m,6H),1.05-0.93(m,2H),0.67(m,2H).

[0558] Example 33 Synthesis of Compound B-16

[0559]

[0560] Step 1:

[0561] B-14-a (105 mg, 0.24 mmol), cyclopropylsulfonyl chloride (50 mg, 0.48 mmol), and TEA (120 mg, 1.18 mmol) were added to 8 mL of THF, stirred at 30 °C for 3 h, extracted with EA, washed with saturated ammonium chloride aqueous solution, dried the organic phase, concentrated, and purified by column chromatography (PE:EA = 2:1) to give a pale yellow solid B-16-a (65 mg, 51%). LCMS (ESI): m / z = 548.1 [M+H] + .

[0562] Step 2:

[0563] B-16-a (65 mg, 0.12 mmol), Int-A-1 (91 mg, 0.47 mmol), Pd(ACN)₂Cl₂ (15 mg, 0.07 mmol), X-phos (28 mg, 0.07 mmol), DBU (90 mg, 0.58 mmol), and K₂CO₃ (50 mg, 0.36 mmol) were added to ACN (5 mL) / TEA (2 mL). The mixture was stirred at 85 °C under nitrogen protection for 4 h, then water was added. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and subjected to Prep-HPLC to obtain a pale yellow solid B-16 (8.3 mg, yield: 12%). LCMS (ESI): m / z = 587.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.55(d,J=2.4Hz,1H),8.53(d,J=2.2Hz,1H),8.47(s,2H),8.39(d, J=2.4Hz,1H),7.95(d,J=2.2Hz,1H),7.19(s,2H),5.15(d,J=10.3Hz,1H),4.25(t,J=11.2Hz,1H),4.14(d, J=10.9Hz,1H),3.98(d,J=12.6Hz,1H),3.75(d,J=12.7Hz,1H),3.45(t,J=11.8Hz,1H),3.33(s,1H),3.13( m,2H),2.79-2.72(m,1H),2.66(d,J=9.6Hz,1H),2.05-1.94(m,2H),1.03-0.98(m,6H),0.72-0.66(m,2H).

[0564] Example 34 Synthesis of compounds B-17 to B-37, B-42 to B-47

[0565] The following compounds can be synthesized by referring to the synthesis of compound B-15.

[0566]

[0567]

[0568]

[0569] Example 35 Synthesis of compound B-38

[0570]

[0571] Step 1:

[0572] B-14-a (80 mg, 0.18 mmol), methylcarbamoyl chloride (25 mg, 0.27 mmol), and TEA (82 mg, 0.72 mmol) were added to 4 mL of THF, stirred at 30 °C for 3 h, extracted with EA, and the organic phase was washed with saturated ammonium chloride aqueous solution, dried, concentrated, and purified by column chromatography to obtain a pale yellow solid B-38-a (80 mg, yield: 88%). LCMS (ESI): m / z = 501.1 [M+H] + .

[0573] Step 2:

[0574] B-38-a (80 mg, 0.16 mmol), Int-A-1 (85 mg, 0.64 mmol), Pd(ACN)₂Cl₂ (20 mg, 0.08 mmol), X-Phos (35 mg, 0.08 mmol), and K₂CO₃ (60 mg, 0.48 mmol) were added to ACN (5 mL) / TEA (2 mL), and the mixture was reacted at 85 °C for 3 h under nitrogen protection. Water was added, and the mixture was extracted with EA. The organic phase was washed with saturated ammonium chloride aqueous solution, dried, concentrated, and purified by Prep-HPLC to obtain a pale yellow solid B-38 (16.3 mg, yield: 19%). LCMS (ESI): m / z = 554.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.58-8.51(m,3H),8.48(s,1H),8.40(t,J=3.3Hz,1H),7.94(d, J=2.2Hz,1H),7.66(q,J=4.7Hz,1H),6.55(d,J=4.3Hz,1H),5.12(d,J=9.3Hz,1H),4.30-4.12(m,2H),3 0.94 (m, 2H), 3.13 (d, J = 8.8 Hz, 3H), 2.91-2.81 (m, 4H), 2.61 (d, J = 4.2 Hz, 3H), 2.48-2.43 (m, 1H), 2.01-1.89 (m, 1H), 1.74 (d, J = 14.3 Hz, 1H), 1.04-0.95 (m, 2H), 0.67 (dd, J = 7.1, 5.1 Hz, 2H). Example 36 Synthesis of compound B-39

[0575]

[0576] Step 1:

[0577] B-14-a (90 mg, 0.20 mmol), N-methyl-2-chloroacetamide (33 mg, 0.30 mmol), and TEA (82 mg, 0.81 mmol) were added to 4 mL of THF and stirred at 30 °C for 13 h. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to give a pale yellow solid, B-39-a (100 mg, yield: 96%). LCMS (ESI): m / z = 515.1 [M+H] + .

[0578] Step 2:

[0579] B-39-a (100 mg, 0.194 mmol) and Int-A-3 (103 mg, 0.78 mmol), Pd(ACN)2Cl 2( 25 mg (0.10 mmol), X-Phos (35 mg, 0.10 mmol), and K2CO3 (60 mg, 0.58 mmol) were added to ACN (5 mL) / TEA (2 mL). The mixture was stirred at 85 °C for 3 h under nitrogen protection. Water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and subjected to Prep-HPLC to obtain a pale yellow solid B-39 (6.9 mg, yield: 6%). LCMS (ESI): m / z = 568.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.12 (s, 1H), 8.55-8.43 (m, 4H), 8.35 (s, 1H), 7.93 (d, J = 2. 2Hz,1H),7.83-7.76(m,1H),7.66(q,J=4.8Hz,1H),5.04(s,1H),4.10(t,J=10.9Hz, 1H),3.50(m,1H),3.26-3.22(d,1H),3.02-2.88(m,3H),2.87(m,6H),2.66(d,J=4.7 Hz,3H),2.57(d,J=12.0Hz,2H),1.97-1.90(m,2H),0.98(m,2H),0.71-0.63(m,2H).

[0580] Example 37 Synthesis of Compound B-40

[0581]

[0582] Step 1:

[0583] B-14-a (70 mg, 0.203 mmol), MsCl (50 mg, 0.30 mmol), and TEA (82 mg, 0.81 mmol) were added to 4 mL of THF and stirred at 30 °C for 13 h. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a pale yellow solid, B-40-a (72 mg, 87.8%). LCMS (ESI): m / z = 522.1 [M+H] + .

[0584] Step 2:

[0585] B-40-a (72 mg, 0.138 mmol), Int-A-3 (75 mg, 0.552 mmol), Pd(ACN)₂Cl₂ (18 mg, 0.07 mmol), X-Phos (28 mg, 0.07 mmol), and K₂CO₃ (57 mg, 0.42 mmol) were added to ACN (5 mL) / TEA (2 mL), and the mixture was stirred at 85 °C under nitrogen protection for 3 h. Water was added, and the mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and subjected to Prep-HPLC to obtain a pale yellow solid A-40 (11.5 mg, 14.5%). LCMS (ESI): m / z = 575.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.54(m,3H),8.48(s,1H),8.39(d,J=2.4Hz,1H),7.95(d,J=2.2H z,1H),7.67(q,J=4.7Hz,1H),5.14(d,J=8.9Hz,1H),4.22(t,J=11.1Hz,1H),4.14(d,J=11.6Hz,1H),3. 95(d,J=12.5Hz,1H),3.74(d,J=13.0Hz,1H),3.31-3.15(m,2H),3.08(s,3H),2.84(d,J=4.8Hz,3H),2. 61(d,J=10.2Hz,1H),2.54(s,2H),2.01-1.93(m,2H),1.02-0.97(m,2H),0.67(dt,J=13.3,6.7Hz,2H).

[0586] Example 38 Synthesis of Compound B-41

[0587] Compound B-41 can be synthesized by referring to the synthesis of compound B-40.

[0588]

[0589] Example 39 Synthesis of Compound C-1

[0590]

[0591] Step 1:

[0592] C-1-a (140 mg, 0.24 mmol) was dissolved in dioxane (4 mL), and HCl / dioxane (4 mL) was added. The mixture was reacted at room temperature for 1 h, and the solution was concentrated to give a white oily C-1-b (150 mg, crude). LCMS (ESI): m / z = 491.1 [M+H] + .

[0593] Step 2:

[0594] C-1-b (70 mg, 0.14 mmol), paraformaldehyde (44 mg, 0.57 mmol), AcOH (8 drops), and DCM (5 mL) were added to MeOH (5 mL). The mixture was stirred at 0 °C for ten minutes. NaBH3CN (27 mg, 0.43 mmol) was then added, and the reaction proceeded overnight at room temperature. Water was added, and the mixture was extracted with DCM, washed with saturated ammonium chloride solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a white oily C-1-c (20 mg, 28.1%). LCMS (ESI): m / z = 505.1 [M+H] + .

[0595] Step 3:

[0596] The following were added: C-1-c (20 mg, 0.04 mmol), Int-A-1 (30 mg, 0.16 mmol), Pd(ACN)2Cl2 (5 mg, 0.02 mmol), X-Phos (10 mg, 0.02 mmol), and K2CO. 3( 16 mg (0.12 mmol) and DBU (30 mg, 0.20 mmol) were added to ACN (2.5 mL) / TEA (0.5 mL), and the mixture was sealed and stirred at 85 °C for 5 h under nitrogen protection. After cooling, water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and purified by prep-HPLC to obtain a pale yellow solid C-1 (5.5 mg, yield: 27.5%). LCMS (ESI): m / z = 496.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.44(s,2H),8.40(s,1H),8.14(s,1H),7.88(s, 1H),7.69(d,J=6.6Hz,1H),7.25(d,J=8.6Hz,1H),7.13(s,2H),4.27(s,1H),4.12(s,1H ),3.90(s,1H),3.61-3.52(m,1H),3.33(s,2H),3.22(s,1H),2.67(s,1H),2.52(s,1H), 2.37(s,3H),2.09(s,1H),1.91(dd,J=8.2,5.0Hz,2H),1.00-0.93(m,2H),0.65(s,2H).

[0597] Example 40 Synthesis of compound C-2

[0598]

[0599]

[0600] Step 1:

[0601] Dissolve 6774-38-3 (1.185 g, 5 mmol) in THF (50 mL), then add Int-B-1 (1.15 g, 5 mmol) and K2CO3. ( 1.38 g (6 mmol) was stirred at 80 °C for 12 h. After filtration, the sample was washed with EA, concentrated, and purified by column chromatography to obtain C-2-a (2 g, yield: 92%). LCMS (ESI) m / z = 331.0 [M-99] + .

[0602] Step 2:

[0603] C-2-a (1.66 g, 3.86 mmol) was dissolved in dioxane (25 mL) and H₂O (5 mL). Cyclopropylboronic acid (1.33 g, 15.44 mmol), Pd(PPh₃)₄ (445 mg, 0.37 mmol), and sodium carbonate (818 mg, 7.72 mmol) were added, and the mixture was stirred at 100 °C for 12 h. The reaction solution was purified by column chromatography to obtain C-2-b (1.1 g, yield: 73%). LCMS (ESI) m / z = 331.0 [M-99] + .

[0604] Step 3:

[0605] C-2-b (1.1 g, 2.81 mmol), methanol (40 mL), and Pd / C (200 mg) were stirred at room temperature under a H2 atmosphere for 12 h. The mixture was filtered, and the filtrate was concentrated to give a white solid C-2-c (320 mg, yield: 32%). LCMS (ESI) m / z = 363.3 [M+H] + .

[0606] Step 4:

[0607] C-2-c (400 mg, 1.10 mmol) and 625471-27-4 (371 mg, 1.33 mmol) were dissolved in THF (20 mL). LiHMDS (2.2 mL, 2.2 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 h. The solution was quenched with NH4Cl aqueous solution (20 mL), extracted with EA, and the organic phase was washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give C-2-d (460 mg, yield: 68%). LCMS (ESI) m / z = 611.2 [M+H] + .

[0608] Step 5:

[0609] Dissolve C-2-d (460 mg, 0.75 mmol) in DMF (6 mL), add Int-A-1 (8 mg, 1.51 mmol), and Pd(PPh)2Cl. 2( 53 mg (0.08 mmol), CuI (14 mg, 0.08 mmol), DBU (573 mg, 3.77 mmol), and THF of TBAF (1.5 mL, 1.5 mmol) were added and stirred at 100 °C for 2 h. The reaction mixture was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give C-2-e (360 mg, yield: 82%). LCMS (ESI) m / z = 582.3 [M+H) + .

