Nitrogen-containing heterocyclic derivative agonist, preparation method therefor, and use thereof

Abstract

The present invention relates to a nitrogen-containing heterocyclic derivative agonist, a preparation method therefor, and use thereof. In particular, the present invention relates to a compound represented by the general formula, a preparation method therefor, a pharmaceutical composition comprising the compound, and use thereof as an agonist in the treatment of diseases such as endocrine diseases, cardiovascular diseases, and pain.

Description

Nitrogen-containing heterocyclic derivative agonists, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a nitrogen-containing heterocyclic derivative agonist, its preparation method, and its application. Background Technology

[0002] Pancreatic amyloid polypeptide (IAPP), also known as amylin, is composed of 37 amino acids and is mainly synthesized and secreted by pancreatic β cells. The amylin receptor (AMYR) is a heterodimer composed of a class B GPCR calcitonin receptor and different receptor activity modifying proteins (RAMP1, 2, and 3), classified as AMY1R, AMY2R, and AMY3R. RAMP3 plays a leading role in amylin-induced brain signal transduction and weight regulation. When stimulated by glucose or other nutrients, amylin is secreted in conjunction with insulin. Amylin binding to its receptor delays gastric emptying, inhibits glucagon secretion, and lowers blood glucose levels to maintain glycemic homeostasis. Furthermore, amylin can suppress appetite. After meals, amylin secretion activates receptors in the gastrointestinal tract and various brain regions, forming the second messenger cyclic guanosine monophosphate (cGMP). Through multiple cascade signal transduction, it generates a feeling of satiety, controlling food intake and weight. Therefore, amylin and its receptors are important drug targets for the treatment of obesity and diabetes.

[0003] Calcitonin is secreted by thyroid C cells. Under physiological conditions, it binds to the calcitonin receptor to regulate downstream cAMP and PLC / IP3 pathways, primarily functioning in osteoclasts and the kidneys. In the renal tubules, calcitonin promotes renal calcium secretion and reduces calcium reabsorption, lowering serum calcium and phosphate levels. In bone, calcitonin promotes osteoclast contraction, reduces osteoclast activity, inhibits carbonic anhydrase II, disrupts the acidic environment required by osteoclasts, and prevents osteoclast precursors from differentiating into mature cells, among other mechanisms that reduce osteoclast bone resorption capacity. Furthermore, mammalian-derived calcitonin can enhance insulin sensitivity, while the more potent salmon calcitonin can inhibit gastric emptying, increase energy expenditure, induce satiety, and reduce weight. Calcitonin precursors are expressed in adipocytes, and their expression levels are associated with obesity, insulin resistance, and metabolic syndrome, all suggesting that the calcitonin receptor is a potential therapeutic target for obesity and related conditions.

[0004] Pramlintide is the only FDA-approved amylin peptide analog for complementary treatment of type 1 / 2 diabetes. In multiple studies, pramlintide has demonstrated sustained weight loss, whether used alone (for weight loss <5 kg) or in combination with leptin. However, pramlintide has a short half-life (20-45 minutes), requiring three subcutaneous injections daily, and may cause side effects such as nausea and vomiting during the initial treatment phase. Several companies are currently developing amylin peptide analogs and amylin receptor agonists.

[0005] CagriSema (a fixed-dose combination of Cagrilintide 2.4 mg and Semaglutide 2.4 mg) is a combination of a long-acting amylinin peptide analog and semaglutide. Results from the Phase III REDEFINE 1 clinical trial in obese adults without diabetes or with one or more comorbidities showed that at 68 weeks, the CagriSema group experienced a 22.7% weight loss, the Cagrilintide 2.4 mg group an 11.8% weight loss, and the Semaglutide 2.4 mg group a 16.1% weight loss. Similar to GLP-1 receptor agonists, the most common adverse events in the CagriSema group were gastrointestinal adverse events, the vast majority of which were mild to moderate and decreased over time. This suggests a promising future for the development of combination therapy between amylinin receptor agonists and GLP-1R agonists. The long-acting amylinin analog GUBamy achieved positive results in a single-dose escalation Phase I clinical trial. GUBamy is well-tolerated, exhibits favorable pharmacokinetic characteristics, and has a half-life of 11 days, supporting a once-weekly dosing regimen. Furthermore, a single dose of GUBamy resulted in dose-dependent weight loss, an effect that persisted throughout the trial period (6 weeks). Both of these long-acting amylin peptide analogs require subcutaneous injection, thus highlighting an unmet clinical need for oral agonists of both amylin analogs and their receptors.