[0610] Step 6:

[0611] C-2-e (360 mg, 0.62 mmol) was dissolved in DCM (10 mL), and compound HCl / dioxane (1.5 mL, 6 mmol) was added. The mixture was stirred in an ice bath for 2 h. After concentration, C-2-f (310 mg) was obtained. LCMS (ESI) m / z = 482.4 [M+H] + .

[0612] Step 7:

[0613] C-2-f (80 mg, 0.15 mmol) was dissolved in DCM (8 mL) and MeOH (2 mL), and 3 drops of 37% formaldehyde aqueous solution were added. After stirring for 1 h, sodium borohydride acetate (98 mg, 0.46 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to give a white solid C-2 (31 mg, yield: 40%). LCMS (ESI) m / z = 496.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.44(s,3H),8.07(s,1H),7.89(d,J=2.2Hz,1H),7.67(dd,J=8.6,2.3Hz,1H ),7.24(d,J=8.7Hz,1H),7.14(s,2H),4.70-4.60(m,1H),4.05(dd,J=11.5,9.0Hz,1H),3.82(s,1H),3.30(dd,J=1 1.8,3.9Hz,2H),3.13-2.99(m,1H),2.88(d,J=11.2Hz,1H),2.77(td,J=11.8,3.1Hz,1H),2.62-2.52(m,2H),2.34 (s,3H),2.04-1.94(m,1H),1.91(td,J=8.4,4.2Hz,1H),0.97(dq,J=7.9,2.6Hz,2H),0.65(qt,J=4.0,2.4Hz,2H).

[0614] Example 41 Synthesis of compound C-3

[0615]

[0616] Step 1:

[0617] C-2-f (28 mg, 0.05 mmol) was dissolved in 2 mL of methanol, TBS-protected hydroxyacetaldehyde (8.94 mg, 0.05 mmol), and sodium cyanoborohydride (3.22 mg, 0.05 mmol). The mixture was stirred at room temperature for 16 h, filtered, and the organic phase was concentrated and then subjected to column chromatography to obtain C-3-a (20 mg, yield: 58.8%). LCMS (ESI) m / z = 668.4 [M+H] + .

[0618] Step 2:

[0619] 2 mL of THF containing C-3-a (20 mg, 0.03 mmol) was added to 5 drops of tetrabutylammonium fluoride tetrahydrofuran solution (1 M), and the mixture was stirred at 25 °C for 2 h. The reaction solution was concentrated and purified by column chromatography to obtain C-3 (4.3 mg, yield: 27%). LCMS (ESI) m / z = 554.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.00(s,1H),8.45(s,3H),8.13-8.05(m,1H),7.73(dd, J=8.6,2.3Hz,1H),7.29(d,J=8.7Hz,1H),7.14(s,2H),4.70-4.65(m,1H),4.44(t,J=5.4Hz,1 H),4.18-4.04(m,2H),3.55-3.49(m,3H),3.06(d,J=11.2Hz,1H),2.85(p,J=6.5Hz,2H),2.78 -2.73(m,1H),2.64(q,J=7.8,6.6Hz,2H),2.59(q,J=6.2Hz,1H),1.99(dd,J=15.9,4.7Hz,2H).

[0620] Example 42 Synthesis of compounds C-4 to C-18

[0621] By referring to the synthesis of compound C-2, compounds C-4 to C-18 can be synthesized.

[0622]

[0623]

[0624] Example 43 Synthesis of compound C-19

[0625] Step 1:

[0626] C-2-d (250 mg, 0.41 mmol) was dissolved in DMF (5 mL), and DBU (314 mg, 2.05 mmol) was added. The mixture was stirred at 100 °C for 4 h. The reaction was quenched with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography to give C-19-a (186 mg, yield: 77%). LCMS (ESI) m / z = 591.1 [M+H] + .

[0627] Step 2:

[0628] C-19-a (186 mg, 0.32 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (1 mL, 4 mmol) was added. The mixture was stirred in an ice bath for 2 h. After concentration, C-19-b (152 mg, yield: 92%) was obtained. LCMS (ESI) m / z = 491.1 [M+H] + .

[0629] Step 3:

[0630] C-19-b (50 mg, 0.095 mmol), 2,2-dimethylethylene oxide (14.0 mg, 0.19 mmol), DMF (2 mL), and potassium carbonate (26 mg, 0.19 mmol) were mixed. The mixture was heated and stirred at 100 °C for 16 h. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain C-19-c (33 mg, yield: 35%).

[0631] Step 4:

[0632] C-19-c (33 mg, 0.059 mmol), Int-A-3 (10 mg, 0.076 mmol), cuprous iodide (1.12 mg, 0.006 mmol), Pd(PPh3)2Cl2 (4.12 mg, 0.0059 mmol), TEA (18 mg, 0.018 mmol), TBAF (10 mg), DBU (0.5 mL), and DMF (2.0 mL) were reacted at 80 °C for 4 h under nitrogen protection. The reaction solution was concentrated and purified by column chromatography to obtain C-19 (12.4 mg, yield: 37%). LCMS (ESI) m / z = 568.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.48(d,J=31.1Hz,3H),8.12(d,J=1.8Hz,1H),7.90(d,J=2.2Hz,1H),7 .70(dd,J=8.5,2.2Hz,1H),7.59(q,J=4.7Hz,1H),7.27(d,J=8.7Hz,1H),4.68(s,1H),4.06(t,J=10.0Hz,2H), 3.85(s,1H),3.05-2.95(m,3H),2.84(d,J=4.8Hz,3H),2.79(d,J=12.4Hz,2H),2.69(s,1H),2.46(d,J=13.5Hz ,1H),2.30(d,J=13.5Hz,1H),1.96-1.90(m,2H),1.10(d,J=7.5Hz,6H),0.99-0.95(m,2H),0.70-0.63(m,2H).

[0633] Example 44 Synthesis of compounds C-20 to C-36

[0634] By referring to the synthesis of compound A-25, compounds C-20 to C-36 can be synthesized.

[0635]

[0636]

[0637]

[0638] Example 45 Synthesis of compound C-37

[0639]

[0640] Step 1:

[0641] C-2-c (350 mg, 0.97 mmol) and C-37-a (309 mg, 0.97 mmol) were dissolved in THF (20 mL), and LiHMDS (2 mL, 2 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 1 h. The solution was quenched with NH4Cl aqueous solution (20 mL), extracted with EA, and the organic phase was washed with saturated saline solution (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give C-37-b (560 mg, yield: 89%). LCMS (ESI) m / z = 651.3 [M+H] + .

[0642] Step 2:

[0643] C-37-b (560 mg, 0.86 mmol) was dissolved in DMF (7 mL), and Int-A-1 (247 mg, 1.29 mmol), Pd(PPh)₂Cl₂ (60 mg, 0.086 mmol), CuI (17 mg, 0.086 mmol), DBU (655 mg, 4.31 mmol), and a THF solution of TBAF (1.3 mL, 1.3 mmol) were added. The mixture was stirred at 100 °C for 2 h. The reaction solution was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain C-37-c (280 mg, yield: 52.3%). LCMS (ESI) m / z = 622.5 [M+H] + .

[0644] Step 3:

[0645] C-37-c (280 mg, 0.45 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (1 mL, 4 mmol) was added. The mixture was stirred in an ice bath for 2 h. After concentration, C-37-d (240 mg) was obtained. LCMS (ESI) m / z = 522.3 [M+H] + .

[0646] Step 4:

[0647] Under ice bath conditions, C-37-d (80 mg, 0.15 mmol) was dissolved in DCM (6 mL) and MeOH (2 mL), followed by the addition of 3 drops of 37% formaldehyde aqueous solution. After stirring for 1 h, sodium borohydride acetate (93 mg, 0.44 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to give a white solid C-37 (8 mg, yield: 10.2%). LCMS (ESI) m / z = 536.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.46(s,3H),8.06(m,1H),7.89(d,J=2.3Hz,1H),7.13(s,2H),6.59(s ,1H),4.71(s,1H),4.10-4.00(m,1H),3.84(s,1H),3.31-3.21(m,1H),3.14-3.01(m,1H),2.88(d,J=11.2Hz, 1H),2.79(td,J=11.9,3.1Hz,1H),2.72-2.51(m,3H),2.44(td,J=8.3,4.2Hz,1H),2.35(s,3H),2.03-1.95( m,1H),1.91(td,J=8.5,4.2Hz,1H),1.19-1.07(m,2H),1.02-0.85(m,4H),0.65(ddt,J=5.2,3.7,1.8Hz,2H).

[0648] Example 46 Synthesis of compounds C-38 and C-39

[0649] Compounds C-38 and C-39 can be synthesized by referring to the synthesis of compound C-37.

[0650]

[0651] Example 47 Synthesis of compound C-40

[0652]

[0653] Step 1:

[0654] C-2-a (750 mg, 1.74 mmol), vinyl borate (403 mg, 2.61 mmol), Pd(dppf)Cl2 (638 mg, 0.87 mmol), Na2CO3 (554 mg, 0.23 mmol), H2O (5 mL), and dioxane (20 mL) were stirred at 90 °C under nitrogen protection for 3 h. Water was added to the reaction mixture, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 3:1) to give a yellow oily liquid C-40-a (440 mg, yield: 59%). LCMS (ESI): m / z = 379.19 [M+H] + .

[0655] Step 2 :

[0656] C-40-a (400 mg, 1.06 mmol), MeOH (30 mL), and Pd / C (40 mg) were stirred overnight at 30 °C under a hydrogen atmosphere (1 atm). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude black oily liquid C-40-b (320 mg, yield: 86%). LCMS (ESI): m / z = 351.23 [M+H] + .

[0657] Step 3:

[0658] C-40-b (320 mg, 0.91 mmol) and compound 625471-27-4 (256 mg, 0.91 mmol) were added to THF (30 mL) and stirred at 0 °C for 10 min. LiHDMS (610 mg, 3.65 mmol) was added, and the mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (PE:EA = 1:1) yielded a black solid C-40-c (255 mg, yield: 47%). LCMS (ESI): m / z = 599.15 [M+H] + .

[0659] Step 4:

[0660] C-40-c (260 mg, 0.43 mmol) and DBU (1.5 mL) were added to DMF (15 mL), and the mixture was stirred at 100 °C for 2 h. The reaction solution was extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 3:1) to obtain a white solid C-40-d (160 mg, yield: 64%). LCMS (ESI): m / z = 579.14 [M+H] + .

[0661] Step 5:

[0662] C-40-d (160 mg, 0.27 mmol) was dissolved in a 5 mL solution of dioxane in HCl, followed by the addition of 5 mL of 1,4-dioxane and 1 mL of MeOH. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to give a white solid, C-40-e (210 mg, crude). LCMS (ESI): m / z = 479.09 [M+H] + .

[0663] Step 6:

[0664] C-40-e (180 mg, 0.37 mmol), cyclopropylformyl chloride (78 mg, 0.75 mmol), and THF (20 mL) were added, followed by TEA (152 mg, 1.5 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1) to obtain a white solid C-40-f (160 mg, yield: 78%). LCMS (ESI): m / z = 547.11 [M+H] + .

[0665] Step 7:

[0666] The following were added: C-40-f (150 mg, 0.31 mmol), Int-A-1 (240 mg, 0.26 mmol), CuI (12 mg, 0.06 mmol), and Pd(PPh)3Cl. 2( 44 mg (0.06 mmol), ACN (15 mL), TEA (3 mL), and DBU (230 mg, 1.5 mmol). The mixture was stirred at 70 °C under nitrogen protection for 4 h. The reaction solution was filtered, and the filtrate was extracted with EA after adding water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain the crude product. Further purification yielded a white solid C-40 (22.6 mg, yield: 14.4%). LCMS (ESI): m / z = 538.25 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.98(d,1H),8.51(dd,1H),8.24(s,2H),7.92(d,1H),7.75(s,1H),7.49 (dd,1H),7.10(dd,1H),6.93(s,2H),4.46(d,2H),4.23-4.11(m,1H),4.01(m,1H),3.84(m,1H), 3.32 (t, 1H), 3.09 (s, 1H), 2.99 (m, 1H), 2.87 (m, 1H), 2.83-2.68 (m, 1H), 2.41-2.35 (m, 2H), 1.83 (d, 1H), 1.66-1.40 (m, 1H), 1.00 (t, 3H), 0.66-0.59 (m, 1H), 0.59-0.49 (m, 3H). Example 48 Synthesis of compound C-41

[0667]

[0668] Step 1:

[0669] Compound 59237-53-5 (1.00 g, 4.63 mmol) was dissolved in THF (10 mL), and Int-B-1 (1.06 g, 4.63 mmol) and K2CO were added. 3( 1.28 g (9.26 mmol) was heated to reflux and stirred for 5 h. Water (30 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give a yellow solid C-6-a (1.80 g, yield: 95%). LCMS (ESI) m / z = 433.3 [M + Na] + .

[0670] Step 2:

[0671] C-41-a (0.90 g, 2.20 mmol) was dissolved in ethanol (20 mL), and Pd / C (90 mg) was added. The mixture was stirred at 50 °C for 12 h in a H2 environment. The solution was filtered, and the filtrate was concentrated to give a white solid C-41-b (0.70 g, yield: 84%). LCMS (ESI) m / z = 381.3 [M+H] + .

[0672] Step 3:

[0673] C-41-b (0.70 g, 1.84 mmol) was dissolved in THF (20 mL), and MgBrMe (18.4 mL, 18.4 mmol, 1 mol / L) was slowly added dropwise at -78 °C, with stirring at room temperature for 2 h. A saturated NH4Cl aqueous solution (30 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100~1 / 9~DCM / MeOH = 10 / 1) to give a yellow solid C-41-c (0.35 g, yield: 50%). LCMS (ESI) m / z = 381.3 [M+H] + .

[0674] Step 4:

[0675] C-41-c (0.35 g, 0.92 mmol) and 625471-27-4 (0.26 g, 0.92 mmol) were dissolved in THF (10 mL), and LiHMDS (3.68 mL, 3.68 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl aqueous solution (20 mL), extracted with EA, washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 1 / 100–1 / 9 - DCM / MeOH = 10 / 1) to give a white solid C-41-d (0.38 g, yield: 66%). LCMS (ESI) m / z = 629.2 [M+H] + .

[0676] Step 5:

[0677] C-41-d (0.38 g, 0.60 mmol), DMF (2 mL), and DBU (0.46 g, 3.05 mmol) were stirred at 100 °C for 3 h. The reaction mixture was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to give a white solid C-41-e (0.33 g, yield: 90%). LCMS (ESI) m / z = 609.2 [M+H] + .

[0678] Step 6:

[0679] C-41-e (0.33 g, 0.54 mmol), DCM (4 mL), and a 4 M solution of 1,4-dioxane hydrochloride (2 mL) were stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give a white solid C-41-f (0.26 g, yield: 94%). LCMS (ESI) m / z = 509.1 [M+H] + .

[0680] Step 7:

[0681] C-41-f (0.13 g, 0.26 mmol), DCM (5 mL), formaldehyde aqueous solution (0.17 g, 2.05 mmol), and NaBH(AcO)3 (0.11 g, 0.51 mmol) were stirred at room temperature for 12 h. The mixture was washed with saturated NaHCO3 aqueous solution (5 mL), dried over anhydrous Na2SO4, filtered, and the crude white solid C-41-g (0.10 g, yield: 75%) was concentrated. LCMS (ESI) m / z = 523.2 [M+H] + .

[0682] Step 8:

[0683] Dissolve C-41-g (50 mg, 0.096 mmol) in DMF (2 mL), then add Int-A-1 (18 mg, 0.096 mmol) and Pd(PPh)2Cl. 2( 6.7 mg (0.0096 mmol), CuI (1.8 mg, 0.0096 mmol), TEA (19.3 mg, 0.19 mmol), and TBAF in THF solution (0.096 mL, 0.096 mmol) were stirred at 50 °C for 3 h. The reaction mixture was purified by column chromatography (PE / EA = 1 / 100–1 / 9–DCM / MeOH = 10 / 1) and reverse-phase preparation (ACN / H₂O = 5 / 95–95 / 5, 0.1% aqueous solution of NH₄CO₂H) to give a white solid C-41 (15 mg, yield: 31%). LCMS (ESI) m / z = 514.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.86(s,1H),8.44(s,2H),8.14-8.08(m,2H),7 .69(d,J=8.4Hz,1H),7.27(d,J=8.4Hz,1H),7.13(s,2H),5.14(brs,1H),4.67(s,1H), 4.07(t,J=10.0Hz,1H),3.84(brs,1H),3.35-3.25(m,1H),3.18-3.10(m,1H),2.91-2. 77(m,3H),2.56-2.53(m,2H),2.35(s,3H),2.01(d,J=10.0Hz,1H),1.56-1.45(m,6H).

[0684] Example 49 Synthesis of compound C-42

[0685]

[0686] Step 1:

[0687] C-19-b (75 mg, 0.14 mmol), paraformaldehyde (30 mg, 0.56 mmol), and acetic acid (10 drops) were added to 6 mL of a 1:1 mixture of DCM and MeOH and stirred at room temperature for 15 minutes. NaBH3CN (30 mg, 0.48 mmol) was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 1 h. The mixture was extracted with DCM, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, and concentrated. Purification by column chromatography (DCM / MeOH = 30 / 1) yielded a white solid C-42-a (40 mg, yield: 56%). LCMS (ESI): m / z = 505.0 [M+H] + .

[0688] Step 2:

[0689] C-42-a (40 mg, 0.08 mmol) and C-42-b (26 mg, 0.1 mmol), Cs2CO 3( 65 mg (0.2 mmol) and Pd(dppf)Cl2 (8.7 mg, 0.012 mmol) were added to 1,4-dioxane (5 mL) / H2O (1 mL). The mixture was stirred at 95 °C for 2 h under nitrogen protection, then cooled. Water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and subjected to Prep-HPLC to give a white solid C-42 (4.4 mg, yield: 11%). LCMS (ESI): m / z = 522.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.20(s,1H),8.49(s,1H),8.39(s,1H),8.13(s,1H),8.04(d,1H),7.9 7(d,J=8.2Hz,1H),7.93(d,1H),7.51(d,1H),7.37(d,1H),6.91(s,2H),4.74(s,1H),4.10(t,J=10.3Hz,1H), 3.88(s,1H),3.28-3.18(m,3H),3.11(d,J=12.7Hz,1H),2.93(d,J=10.7Hz,1H),2.83(t,1H),2.57(d,J=11.1 Hz,1H),2.37(s,3H),2.04(d,1H),1.93(ddd,J=13.5,8.6,5.1Hz,1H),1.05-0.84(m,2H),0.72-0.55(m,2H).

[0690] Example 50 Synthesis of compound C-43

[0691]

[0692] Step 1:

[0693] C-19-a (193 mg, 0.33 mmol) was dissolved in 1,4-dioxane (20 mL), and C-43-a (97 mg, 0.39 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), Cs2CO3 (267 mg, 0.82 mmol), and water (4 mL) were added. The mixture was stirred at 90 °C for 2 h under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted three times with EA extract (15 mL), washed with saturated brine of the organic phase, purified by silica gel column chromatography (DCM:MeOH = 15:1), and concentrated to obtain product C-43-b (122 mg, 0.21 mmol), a yellow oily liquid. Yield: 58%. LCMS (ESI): m / z 584.4 [M+H] + .

[0694] Step 2:

[0695] C-43-b (1.1 g, 4.03 mmol) was dissolved in methanol (2 mL) at room temperature, and dioxane hydrochloride solution (1 mL, 1 M) was added. The mixture was stirred for 2 h. After concentration, C-43-c (1.4 mg, 0.002 mmol) was obtained as a yellow solid with a yield of 6%. LCMS (ESI): m / z 484.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.94(s,1H),8.76(s,1H),8.54(s,3H),7.94(t ,J=5.6Hz,1H),7.73(d,J=8.4Hz,1H),7.26(d,J=8.7Hz,1H),7.18(d,J=16.6Hz,1H), 7.03(d,J=16.6Hz,1H),6.89(s,1H),4.68(s,1H),4.20(s,1H),3.84(d,J=15.4Hz,2H ),3.45(s,4H),3.37(s,3H),2.10-1.86(m,2H),1.08-0.90(m,2H),0.79-0.59(m,2H).

[0696] Step 3:

[0697] C-43-c (30 mg, 0.062 mmol) and triethylamine (20 mg, 0.186 mmol) were stirred in an ice bath for 10 minutes. Acetic anhydride (8 mg, 0.074 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified to obtain product C-43 (15.2 mg, 0.029 mmol), a white solid, in 46% yield. LCMS (ESI): m / z 526.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.59-8.49(m,3H),8.23(d,J=2.2Hz,1H),7.93(t,J=2.6Hz,1H),7.73(s ,1H),7.30(s,1H),7.17(d,J=16.6Hz,1H),7.02(d,J=16.6Hz,1H),6.78(s,2H),4.67(d,J=9.8Hz,2H),4.22(dt ,J=20.5,10.5Hz,1H),4.01(d,J=12.8Hz,1H),3.51(t,J=11.8Hz,1H),3.29-2.85(m,4H),2.55(d,J=11.4Hz,1 H),2.07(d,J=4.1Hz,3H),1.99-1.88(m,1H),1.69(d,J=14.8Hz,1H),1.07-0.92(m,2H),0.68(d,J=5.4Hz,2H).

[0698] Example 51 Synthesis of Compound D-1

[0699]

[0700] Step 1:

[0701] Compound 186413-75-2 (3.0 g, 12.0 mmol) was dissolved in 50 mL of THF, and Int-B-1 (2.75 g, 12 mmol) and potassium carbonate (4.1 g, 30 mmol) were added. The mixture was stirred overnight at 70 °C. The solid was removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography to give D-1-a (4.2 g, yield: 79%). LCMS (ESI): m / z = 347.0 [M+H] +

[0702] Step 2:

[0703] D-1-a (4.2 g, 9.43 mmol), cyclopropylboronic acid (2.43 g, 3.0 mmol), palladium acetate (0.21 g, 0.94 mmol), Sphos (0.77 g, 1.9 mmol), and potassium phosphate (4.0 g, 18.8 mmol) were added to 20 mL of toluene and 10 mL of water. The reaction was carried out overnight at 100 °C under nitrogen protection. Saturated sodium carbonate was added and stirred for 30 minutes. The mixture was extracted with 20 EA, the organic phase was concentrated, and the residue was purified by column chromatography to give D-1-b (3.6 g, yield: 94%). LCMS (ESI): m / z = 307.2 & 351.2 [M+H] +

[0704] Step 3:

[0705] D-1-b (3.6 g, 8.9 mmol) was dissolved in methanol, followed by the addition of potassium carbonate (2.45 g, 17.8 mmol) and palladium on carbon (0.36 g, 10% wt). The reaction was carried out at room temperature for 2 h under a hydrogen atmosphere. The mixture was filtered, the filtrate was concentrated, washed with 10 mL of water, extracted with DCM, and the organic phase was concentrated to give D-1-c (3.2 g, 96% yield). LCMS (ESI): m / z = 377.3 [M+H] +

[0706] Step 4:

[0707] D-1-c (3.2 g, 8.5 mmol) was dissolved in 50 mL of THF. Under nitrogen protection, bis(trimethylsilylaminolithium) (30 mL, 1 M, 30 mmol) was added dropwise at -40 °C. After stirring for 20 minutes, compound 625471-27-4 (3.8 g, 12.8 mmol) was added. The mixture was stirred at -40 °C for 2 h, and the reaction was quenched with 50 mL of water. The mixture was extracted with EA, and the organic phase was concentrated and purified by column chromatography to obtain D-1-d (3.4 g, yield: 62%). LCMS (ESI): m / z = 642.2 & 644.2 [M+H] +

[0708] Step 5:

[0709] D-1-d (3.4 g, 5.3 mmol) was dissolved in 20 mL of DMF with stirring. 1,8-diazabicyclo[5.4.0]undec-7-ene (1.6 mmol, 10.6 mmol) was added, and the mixture was stirred at 100 °C for 4 h. The mixture was then quenched with 100 mL of water, and the reaction solution was extracted with EA. The organic phase was concentrated, and the residue was purified by column chromatography to give D-1-e (3.0 g, yield: 93%). LCMS (ESI): m / z = 606.2 [M+H] +

[0710] Step 6:

[0711] D-1-e (3.0 g, 5.0 mmol) was dissolved in methanol, followed by the addition of 25 mL of methanol hydrochloric acid (25 mmol). The mixture was stirred overnight at room temperature. The reaction solution was concentrated to give solid D-1-f (2.5 g, yield: 93%).

[0712] Step 7:

[0713] D-1-f (500 mg, 0.97 mmol), TEA (300 mg, 3.0 mmol), 10 mL DCM, cyclobutylcarboxylic acid (149 mg, 1.5 mmol), and HATU (562 mg, 1.5 mmol) were stirred at room temperature for 2 h. The reaction solution was concentrated, and the residue was purified by column chromatography to give D-1-g (520 mg, yield: 96%). LCMS (ESI): m / z = 588.2 [M+H] +

[0714] Step 8:

[0715] D-1-g (50 mg, 0.09 mmol), Int-A-15 (30 mg, 0.13 mmol), cuprous iodide (1.6 mg, 0.009 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.009 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (39 mg, 0.26 mmol), tetrabutylammonium fluoride / THF solution (1 M, 130 μL), and 2.0 mL DMF were stirred at 100 °C for 1 h under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain D-1 (10.6 mg, yield: 20%). LCMS (ESI): m / z = 619.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.04(m,1H),8.53(d,3H),8.41(m,1H),8.36(t,1H),7.92(d,1H),5 .06(m,1H),4.64(m,0.82H),4.42(m,0.47H),4.26(m,1H),4.09-3.89(m,1H),3.72(m,1H),3. 41(m,1H),3.10(m,3H),2.92-2.64(m,2H),2.47(s,3H),2.38(m,1H),2.26(m,1H),2.20-2.0 2(m,3H),1.96-1.85(m,2H),1.71(m,2H),0.97(d,2H),0.73-0.65(m,2H),0.61-0.46(m,4H).

[0716] Example 52 Synthesis of compounds D-2 to D-11

[0717] Following the synthesis of compound D-1, compounds D-2 to D-11 can be synthesized.

[0718]

[0719]

[0720] Example 53 Synthesis of Compound E-1

[0721]

[0722] Step 1:

[0723] Compound 400-93-1 (5 g, 0.03 mol) was dissolved in DCM (60 mL). Under nitrogen protection, DAST (22 g, 0.14 mol) was added dropwise using a constant pressure dropping funnel at -70 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was slowly added to 100 mL of saturated NaHCO3 solution, extracted with DCM, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 20 / 1) to give a yellow oily E-1-a (5.6 g, yield: 95%). 1 H NMR (400MHz, DMSO-d6) δ8.30(dd,J=7.2,2.4Hz,1H),8.06-8.03(m,1H),7.75(dd,J=11.2,9.2Hz,1H),2.04(t,J=19.2Hz,3H).

[0724] Step 2:

[0725] E-1-a (2 g, 0.01 mol), Int-B-1 (2.23 g, 0.01 mol), K₂CO₃ (2.68 g, 0.02 mol), and THF (20 mL) were reacted at 70 °C for 3 h. The mixture was cooled, quenched with saturated ammonium chloride aqueous solution, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 3 / 1) to give a yellow oily E-1-b (3 g, yield: 72%). LCMS (ESI): m / z = 438.2 [M + Na] + .

[0726] Step 3:

[0727] E-1-b (2.4 g, 0.006 mol) was dissolved in methanol (10 mL), and Pd / C (0.25 g) was added. The mixture was reacted at room temperature for 3 h under a H2 atmosphere. The solution was filtered. The filtrate was concentrated to give a yellow solid E-1-c (2 g, yield: 77%). LCMS (ESI): m / z = 386.2 [M+H] + .

[0728] Step 4:

[0729] E-1-c (2 g, 0.005 mol) and compound 78686-83-6 (1.7 g, 0.005 mol) were sequentially added to THF (10 mL), followed by injection of 2.6 mL of LiHMDS (1 M in THF) at 0 °C and stirring at 0 °C for 1 h under nitrogen protection. A saturated ammonium chloride aqueous solution (10 mL) was added, and the mixture was extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was purified by column chromatography (PE / EA = 2 / 1) to give a yellow solid E-1-d (3 g, yield: 85%). LCMS (ESI): m / z = 651.1 [M+H] + .

[0730] Step 5:

[0731] E-1-d (3 g, 0.007 mol), DBU (2.37 g, 0.015 mol), and DMF (10 mL) were reacted at 100 °C for 2 h. The reaction solution was poured into a saturated ammonium chloride aqueous solution (20 mL), extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA = 2 / 1) to give a white solid E-1-e (2.5 g, yield: 85%). LCMS (ESI): m / z = 615.1 [M+H] + .

[0732] Step 6:

[0733] E-1-e (2.5 g, 0.004 mol) was dissolved in DCM (10 mL), followed by the addition of HCl / dioxane (1 M, 5 mL). The reaction was carried out at room temperature for 30 min, and the solution was concentrated to give a white solid E-1-f (2 g, yield: 95%). LCMS (ESI): m / z = 551.1 [M+H] + .

[0734] Step 7:

[0735] E-1-f (200 mg, 0.39 mmol) and TEA (80 mg, 0.78 mmol) were dissolved in DCM (8 mL), and cyclobutylformyl chloride (55 mg, 0.47 mmol) was added dropwise at 0 °C, reacting for 1 h. A saturated ammonium chloride aqueous solution was added, and the mixture was extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography (PE / EA = 1 / 1) to give a white solid E-1-g (140 mg, yield: 61%). LCMS (ESI): m / z = 597.1 [M+H] + .

[0736] Step 8:

[0737] E-1-g (70 mg, 0.12 mmol), Int-A-1 (67 mg, 0.35 mmol), X-Phos (28 mg, 0.06 mmol), Pd(CAN)2Cl2 (15 mg, 0.06 mmol), DBU (53 mg, 0.35 mmol), K2CO3 (48 mg, 0.35 mmol), TEA (1 mL), and ACN (5 mL) were reacted in a sealed tube at 85 °C for 5 h under nitrogen protection. After cooling, the reaction solution was poured into 10 mL of saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to prepare E-1-c (10 mg, yield: 14%). LCMS (ESI): m / z = 588.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ10.22-10.28(d,1H),8.83-8.87(m,1H),8.47(d,1H),8.40(s,2H),8.3 9(s,1H),7.32-7.37(m,2H),7.19(s,2H),5.24(m,1H),4.30-4.68(m,1H),4.20(m,1H),3.70-4. 05(m,2H), 2.97-3.05(m,4H), 2.76-2.89(m,1H), 2.40-2.50(m,1H), 2.22-2.33(m,1H), 2.01-2.18(m,3H), 1.92-2.01(m,4H), 1.82-1.66(m,2H). Example 54: Synthesis of compounds E-2 to E-33, E-36 to E-39, E-43 to E-65.

[0738] The following compounds can be synthesized by referring to the synthesis of compound E-1.

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745] Example 55 Synthesis of compound E-34

[0746]

[0747] Step 1:

[0748] Compound 654-99-9 (4.16 g, 20 mmol) was dissolved in THF (80 mL). HATU (11.40 g, 30 mmol), DIPEA (5.16 g, 40 mmol), and dimethylamine hydrochloride (1.94 g, 24 mmol) were added under ice bath conditions. The mixture was slowly heated to room temperature and reacted overnight. After adding water, the mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give E-34-a (3.5 g, yield: 74%). LCMS (ESI) m / z = 236.1 [M+H] + .

[0749] Step 2:

[0750] E-34-a (3.50 g, 14.89 mmol) was dissolved in THF (40 mL), and boranetetrahydrofuran solution (75 mL, 75 mmol) was added. The mixture was stirred at room temperature for 0.5 h, then heated under reflux overnight. After quenching the reaction with methanol, the mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain E-34-b (2.8 g, yield: 85%). LCMS (ESI) m / z = 222.2 [M+H] + .

[0751] Step 3:

[0752] E-34-b (700 mg, 3.17 mmol) was dissolved in concentrated sulfuric acid (5 mL) under ice bath conditions. Potassium nitrate (640 mg, 6.33 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with ice, and NaOH was added to bring the pH to approximately 12. The mixture was extracted with EA, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain E-34-c (380 mg, yield: 45%). LCMS (ESI) m / z = 267.1 [M+H] + .

[0753] Step 4:

[0754] E-34-c (380 mg, 1.43 mmol) was dissolved in THF (20 mL), and K₂CO₃ (394 mg, 2.86 mmol) and S-Int-B-3 (348 mg, 1.43 mmol) were added. The mixture was stirred at 80 °C for 12 h. The mixture was filtered, the filter cake was washed with THF, and the filtrate was concentrated under reduced pressure to dryness. E-34-d (480 mg, yield: 68%) was purified by column chromatography. LCMS (ESI) m / z = 491.3 [M+H] + .

[0755] Step 5:

[0756] E-34-d (480 mg, 0.98 mmol) was dissolved in methanol (20 mL), Pd / C (0.11 g), and stirred at room temperature in a H2 environment for 12 h. The mixture was filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure until dry to obtain E-34-e (360 mg, yield: 80%). LCMS (ESI) m / z = 461.3 [M+H] + .

[0757] Step 6:

[0758] Under Ar protection and on ice bath, E-34-e (360 mg, 0.78 mmol) was dissolved in THF (15 mL), and 78686-83-6 (232 mg, 0.78 mmol) and LiHMDS (2.5 mL, 2.5 mmol) were added. The mixture was stirred for 2 h. The solution was quenched with saturated aqueous NH4Cl, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give a white solid E-34-f (380 mg, yield: 60.48%). LCMS (ESI) m / z = 726.3 [M+H] + .

[0759] Step 7:

[0760] E-34-f (380 mg, 0.52 mmol) was dissolved in DMF (5 mL), and DBU (0.73 g, 2.38 mmol) was added. The mixture was stirred at 120 °C for 3 h. Column chromatography yielded a white solid E-34-g (300 mg, yield: 83%). LCMS (ESI) m / z = 690.3 [M+H] + .

[0761] Step 8:

[0762] E-34-g (300 mg, 0.435 mmol) was dissolved in DCM (0 mL), and 4 M 1,4-dioxane hydrochloride solution (3 mL) was added. The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure until dry to give crude white solid E-34-h (270 mg, yield: 99%). LCMS (ESI) m / z = 590.2 [M+H] + .

[0763] Step 9:

[0764] E-34-h (100 mg, 0.16 mmol) was dissolved in DCM (10 mL). TEA (62 mg, 0.48 mmol) and acetyl chloride (16 mg, 0.20 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted with DCM. The organic phase was washed with saturated saline solution (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The reaction mixture was purified by column chromatography to give a white solid E-34-i (80 mg, yield: 80%). LCMS (ESI) m / z = 632.3 [M+H] + .

[0765] Step 10:

[0766] Dissolve E-34-i (80 mg, 0.13 mmol) in DMF (2 mL), then add Int-A-15 (38 mg, 0.24 mmol) and Pd(PPh)2Cl. 2( 12 mg (0.02 mmol), CuI (3 mg, 0.02 mmol), and DBU (74 mg, 0.49 mmol) were added under Ar protection and microwaved at 100 °C for 1 h. The reaction solution was purified by column chromatography (PE / EA = 1 / 100~1 / 9~DCM / MeOH = 10 / 1) and reverse-phase preparation (ACN / H2O = 5 / 95~95 / 5, 0.1% aqueous solution of NH4HCO3) to give a white solid E-34 (40 mg, yield: 47%). LCMS (ESI) m / z = 663.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ10.09(d,1H),9.00(d,1H),8.54(s,3H),8.37(dd,1H) ,7.93(d,1H),7.60(d,1H),5.75-5.62(m,1H),4.96-4.55(m,1H),4.48-3.84(m ,2H),3.51-3.41(m,4H),3.19-3.17(m,1H),3.05-2.61(m,4H),2.20-2.09(m,8 H),1.81-1.61(m,1H),1.50-1.44(m,3H),0.76-0.63(m,2H),0.56-0.47(m,2H).

[0767] Example 56 Synthesis of compounds E-35, E-40 to E-42

[0768] By referring to the synthesis of compound E-34, compounds E-35, E-40 to E-42 can be synthesized.

[0769]

[0770] Example 57 Synthesis of compound E-67

[0771]

[0772] Step 1:

[0773] E-1-a (2 g, 9.8 mmol), compound 122536-77-0 (2 g, 10.7 mmol), K₂CO₃ (2.7 g, 19.6 mmol), and THF (40 mL) were reacted at 70 °C for 3 h. The mixture was cooled, quenched with water (40 mL), extracted with EA (40 mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 3:1) to give a yellow solid E-67-a (3 g, 83%). LCMS (ESI): m / z = 372.1 [M+H] + .

[0774] Step 2:

[0775] E-67-a (1.3 g, 3.5 mmol) was dissolved in DCM (20 mL), and HCl (g) / dioxane (1 M, 5 mL) was added. The mixture was reacted at room temperature for 30 min, and the solvent was removed to obtain a yellow solid E-67-b (900 mg, crude). LCMS (ESI): m / z = 272.0 [M+H] + .

[0776] Step 3:

[0777] Add E-67-b (900 mg, 3.3 mmol), TBS-protected hydroxyacetaldehyde (809 mg, 4.6 mmol), AcOH (0.5 mL), DCM (20 mL), and MeOH (1 mL) to the reaction flask; stir at 0°C for ten minutes, then add NaBH(OAc). 3( 2.1 g (9.9 mmol) was added, and the mixture was reacted at room temperature for 3 h. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL). The extract was washed with saturated brine, the organic phase was dried, and the mixture was concentrated to give a crude yellow solid, E-67-c (1 g). LCMS (ESI): m / z = 430.4 [M+H] + .

[0778] Step 4:

[0779] E-67-c (1 g, crude) was dissolved in DCM (20 mL), and HCl (g) / dioxane (1 M, 2 mL) was added. The mixture was reacted at room temperature for 1 h, and the solvent was removed to obtain crude yellow solid E-67-d (1 g). LCMS (ESI): m / z = 316.2 [M+H] + .

[0780] Step 5:

[0781] E-67-d (1 g, 3.2 mmol) was dissolved in DCM (20 mL), and TEA (970 mg, 9.6 mmol) and Boc₂O (1 g, 4.8 mmol) were added. The mixture was stirred at room temperature for 6 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (20 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 1) to give a yellow oily substance, E-67-e (400 mg, yield: 31%). LCMS (ESI): m / z = 416.4 [M+H] + .

[0782] Step 6:

[0783] E-67-e (400 mg, 0.96 mol) was dissolved in an EA (10 mL) reaction flask, and Pd / C (40 mg) was added. The mixture was reacted at room temperature for 3 h under a H2 atmosphere. After filtration, the solvent was removed to obtain a yellow solid E-67-f (370 mg, 100%). LCMS (ESI): m / z = 386.3 [M+H] + .

[0784] Step 7:

[0785] E-67-f (370 mg, 0.96 mol), compound 78686-83-6 (285 mg, 0.96 mol), and THF (10 mL) were sequentially added to a three-necked flask. Under nitrogen protection, LiHMDS (1 M in THF, 2.9 mL) was added dropwise at 0 °C, and the reaction was continued for 0.5 h. Then, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with EA (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to give a white solid E-67-g (280 mg, 33%). LCMS (ESI): m / z = 651.2 [M+H] + .

[0786] Step 8:

[0787] E-67-g (280 mg, 0.43 mmol), DBU (196 mg, 1.3 mmol), and DMF (20 mL) were added sequentially to a reaction flask. The mixture was reacted at 100 °C for 2 h. After cooling, the reaction solution was added to water (20 mL), extracted with EA (20 mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to give a white solid E-67-h (200 mg, 76%). LCMS (ESI): m / z = 615.2 [M+H] + .

[0788] Step 9:

[0789] E-67-h (200 mg, 0.33 mol) was dissolved in DCM (10 mL), and HCl / dioxane (1 M, 2 mL) was added. The mixture was reacted at room temperature for 30 min, and the solvent was removed to give a white solid E-67-i (180 mg, 100%). LCMS (ESI): m / z = 515.1 [M+H] + .

[0790] Step 10:

[0791] E-67-i (30 mg, 0.058 mmol), formaldehyde aqueous solution (2 d), AcOH (0.2 mL), DCM (5 mL), and MeOH (1 mL) were added to a reaction flask and stirred at 0 °C for 10 minutes. NaBH(OAc)3 (37 mg, 0.17 mmol) was then added, and the reaction was continued at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL), washed with saturated brine, dried over the organic phase, concentrated, and purified by column chromatography to obtain a white solid E-67-j (30 mg, 100%). LCMS (ESI): m / z = 529.1 [M+H] + .

[0792] Step 11:

[0793] E-67-j (30 mg, 0.057 mmol), Int-A-15 (9 mg, 0.057 mmol), CuI (1 mg, 0.0057 mmol), Pd(PPh3)2Cl2 (4 mg, 0.0057 mmol), TEA (17 mg, 0.17 mmol), and DMF (2 mL) were added sequentially to a reaction flask. The mixture was reacted at 70 °C for 2 h under nitrogen protection. After cooling, 10 mL of water was added, and the mixture was extracted with EA (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified to obtain E-67 (6 mg, 18.7%) after solvent removal. LCMS (ESI): m / z = 560.2 [M+H] + ; 1H NMR (600MHz, DMSO-d6): δ10.04(s,1H),8.71(s,1H),8.54-8.53(m,3H),8.45-8.44( m,1H),7.92(d,J=3.6Hz,1H),7.30-7.25(m,2H),4.43-4.34(m,2H),3.90-3.88(m,1H ),3.32-3.30(m,1H),3.21-3.18(m,3H),2.82-2.75(m,2H),2.48-2.45(m,1H),2.36 (s,3H),2.19-2.15(m,1H),1.99-1.91(m,4H),0.72-0.69(m,2H),0.53-0.50(m,2H).

[0794] Example 58 Synthesis of compound E-69

[0795]

[0796] Step 1:

[0797] E-67-i (50 mg, 0.097 mmol) and TEA (29 mg, 0.29 mmol) were dissolved in DCM (5 mL). Acetyl chloride (12 mg, 0.14 mmol) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, water (10 mL) was added, followed by extraction with DCM (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The solution was purified by column chromatography (DCM:methanol = 50:1) to give a white solid E-69-a (45 mg, 83%). LCMS (ESI): m / z = 557.0 [M+H] +

[0798] Step 2:

[0799] E-69-a (45 mg, 0.081 mmol), Int-A-15 (13 mg, 0.081 mmol), CuI (2 mg, 0.0081 mmol), Pd(PPh3)2Cl2 (6 mg, 0.0081 mmol), TEA (25 mg, 0.24 mmol), and DMF (2 mL) were reacted at 70 °C for 2 h under nitrogen protection. After cooling, 10 mL of water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a pink solid E-69 (14 mg, 30%). LCMS (ESI): m / z = 588.3 [M+H] + ; 1HNMR (600MHz, DMSO-d6): δ10.07(s,1H),8.56-8.47(m,5H),7.93-7.92(m,1H),7.33-7.32(m,1H),7.23 -7.21(m,1H),4.84-4.75(m,2H),4.43-4.41(m,1H),4.21-4.19(m,1H),3.93-3.91(m,1H),3.76-3.72(m 1H),3.34-3.32(m,1H),3.31-3.30(m,1H),3.14-3.09(m,1H),2.78-2.75(m,1H),2.6 0-2.56(m,1H),2.11(s,3H),2.00-1.90(m,4H),0.72-0.69(m,2H),0.53-0.50(m,2H).

[0800] Example 59 Synthesis of Compound E-70

[0801] Compound E-70 can be synthesized by referring to the synthesis of compound E-69.

[0802]

[0803] Example 60 Synthesis of compound E-72

[0804]

[0805] Step 1:

[0806] E-72-a (60 mg, 0.12 mmol), 6704-31-0 (17 mg, 0.24 mmol), DCM (5 mL), and NaBH(OAc)3 were added. ( 76 mg (0.36 mmol) was reacted at 40 °C for 4 h. Water (10 mL) was added, and the mixture was extracted with DCM, washed with saturated brine, dried over the organic phase, concentrated, and the residue purified by column chromatography (DCM:MeOH = 50:1) to give a white solid E-72-b (50 mg, 76%). LCMS (ESI): m / z = 571.1 [M+H] + .

[0807] Step 2:

[0808] E-72-b (50 mg, 0.088 mmol), Int-A-15 (17 mg, 0.1 mmol), CuI (2 mg, 0.01 mmol), and Pd(PPh3)2Cl were added. 2(6 mg (0.01 mmol), TEA (27 mg, 0.26 mmol), and DMF (2 mL) were reacted at 50 °C for 10 h under nitrogen protection. After cooling, 10 mL of water was added, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was used to prepare a white solid E-72 (20 mg, 38%). LCMS (ESI): m / z = 602.3 [M+H] + ; 1 H NMR (600MHz, DMSO-d6): δ10.08(s,1H),8.89-8.87(m,1H),8.58-8.48(m,4H),7.92(d,J=3.6Hz,1H),7.63-7.56 (m,1H),7.30-7.29(m,1H),7.18-7.17(m,1H),4.60-4.45(m,5H),4.34-4.32(m,1H),4.12-4.10(m,1H),4.05-4 .03(m,1H),3.64-3.63(m,1H),3.56-3.52(m,1H),3.27-3.24(m,1H),3.13-3.12(m,1H),2.88-2.86(m,1H),2.7 8-2.75(m,1H),2.53-2.51(m,1H),2.18-2.15(m,1H),2.15-1.86(m,4H),0.72-0.69(m,2H),0.53-0.50(m,2H).

[0809] Example 61 Synthesis of compound E-73

[0810]

[0811] Step 1:

[0812] E-73-a (1 g, 0.004 mol) was dissolved in dioxane (6 mL), and HCl / dioxane (3 mL) was added. The mixture was reacted at 35 °C for 8 h, and then concentrated to a white solid E-73-b (950 mg, crude). LCMS (ESI): m / z = 143.1 [M+H] + .

[0813] Step 2:

[0814] E-73-b (950 mg, 6.64 mmol), compound 367-86-2 (3.02 g, 13.28 mmol), and K₂CO₃ (240 mg, 19.92 mmol) were dissolved in THF (15 mL) and reacted at 70 °C for 4 h under nitrogen protection. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to give a pale yellow oil, E-73-c (520 mg, 40%). LCMS (ESI): m / z = 333.1 [M+H] + .

[0815] Step 3:

[0816] E-73-c (520 mg, 4.58 mmol) was dissolved in MeOH (20 mL), and Pd / C (300 mg) was added. The mixture was reacted at 35 °C under a H2 atmosphere for 5 h. After filtration and concentration under reduced pressure, a white oily substance, E-73-d (420 mg, 89.3%), was obtained. LCMS (ESI): m / z = 303.1 [M+H] + .

[0817] Step 4:

[0818] E-73-d (400 mg, 1.32 mmol), 4068-75-1 (733 mg, 2.64 mmol), DBAD (612 mg, 2.64 mmol), and PPh3 (695 mg, 2.64 mmol) were added to THF (20 mL) and reacted at 70 °C for 10 h under nitrogen protection. The mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and purified by column chromatography to obtain a pale yellow oil, E-73-e (340 mg, 46.0%). LCMS (ESI): m / z = 563.1 [M+H] +

[0819] Step 5:

[0820] E-73-e (330 mg, 0.23 mmol) and LiOH (40 mg, 0.92 mmol) were dissolved in THF (3 mL) / H₂O (1 mL), reacted at 25 °C for 3 h, water was added, and the mixture was extracted with EA, washed with saturated ammonium chloride aqueous solution, dried the organic phase, concentrated, and purified by column chromatography to obtain a yellow solid E-73-f (280 mg, 87.5%). LCMS (ESI): m / z = 549.1 [M+H] + .

[0821] Step 6:

[0822] E-73-f (280 mg, 0.511 mmol) and T3P (2 mL) were dissolved in Py (6 mL), reacted at 45 °C for 16 h, water was added, and the mixture was extracted with EA. The mixture was washed with saturated ammonium chloride aqueous solution, the organic phase was dried, concentrated, and purified by column chromatography to obtain a yellow solid E-73-g (24 mg, 8.85%). LCMS (ESI): m / z = 531.1 [M+H] + .

[0823] Step 7:

[0824] E-73-g (24 mg, 0.045 mmol), Int-A-1 (35 mg, 0.181 mmol), X-Phos (6 mg, 0.023 mmol), Pd(ACN)₂Cl₂ (15 mg, 0.023 mmol), K₂CO₃ (20 mg, 0.135 mmol), and DBU (33 mg, 0.217 mmol) were added to ACN (3 mL) / TEA (2 mL). The mixture was sealed and stirred at 85 °C for 3 h under nitrogen protection. Water was added, and the mixture was extracted with EA. The solution was washed with saturated ammonium chloride aqueous solution, dried over the organic phase, concentrated, and subjected to Prep-HPLC to obtain a pale yellow solid E-73 (0.4 mg, 1.7%). LCMS (ESI): m / z = 522.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 8.85 (d, J = 2.1Hz, 1H), 8.46 (s, 2H), 8.22 (d, J=2.3Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.64(d,J=8.8Hz,1H),7.16(s,2H),4.03 (d,J=7.1Hz,1H),3.58(s,1H),3.45-3.45(m,2H),3.22(s,1H),2.82-2.78(m,2H), 2.61(s,1H),2.34(d,J=11.4Hz,2H),1.96(d,J=15.1Hz,1H),1.17(d,J=7.1Hz,1H).

[0825] Example 62 Synthesis of compound E-76

[0826]

[0827] Step 1:

[0828] Compound 2680532-23-2 (3 g, 14.63 mmol), compound 122536-77-0 (2.72 g, 14.63 mmol), K₂CO₃ (4.04 g, 29.26 mmol), and THF (20 mL) were stirred at 70 °C for 3 h, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 3:1) to give a yellow oil E-76-a (4.5 g, 12.31 mmol), yield 83%. LCMS (ESI): m / z = 372.1 [M+H] + .

[0829] Step 2:

[0830] E-76-a (500 mg, 1.35 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at room temperature for 2 h and concentrated to give a yellow solid E-76-b (414 mg, 1.35 mmol), with a yield of 99%. LCMS (ESI): m / z = 272.1 [M+H] +

[0831] Step 3:

[0832] E-76-b (414 mg, 1.35 mmol) was dissolved in DMF (20 mL). 2-hydroxyacetic acid (203 mg, 2.67 mmol), DIPEA (518 mg, 4.02 mmol), and HATU (1.01 g, 2.67 mmol) were added sequentially under stirring at room temperature for 2 h. The mixture was then diluted with water (20 mL), extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE = 2:1) to obtain E-76-c (350 mg, 1.06 mmol), yield: 79%. LCMS (ESI): m / z = 330.2 [M+H] + .

[0833] Step 4:

[0834] E-76-c (400 mg, 1.22 mmol) was dissolved in EA (20 mL), and Pd / C (150 mg, 10% wt) was added. The reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated to give a pale yellow solid E-76-d (230 mg, 0.77 mmol), yield: 63%. LCMS (ESI): m / z = 300.2 [M+H] + .

[0835] Step 5:

[0836] E-76-d (230 mg, 0.77 mmol) and compound 78686-83-6 (228 mg, 0.77 mol) were added sequentially to a three-necked flask and dissolved in 10 mL of THF. LiHMDS (3.08 mL, 1 M in THF) was added dropwise at 0 °C. After the addition was complete, stirring was continued for 1 h. Once the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (DCM:methanol = 20:1) to obtain a pale yellow solid E-76-e (150 mg, 0.27 mmol), yield: 35%. LCMS (ESI): m / z = 565.1 [M+H] + .

[0837] Step 6:

[0838] E-76-e (170 mg, 0.30 mmol) and DBU (46 mg, 0.60 mol) were added sequentially to DMF (10 mL), stirred at 100 °C for 2 h, cooled, and then 20 mL of saturated ammonium chloride aqueous solution (20 mL) was added. Extraction was performed using EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography (DCM:methanol = 20:1) to obtain a pale yellow solid E-76-f (150 mg, 0.27 mmol), yield: 19%. LCMS (ESI): m / z = 529.1 [M+H] + .

[0839] Step 7:

[0840] E-76-f (30 mg, 0.06 mmol), Int-A-15 (9 mg, 0.06 mmol), CuI (2.1 mg, 0.01 mmol), Pd(PPh)₂Cl₂ (4 mg, 0.01 mmol), and triethylamine (17.2 mg, 0.17 mmol) were added to DMF (10 mL) and stirred at 50 °C for 8 h under nitrogen protection. The reaction mixture was diluted with EA (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain product E-76 (8 mg), a white solid, yield: 25.2%. LCMS (ESI): m / z = 560.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.86(s,1H),8.64(d,J=8.0Hz,1H),8.55(m,3H),8.38(d,J=2 .4Hz,1H),7.92(d,J=3.6Hz,1H),7.60(d,J=8.4Hz,1H),7.32(d,J=8.0Hz,1H),5.03(d,J=10.4Hz,1H ),4.30-4.21(m,2H),3.14-3.12(m,2H),2.94(d,J=8.8Hz,1H),2.78-2.74(m,1H),2.68(d,J=6.8Hz ,1H),2.33(m,1H),1.97(t,J=18.8Hz,3H),1.89-1.80(m,1H),0.73-0.68(m,2H),0.53–0.49(m,2H).

[0841] Example 63 Synthesis of compound F-1

[0842]

[0843] Step 1:

[0844] Compound 1805185-41-4 (1 g, 4.52 mmol) was dissolved in THF (50 mL), and Int-B-1 (1.04 g, 4.52 mmol) and K₂CO₃ (1.248 g, 9.05 mmol) were added. The mixture was stirred at 80 °C for 12 hours. After filtration, the solution was washed with EA, and the filtrate was concentrated and purified by column chromatography to give F-1-a (1.643 g, yield: 84.2%). LCMS (ESI) m / z = 331.0 [M-99] + .

[0845] Step 2:

[0846] F-1-a (1.64 g, 3.81 mmol) was dissolved in dioxane (25 mL) and H₂O (5 mL). Cyclopropylboronic acid (1.31 g, 15.25 mmol), Pd(dppf)Cl₂ (278 mg, 0.38 mmol), and sodium carbonate (808 mg, 7.62 mmol) were added, and the mixture was stirred at 100 °C for 12 hours. After concentration, F-1-b (843 mg, yield: 56%) was obtained by column chromatography. LCMS (ESI) m / z = 393.3 [M+H] + .

[0847] Step 3:

[0848] F-1-b (0.84 g, 2.15 mmol) was dissolved in methanol (40 mL), and Pd / C (80 mg) was added under Ar protection. The mixture was stirred at room temperature for 12 hours under H2 atmosphere. The solution was filtered, and the filtrate was concentrated to give a white solid F-1-c (200 mg, yield: 25%). LCMS (ESI) m / z = 363.3 [M+H] + .

[0849] Step 4:

[0850] F-1-c (200 mg, 0.55 mmol) and compound 625471-27-4 (155 mg, 0.55 mmol) were dissolved in THF (10 mL). LiHMDS (1.5 mL, 1.5 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. The solution was quenched with NH4Cl aqueous solution (20 mL), extracted with EA, washed with saturated saline solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography to obtain F-1-d (162 mg, yield: 48%). LCMS (ESI) m / z = 611.2 [M+H] + .

[0851] Step 5:

[0852] F-1-d (162 mg, 0.27 mmol) was dissolved in DMF (4 mL), and Int-A-1 (76 mg, 0.398 mmol), Pd(PPh)₂Cl₂ (18 mg, 0.026 mmol), CuI (5 mg, 0.026 mmol), DBU (202 mg, 1.33 mmol), and TBAF were added to THF (0.5 mL, 0.5 mmol). The mixture was stirred at 100 °C for 2 hours. The reaction solution was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain F-1-e (126 mg, yield: 82%). LCMS (ESI) m / z = 582.3 [M+H] + .

[0853] Step 6:

[0854] F-1-e (126 mg, 0.22 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (1 mL, 4 mmol) was added. The mixture was stirred in an ice bath for 2 hours. After concentration, F-1-f (100 mg) was obtained and used directly in the next step. LCMS (ESI) m / z = 482.4 [M+H] + .

[0855] Step 7:

[0856] F-1-f (52 mg, 0.1 mmol) was dissolved in DCM (8 mL), and an aqueous solution of formaldehyde (37%, 4 drops) was added. NaBH(AcO)3 (62 mg, 0.3 mmol) was added under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to obtain F-1 (18 mg, yield: 36%). LCMS (ESI) m / z = 496.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.44(d,J=4.6Hz,3H),8.22(s,1H),8.13(d,J= 2.1Hz,1H),7.71(dd,J=8.6,2.3Hz,1H),7.30(d,J=8.8Hz,1H),7.14(s,2H),4.70(s, 1H),4.08(t,J=10.2Hz,1H),3.64(d,J=10.8Hz,1H),3.35(d,J=6.7Hz,1H),3.00-2.7 6(m,3H),2.56(d,J=10.5Hz,3H),2.36(s,3H),2.07-1.96(m,2H),0.94-0.75(m,4H).

[0857] Example 64 Synthesis of compound F-2

[0858]

[0859] Step 1:

[0860] F-1-f (52 mg, 0.10 mmol) was dissolved in DCM (8 mL), and TEA (41 mg, 0.40 mmol) was added. Acetic anhydride (21 mg, 0.22 mmol) was added under ice bath conditions. The mixture was stirred overnight at room temperature. The reaction solution was purified by column chromatography to obtain F-2 (21 mg, yield: 40%). LCMS (ESI) m / z = 524.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.43(d,J=14.3Hz,1H),8.46(d,J=7.7Hz,3H),8.17(dd,J=21.7,5.6 Hz,2H),7.71(dd,J=8.6,2.1Hz,1H),7.32(dd,J=8.8,2.3Hz,1H),7.14(s,2H),4.53(dd,J=98 .6,11.6Hz,2H),4.31-3.62(m,3H),3.51(t,J=11.5Hz,1H),3.30-2.76(m,4H),2.47-2.35(m, 1H),2.07(t,J=5.6Hz,3H),2.02(td,J=8.2,4.1Hz,1H),1.94-1.67(m,1H),0.96-0.80(m,4H).

[0861] Example 65 Synthesis of compound F-3

[0862]

[0863] Step 1:

[0864] F-1-d (400 mg, 0.64 mmol) was dissolved in DMF (4 mL), and DBU (388 mg, 2.55 mmol) was added. The mixture was stirred at 120 °C for 2 h. The reaction solution was purified by column chromatography to obtain F-3-a (300 mg, yield: 80%). LCMS (ESI) m / z = 592.2 [M+1] + .

[0865] Step 2:

[0866] F-3-a (300 mg, 0.51 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (1 mL, 4 mmol) was added. The mixture was stirred in an ice bath for 2 h. After concentration, F-3-b (200 mg) was obtained and used directly in the next step. LCMS (ESI) m / z = 492.1 [M+1] + .

[0867] Step 3:

[0868] F-3-b (200 mg, 0.38 mmol) was dissolved in DCM (20 mL), and TEA (115 mg, 1.14 mmol) and cyclobutylformyl chloride (76 mg, 0.57 mmol) were added under ice bath conditions. The reaction mixture was reacted for 1 h. The reaction solution was purified by column chromatography to obtain F-3-d (130 mg, yield: 60%).

[0869] Step 4:

[0870] F-3-d (60 mg, 0.1047 mmol) was dissolved in DMF (3 mL), and Int-A-1 (30 mg, 0.16 mmol), Pd(PPh)₂Cl₂ (7 mg, 0.01 mmol), CuI (2 mg, 0.01 mmol), TBAF in THF (0.2 mL, 0.20 mmol), and DBU (52 mg, 0.34 mmol) were added. The mixture was microwaved at 100 °C for 1 h. The reaction solution was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain F-3 (15 mg, yield: 25%). LCMS (ESI) m / z = 565.3 [M + H₂] + . 1 H NMR (600MHz, DMSO-d6) δ10.37(s,1H),8.55(dd,J=2.2,1.5Hz,1H),8.47(d,J=1.0Hz,2H),8.43- 8.35(m,2H),8.24(d,1H),7.20(s,2H),5.21(t,1H),4.52(m,1H),4.22(m,1H),4.10-3.60(m,2H ),3.48-3.36(m,2H),3.21-2.96(m,4H),2.77(m,1H),2.45(m,1H),2.32-1.99(m,5H),1.96-1.8 5(m,1H),1.83-1.67(m,2H),1.57(dt,J=15.8,8.0Hz,1H),1.37-1.27(m,1H),0.92-0.80(m,4H).

[0871] Example 66 Synthesis of compound F-4

[0872]

[0873] Step 1:

[0874] F-3-d (60 mg, 0.11 mmol) was dissolved in DMF (3 mL), and Int-A-15 (36 mg, 0.16 mmol), Pd(PPh)₂Cl₂ (7 mg, 0.01 mmol), CuI (2 mg, 0.01 mmol), TBAF, and DBU (52 mg, 0.34 mmol) were added. The mixture was then microwaved at 100 °C for 1 h in THF (0.2 mL, 0.20 mmol). The reaction solution was purified by column chromatography (PE / EA = 1 / 100 ~ 1 / 9 ~ DCM / MeOH = 10 / 1) to obtain F-4 (15 mg, yield: 24%). LCMS (ESI) m / z = 605.4 [M + H₂] + . 1 H NMR(600MHz,DMSO-d6)δ10.33(d,1H),8.75-8.43(m,3H),8.41-8.34(m,2H),8.23(d ,1H),7.92(d,J=3.6Hz,1H),5.19(s,1H),4.52(dd,1H),4.27-3.60(m,3H),3.51-3.3 5(m,2H),3.26-2.92(m,3H),2.82-2.71(m,2H),2.43(dt,1H),2.31-1.99(m,5H),1.9 6-1.82(m,1H),1.81-1.66(m,2H),0.87(m4H),0.74-0.66(m,2H),0.57-0.46(m,2H).

[0875] Example 67 Synthesis of Compound F-5

[0876]

[0877] Step 1:

[0878] F-5-a (5 g, 15.2 mmol), DMF (100 mL), dimethylhydroxylamine salt (2.2 g, 22.7 mmol), EDCI (4.35 g, 22.7 mmol), HOBt (3.06 g, 22.7 mmol), and DIEA (5.8 g, 44.7 mmol) were stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the solution was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil, F-5-b (5.6 g, crude). LCMS (ESI): m / z = 374 [M+H] + .

[0879] Step 2:

[0880] F-5-b (2.5 g, 6.7 mmol) and THF (30 mL) were cooled to -50 °C, and then MeLi (12.6 mL, 20.2 mmol, 1.6 mol / L THF solution) was added. The mixture was stirred at 0 °C for 5 hours under nitrogen protection. Water was added to the reaction solution, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude yellow solid F-5-c (2.29 g, crude product). LCMS (ESI): m / z = 329 [M+H] + .

[0881] Step 3:

[0882] F-5-c (2.2 g, 6.70 mmol) and MeOH (40 mL) were cooled to 0 °C, and then NaBH4 (760 mg, 20 mmol) was added. The mixture was stirred at room temperature for 4 h under nitrogen protection. Water was added to the reaction solution, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude yellow solid F-5-d (1.8 g, crude product). LCMS (ESI): m / z = 331 [M+H] + .

[0883] Step 4:

[0884] F-5-d (1.8 g), DCM (20 mL), and TFA (5 mL) were stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude yellow oily product F-5-e (900 mg, crude product). LCMS (ESI): m / z = 131 [M+H] + .

[0885] Step 5:

[0886] F-5-e (900 mg, 6.92 mmol), THF (40 mL), potassium carbonate (2.8 g, 20.29 mmol), and 367-86-2 (2.2 g, 10.53 mmol) were stirred at 70 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (DCM:MeOH = 8:1) yielded a yellow solid, F-5-f (1.03 g, yield: 47%). LCMS (ESI): m / z = 320 [M+H] + .

[0887] Step 6:

[0888] The following medications were administered: F-5-f (400 mg, 1.25 mmol), THF (15 mL), compound 850146-80-4 (550 mg, 1.88 mmol), TMAD (540 mg, 3.14 mmol), and n-Bu3P. ( The reaction mixture (630 mg, 3.12 mmol) was stirred overnight at 30 °C. Water was added to the reaction solution, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography (PE:EA = 2:1) to give a yellow oil, F-5-g (250 mg, yield: 34%). LCMS (ESI): m / z = 594 [M+H] + .

[0889] Step 7:

[0890] F-5-g (200 mg, 0.34 mmol), MeOH (10 mL), and Boc₂O (200 mg, 0.92 mmol) were stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 1:2) to obtain a yellow oily substance F-5-h (120 mg, yield: 51%). LCMS (ESI): m / z = 694 [M+H] + .

[0891] Step 8:

[0892] F-5-h (80 mg, 0.12 mmol), EtOH (8 mL), Fe (64 mg, 1.2 mmol), and NH4Cl (64 mg, 1.2 mmol) were reacted and stirred at 80 °C for 3 h under a hydrogen atmosphere (1 atm). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography (PE:EA = 1:1) to give a yellow oily substance, F-5-i (66 mg, yield: 83%). LCMS (ESI): m / z = 664 [M+H] + .

[0893] Step 9:

[0894] F-5-i (66 mg, 0.1 mmol), THF / H₂O / MeOH (3 mL / 1 mL / 3 mL), and LiOH·H₂O (13 mg, 0.3 mmol) were stirred at room temperature for 48 h. The reaction mixture was then added to water and a 1 N dilute hydrochloric acid solution and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (PE:EA = 1:1) yielded a yellow oil, F-5-j (51 mg, yield: 78%). LCMS (ESI): m / z = 650 [M+H] +.

[0895] Step 10:

[0896] F-5-j (40 mg, 0.06 mmol), pyridine (8 mL), and T3P (0.4 mg) were stirred at room temperature for 4 h. Water was added to the reaction mixture, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to give a yellow solid F-5-k (30 mg, yield: 38%). LCMS (ESI): m / z = 632 [M+H] + .

[0897] Step 11:

[0898] F-5-k (15 mg, 0.023 mmol), TEA (1 mL), Int-A-1 (19 mg, 0.1 mmol), Pd(ACN)₂Cl₂ (5 mg, 0.019 mmol), X-phos (6.7 mg, 0.014 mmol), K₂CO₃ (10 mg, 0.072 mmol), and TBAF (0.12 mL, 0.069 mmol) were stirred overnight at 85 °C under nitrogen protection. Water was added to the reaction mixture, and the solution was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (PE:EA = 5:1) yielded a yellow solid, F-5-l (15 mg, crude product). LCMS (ESI): m / z = 623 [M+H] + .

[0899] Step 12:

[0900] F-5-l (15 mg), 1,4-dioxane / methanol (2 mL / 2 mL), and HCl (2 mL) were stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified to obtain a pale yellow solid F-5 (1.4 mg, yield: 10%). LCMS (ESI): m / z = 523 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.45(s,2H),8.78(d,J=2.0Hz,1H),7.6 9(s,1H),7.55(t,J=1.6Hz,1H),7.22(d,J=8.4Hz,1H),7.17(s,1H),7.16(s,2H ),4.84(t,J=7.6Hz,1H),3.86(d,J=12.0Hz,1H),3.04-2.98(m,2H),2.85-2.77 (m,2H),2.67-2.65(m,1H),2.54(s,3H),2.03-1.97(m,2H),1.30-1.23(m,3H).

[0901] Example 68 Compound's inhibitory activity against TIE2

[0902] Experimental objective: To test the IC50 of the target compound on TIE2 and KDR kinases using the Lantha Screen Assay method under Km ATP conditions. 50 .

[0903] Experimental Background: Using the Lantha Screen Assay method, the IC50 of the test compound on two kinases was analyzed. 50 The test was conducted with an initial concentration of 10 μM for the compound, 10 concentrations, 3-fold dilution, and replicate testing.

[0904] Experimental reagents: All reagents used were commercially available products, including TIE2 (BPS 40270) or Carna (08-185), Fluorescein-Poly GT (Invitrogen PV3611). Tb-PY20 Antibody Kit: Invitrogen (PV3552), EDTA: Gibco (15575-038), HEPES (pH7.5): Gibco (15630-080), Tween-2 0: Sigma(P2287), BSA: Sigma(A9647-500G), DTT: Sigma(D0632-10G), MgCl2: Sigma(M2670-500G).

[0905] Experimental methods:

[0906] 1. Prepare a 1x kinase buffer solution

[0907] 50mM HEPES, pH 7.5, 10mM MgCl2, 4mM DTT, 0.01% Tween-20, 0.01% BSA.

[0908] 2. Preparation of compound working solution

[0909] (1) The initial detection concentration of the test compound is 10 μM: First, dissolve the test compound in 100% DMSO to prepare a compound solution with a concentration 100 times the initial detection concentration, i.e., 1000 μM. Then, transfer the 1000 μM compound solution to the second well of a 96-well Echo plate, and add 30 μL of 100% DMSO to the other wells. Take 15 μL of the compound from the second well and add it to the third well. Perform 3-fold dilutions in sequence, for a total of 10 concentrations. Transfer 100 μL of 100% DMSO to two empty wells as controls without the compound and without the enzyme; transfer more than 40 μL of the compound to a 384-well Echo plate. (2) Use the Echo plate to transfer 200 nL of the compound working solution to a 384-well reaction plate.

[0910] 3. Kinase Response and Termination

[0911] (1) Add kinase and DTT to 1-fold kinase buffer to form a 2-fold kinase solution; (2) Transfer 10 μL of the above 2-fold kinase solution to the reaction wells of a 384-well plate, add 1-fold kinase buffer to the negative control wells, and incubate at room temperature for a certain period of time; (3) Add the substrate Fluorescein-Poly GT and ATP to 1-fold kinase buffer to form a 2-fold substrate solution (substrate concentration is 40 nM, ATP concentration is 156 μM or 2 mM); (4) Transfer 10 μL of the 2-fold substrate solution to a 384-well plate; (5) Incubate at room temperature for a certain period of time; (6) Prepare 2-fold antibody. (7) Add 20 μL of the above mixture of Tb-PY20 and EDTA to a 384-well reaction plate to terminate the reaction; and let it stand at room temperature for 60 minutes.

[0912] 4. Data Reading

[0913] The Envision 2014 Multilable Reader reads the numerical ratio of excitation at 340nm, emission at 520nm, and emission at 495nm.

[0914] 5. Data Calculation

[0915] (1) Reproduce the numerical ratio of fluorescence readings (Lantha signal ratio (520nm / 495nm)); (2) Convert the above data into the inhibition percentage using the formula: Percent inhibition = (max - Lantha signal ratio) / (max - min) * 100, where "min" is the reading of the control well without enzyme; "max" is the reading of the control well with DMSO. (3) Import the data into MS Excel, IC 50 The results were obtained by curve fitting using XLFit Excel add-in version 5.4.0.8. The fitting formula is: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)×HillSlope), where “Bottom” and “Top” are the maximum and minimum inhibition rates, respectively; and “HillSlope” is the absolute value of the maximum slope of the curve. The results are shown in Table 1 below.

[0916] Table 1. Inhibitory effect of the compounds in the examples on TIE2

[0917]

[0918]

[0919] Note: IC 50 In the middle, "A" represents IC. 50 ≤20nM, where “B” indicates 20nM <IC 50 ≤100nM, where "C" represents 100nM <IC 50 ≤500nM, “D” indicates IC 50 >500nM.

[0920] Example 69: Inhibitory effect of compound on cell proliferation in BaF3-FL-TIE2-L914F cell line

[0921] Experimental objective: To evaluate the inhibitory effect of the compound on the proliferation of BaF3-FL-TIE2-L914F cells.

[0922] Experimental reagents: All were commercially available products. BaF3: RIKEN (RCB0805), CellCounting-Lite 3D Luminescent Cell Viability Assay: Vazyme (DD1102-03), Fetal bovine serum: Gibco (10099141C), RPMI 1640: Corning (10-040-CV), penicillin-streptomycin: Dalian Meilun (PWL062), trypsin cell digestion solution (0.25% trypsin, containing phenol red): Beyotime (C0203-100ml), PBS: Gibco (C10010500BT), DMSO: Sigma (D2650).

[0923] Experimental methods:

[0924] Preparation of Day 0 cell detection plate:

[0925] (1) BaF3-FL-TIE2-L914F cells were suspension cells, cultured in RPMI 1640 cell culture medium containing 10% FBS and 1% penicillin / streptomycin at 37°C in a 5% CO2 cell culture incubator. The cells were passaged twice a week at a 1:10 ratio. (The stable cell line BaF3-FL-TIE2-L914F was designed based on the FL-TIE2 sequence (NM_000459.5) and a FL-TIE2-L914F (CTT>TTT) mutant expression vector was obtained. The FL-TIE2-L914F gene was transferred into wild-type BaF3 cells using a retroviral packaging system. After screening with puromycin antibiotic, a stable cell line was finally obtained.)

[0926] (2) The cell culture medium, PBS and 0.25% trypsin-EDTA were preheated in water at 37°C.

[0927] (3) Observe the cells under a microscope to confirm that there are no bacterial or fungal contaminants.

[0928] (4) Collect the cells and transfer them to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cell pellet in cell culture medium.

[0929] (5) Use a pipette to remove 20 μL of resuspended cells, use a cell counter star automated cell counter to count the cells, and record the number and viability of live cells in the cell tracking table.

[0930] (6) Adjust the volume of the cell suspension using cell culture medium to achieve the desired cell concentration (1500 cells / mL), and transfer 90 μL of cell suspension to a 96-well plate (1500 cells / well).

[0931] (7) Incubate overnight in a 37℃ / 5% CO2 cell culture incubator.

[0932] Day 1: Preparation and Dosing of Compound Dosage Gradient Solutions

[0933] (1) Preparation and dosing of compound gradient solutions: First, the 10 mM compound stock solution was diluted to 1 mM with 100% DMSO. Second, the 1 mM compound solution was serially diluted 3-fold with 1% DMSO RPMI 1640 cell culture medium to prepare a total of 9 gradient concentrations. Then, 10 μL of each concentration gradient compound solution diluted with culture medium was transferred to the above-mentioned 96-well cell plate containing 90 μL of cell culture.

[0934] (2) After adding the compound, place the cell culture plate in a 37°C, 5% CO2 cell culture incubator for 3 days.

[0935] Day 4 CTG Detection Experiment:

[0936] (1) Before use, thaw the CellCounting-Lite 3D Luminescent Cell Viability Assay (CTG) reagent and equilibrate to room temperature.

[0937] (2) Add 20 μL of CTG reagent per well to the test plate and place it on a shaker for 2 to 3 minutes.

[0938] (3) Use Multimode microplate reader reads the plate.

[0939] Data Analysis:

[0940] The inhibition rate is calculated based on the original data of the emission signal. The formula for calculating the inhibition rate is as follows:

[0941] Inhibition rate = (1 - (original value - Min average) / (Max average - Min average)) * 100, where Max is 0% inhibition (containing cells and 0.1% DMSO) and Min is 100% inhibition (containing culture medium and 0.1% DMSO).

[0942] The inhibitory effects of compounds on cell proliferation were analyzed using GraphPad Prism 5.0 software. Concentration was plotted on the X-axis, and percentage inhibition rate on the Y-axis. Dose-response curves were fitted using the log(inhibitor) vs. response-variable slope function of GraphPad Prism 5 to derive the IC50 of each compound on cell proliferation inhibition. 50 Values. The results are shown in Table 2 below.

[0943] Table 2. Inhibitory effects of the compounds in the examples on the proliferation of BaF3-FL TIE2-L914F cells.

[0944] serial number <![CDATA[CTG IC 50 ]]> serial number <![CDATA[CTG IC 50 ]]> serial number <![CDATA[CTG IC 50 ]]> serial number <![CDATA[CTG IC 50 ]]> A-13 B A-63 B D-9 A E-14 D A-35 B A-66 C D-10 B E-15 B A-41 C A-68 B D-11 B E-16 B A-45 C A-69 D E-2 A E-17 B A-46 C A-71 B E-5 A E-18 B A-53 B B-16 A E-6 A E-28 A A-56 B C-30 B E-7 C E-29 B A-57 C D-1 B E-8 B E-30 B A-58 D D-4 B E-9 B E-31 B A-59 B D-5 B E-10 A E-32 B A-60 B D-6 B E-11 B E-33 B A-61 B D-7 C E-12 B E-34 A A-62 B D-8 B E-13 C E-35 A E-38 B E-39 A E-42 B E-43 A E-44 B E-45 B E-54 B E-58 A E-59 B E-65 A E-66 B E-70 A

[0945] Note: IC 50 In the middle, "A" represents IC. 50 ≤10nM, where “B” indicates 10nM <IC 50 ≤50nM, where "C" indicates 50nM <IC 50 ≤200nM, “D” indicates IC 50 >200nM.

Claims

1. A compound of formula (I), its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt: in, Ring A is a 5-10 membered heteroaryl group substituted with m R1 atoms and containing at least one N atom; Ring B is: C replaced by n R2s. 6-10 Aryl or 5-6 quinone heteroaryl; The ring C is: a 5-7 membered heteroaryl group or a 4-12 membered heterocyclic alkyl group containing at least one N atom and q R4 substituted; L1 is: bond, ethynyl group or trans vinylene; L2 is selected from: -O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene-O-, -OC 1-6 Alkylene-NR a -、-OC 1-6 Alkylene -C(=O)NH-, -OC 3-6 Cycloalkylene-, -O-4-7-membered heterocycloalkylene-; wherein, the alkylene, cycloalkylene, and heterocycloalkylene are each optionally C 1-6 Alkyl or C 3-6 Cycloalkyl substitution; or L2 together with ring C forms C 5-7 Cycloalkyl or 4-12 membered heterocyclic alkyl; R a -R e -C(=O)R c -S(=O)R c -S(=O)2R c -C(=O)NHR d -CH2C(=O)NHR d ; M is either O or S; Q1, Q2, and Q3 are each individually: C or N; R1 is selected from: halogen, -CN, -NHR b -C(=O)OR c -R c -OR d -SR d -C(=O)NR d R d '; R b For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or 4-12-membered heterocyclic alkyl; and each of the alkyl, cycloalkyl, and heterocyclic alkyl groups is optionally surrounded by deuterium, oxo group, halogen, OH, or NR. d R e C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic alkyl substitutions; R2 is selected from: halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; R3 is selected from: halogen, -CN, -NR a 'R d -C(=O)R c -C(=O)OR c -C(=O)NR d R d ', optionally subjected to halogens, OH, NR a 'R d Or the following groups substituted with 3-7 membered heterocyclic alkyl groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heteroaryl, or 4-7-membered heterocycloalkyl; R4 is selected from: halogens, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -NR a 'R d -C(=O)R f -S(=O)R c -S(=O)2R c , Oxide group, -C(=O)NHR d -CH2C(=O)NHR d The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally further reacted with halogens, NH2, OH, or C. 1-3 Alkyl or C 1-3 Alkyl substitution; R a 'For H, C 1-3 Alkyl or C(=O)R c ; R c C 1-4 Alkyl or C 3-7 cycloalkyl; R d R d Each individually is: hydrogen, or C optionally substituted with halogen, NH2 or OH. 1-6 alkyl; R e For hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic alkyl; wherein, the alkyl, cycloalkyl, or heterocyclic alkyl may optionally be further reacted with halogen, NH2, OH, or C. 1-3 Alkyl or C 1-3 Alkyl substitution; R f To be optionally subjected to OH, CN, halogen, C 1-3 Alkyl or NR a 'R d The following groups are substituted: C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl; m can be 0, 1, 2, or 3; when m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl; n is 0, 1, or 2; q can be 0, 1, 2, or 3; p is 0, 1, 2 or 3; The heteroaryl and heterocyclic alkyl groups contain 1-3 heteroatoms selected from N, O and S.

2. The compound according to claim 1, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein... The ring C is a 4-12 membered heterocyclic alkyl group containing at least one N atom and substituted with q R4 atoms; R1 is selected from: halogen, CN, C 1-6 Alkyl, C 3-6 cycloalkyl, NHR b ; R2 is selected from: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl; R3 is selected from: halogen, C 3-6 Cycloalkyl groups, optionally selected from halogens, OH, NR a 'R d 3-7 membered heterocyclic alkyl-substituted C 1-6 Alkyl, 4-7 membered heteroaryl, or 4-7 membered heterocyclic alkyl; R4 is selected from: halogens, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocycloalkyl, -NHR a '、C(=O)R f S(=O)R c S(=O)2R c C(=O)NHR d CH2C(=O)NHR d The alkyl, cycloalkyl, or heterocycloalkyl groups may optionally be further reacted with halogen, NH2, OH, or C. 1-3 Alkyl substitution; in, R b For hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl or 4-12-membered heterocycloalkyl; and each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally replaced by deuterium, halogen, OH, or NR. d R e C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-7 membered heterocyclic alkyl substitutions; R e For hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl; wherein, the alkyl, cycloalkyl, or heterocyclic alkyl may optionally be further reacted with halogen, OH, NH2, or C. 1-3 Alkyl substitution; R f To be optionally subjected to OH, CN, halogen, C 1-3 The following groups are substituted with alkyl or NH2: C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-12 membered heterocyclic alkyl; m can be 0, 1, or 2; when m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl; q is 0, 1, or 2; p is 0, 1, or 2.

3. The compound according to claim 1, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein, Ring A is selected from: R1 is selected from: halogen, CN, NHR b C, optionally replaced by halogen, NH2 or OH 1-6 Alkyl or C 3-6 cycloalkyl; Preferably, R1 is selected from: F, Cl, -CN, -C 1-4 Alkyl, -CF3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, -(CH2)2NH2, -(CH2)3NH2, -NH2, -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NHCH(CH3)2, -NH( CH2)2OH, -NH(CH2)3OH, -NHCF3, -NHCH2CHF2, -NHCH2CF3, -NHCD3, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)2N(CH3)2, -NH(CH2)3N(CH3)2, m can be 0, 1, or 2. When m = 2, two adjacent R1 atoms can form C together with their linked carbon atoms. 4-7 cycloalkyl or 4-7 membered heterocyclic alkyl; The ring BC=M structure is selected from: R2 is selected from: halogen, C 1-4 Alkyl, C 3-6 cycloalkyl; n is 0 or 1; R3 is selected from: halogen, -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, -CF2-cyclopropyl, -C 1-4 Alkyl groups -OH, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)3N(CH3)2, -NH(CH2)2OH, -CH2NH-C 3-6 Cycloalkyl, -CH2-4-7-membered heterocycloalkyl, -C(=O)-C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(O)NH2, -C(O)NH-C 1-4 Alkyl, 4-7 membered heterocyclic alkyl; wherein the heterocyclic alkyl is optionally C 1-4 Alkyl substitution; p is 1 or 2; The L2-ring C structure is selected from: R4 is selected from: F, =O, C optionally substituted with OH. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic alkyl, -NH2, -NH-C 1-4 Alkyl, -SO2R c , -CH2CONHCH3, -CONHCH3, -C(O)R f ;R f To be optionally subjected to F, OH, CN, NH2, C 1-3 Alkyl-substituted: C 1-6 Alkyl, C 3-10 Cycloalkyl or 4-12-membered heterocycloalkyl; R c C 1-4 Alkyl or C 3-6 cycloalkyl; q is 0 or 1.

4. The compound according to any one of claims 1-3, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, L1 is an ethynyl group, and M is O.

5. The compound according to claim 4, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein, Both Q1 and Q3 are C; and ring B is a pyridine ring or a benzene ring substituted with n R2 atoms.

6. The compound according to claim 5, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein, General formula (I) has the structure shown in the following general formula (IV): In general formula (IV), Q2 is C or N; each R g R h R g '、R h 'Each is independent for H and C' 1-4 Alkyl or C 3-6 cycloalkyl, Preferably, ring A is selected from Where m is 0, 1, or 2; R1 is selected from: F, -CH3, -CH2CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NH(CH2)2OH, -NH(CH2)3OH, -NH(CH2)2NH2, -NH(CH2)3NH2, -NH(CH2)3N(CH3)2, -NHCD3, -NHCH2CHF2, -NHCH2CF3. R2 is selected from: F, C 1-6 Alkyl (e.g., methyl, ethyl), C 3-6 cycloalkyl; R3 is selected from: halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -CF3, -CHF2, -CF2CH3, -CF2CH2CH3, -CF2-cyclopropyl, -C 1-4 alkyl-OH; n is 0 or 1; or General formula (I) has the structure shown in the following general formula (V): In the general formula (V), each R g R h R g '、R h 'Each is independent for H and C' 1-4 Alkyl or C 3-6 Cycloalkyl, R3' is selected from: halogen, CN, -NR a 'R d -C(=O)R c -C(=O)OR c -C(O)NR d R d ', optionally halogenated, OH or -NR a 'R d Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heteroaryl, 4-7-membered heterocycloalkyl; Preferably, R1 is selected from: -NH2, -NHCH3, n is 0; R3' is selected from: -CF3, -CHF2, C 3-6 Cycloalkyl, -CF2CH3, -CF2CH2CH3, -CH2CHF2, -CH2CF3, -CF2-cyclopropyl; or General formula (I) has the structure shown in the following general formula (VI): In general formula (VI), R i Selected from H, C 1-3 Alkyl groups and -C(=O)R c .

7. The compound according to claim 1, wherein its stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt, wherein, The compounds of formula (I) are selected from the following compounds:

8. A pharmaceutical composition comprising at least one compound as described in any one of claims 1-7, or a stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

9. A pharmaceutical combination product comprising at least one compound as described in any one of claims 1-7, or a stereoisomer thereof, hydrate, solvate, or pharmaceutically acceptable salt thereof, and one or more other active agents.

10. The use of the compound, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt of any one of claims 1-7, or the pharmaceutical composition of claim 8, or the pharmaceutical combination product of claim 9, in the preparation of a medicament or TIE2 inhibitor for the prevention, treatment, or relief of a patient’s disorder or disease mediated by TEK gene abnormality, preferably, the disorder or disease including vascular malformations associated with TEK gene mutations.

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