[0006] The purpose of this invention is to develop an oral agonist targeting the amylin receptor and / or calcitonin receptor, which can not only regulate human diet and metabolism to control weight, but also be combined with other target drugs (such as GLP-1R, GIPR, GCGR) to improve the efficacy of treatment for type II diabetes and obesity. Summary of the Invention

[0007] The object of this invention is to provide a compound of general formula (I) or (I′), (I″) or (I″′), its nitrogen oxide compound or a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] M1, M2, and M3 are each independently selected from O, C=O, C=S, N, S, and CR. a R c CR a or NR b

[0010] Or M1 does not exist;

[0011] M4 and M5 are each independently selected from N or CR. a ;

[0012] M 11 and M 12 Each is independently selected from C, N, or CR. d ;

[0013] Ring A is selected from phenyl, C 5-6 Cycloalkyl, 5-6 membered heterocyclic or 5-6 membered heteroaryl; preferably, ring A is selected from phenyl, cyclohexyl, 6 membered heterocyclic or 6 membered heteroaryl;

[0014] Ring A′ is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0015] Ring A″ is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0016] Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0017] Ring C is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0018] L1, L2, L3, and L4 are each independently selected from the bond, -(CH2). n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2-、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NR ee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2 -、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Alynyl group; wherein the -(CH2) group is... n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2 -、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NRee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2 -、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide and C 1-6 Alynyl group, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, COOH, COOCH3, COOCHCH3, CONH2, CONHCH3, CON(CH3)2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0019] Alternatively, L1, L2, L3, and L4 can each be independently selected from -(CH2). n1 S(=NH)O(CH2) n2 -、-(CH2) n1 S(=NH)ONR ee (CH2) n2 -、C 3-12 cycloalkylene L L 3-12-membered subheterocyclic L L C 6-14 Aspartic L L5-14 methyl methacrylate L L C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene, 5-14 methylarylene or Optional further substitution with hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0020] L L Each is independently selected from -(CH2) n1 -(CH2) n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2 -、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NR ee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2-、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2 NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group;

[0021] Cy9 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0022] R a R b R c R d R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n O(CH2) n′ R bb -O(CH2) n R aa -(CH2) n S(CH2) n′ R bb -(CH2)n C(O)(CH2) n′ R cc 、-(CH2) n C(O)O(CH2) n′ R cc 、-(CH2) n S(O) m (CH2) n′ R cc 、-(CH2) n NR aa (CH2) n′ R bb 、-(CH2) n C(O)NR aa (CH2) n′ R bb 、-(CH2) n NR bb C(O)(CH2) n′ R cc 、-(CH2) n NR cc C(O)NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(O)O(CH2) n′ R bb 、-(CH2) n P(O)R aa (CH2) n′ R bb 、-O(CH2) n P(O)R aa (CH2) n′ R bb 、-(CH2) n C(=NR ff )(CH2) n′ R bb 、-(CH2) n S(=NR ff )(O) m (CH2) n′ R bb 、-(CH2) n C(=NR ff )NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(=NR ff )NR aa (CH2)n′ R bb -(CH2) n NR bb S(O) m (CH2) n′ R cc -(CH2) n S(=O)R cc =N(CH2) n′ R bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further divided by 1-6 R groups n replace;

[0023] Preferably, R a R b R c R 1 R 2 R 3 R 4 and R 5Each group is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n O(CH2) n′ R bb -O(CH2) n R aa -(CH2) n S(CH2) n′ R bb -(CH2) n C(O)(CH2) n′ R cc -(CH2) n C(O)O(CH2) n′ R cc -(CH2) n S(O) n (CH2) n′ R cc -(CH2) n NR aa (CH2) n′ R bb -(CH2) n C(O)NR aa (CH2) n′ R bb -(CH2) n NR bb C(O)(CH2) n′ R cc -(CH2) n NR cc C(O)NR aa (CH2) n′ R bb -(CH2) n NR cc C(O)O(CH2) n′ R bb -(CH2) n P(O)Raa (CH2) n′ R bb -O(CH2) n P(O)R aa (CH2) n′ R bb -(CH2) n C(=NR ff (CH2) n′ R bb -(CH2) n C(=NR ff )NR aa (CH2) n′ R bb -(CH2) n NR cc C(=NR ff )NR aa (CH2) n′ R bb -(CH2) n NR bb S(O) m (CH2) n′ R cc -(CH2) n S(=O)R cc =N(CH2) n′ R bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further divided by 1-6 R groups n replace;

[0024] Or R a R b R c R 1 R 2 R 3 R 4 With R 5 Any two links form a substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 5-12 Cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m0 replace;

[0025] Or R a R b or R c and R 1 The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 5-12 Cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m1 replace;

[0026] Or R a R b or R c and R 4 The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m4 replace;

[0027] R m0 R m1 and R m4 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2)n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =NR bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1- 6-Haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0028] Or any two R m0 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c2 replace;

[0029] Or any two R m1 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c3 replace;

[0030] Or any two R m4 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c4 replace;

[0031] R n R aa R bb R cc R dd R ee R ff R H and R H1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n3 -、-(CH2) n3 R gg、 -(CH2) n3 O(CH2) n4 R hh -O(CH2) n3 R gg -(CH2) n3 S(CH2) n4 R hh -(CH2) n3 C(O)(CH2) n4 R ii -(CH2) n3 C(O)O(CH2) n4 R ii、 -(CH2) n3 S(O) m (CH2) n4 R ii -(CH2) n3 NR gg (CH2) n4 Rh h -(CH2) n3 C(O)NR gg (CH2) n4 R hh -(CH2) n3 NR hh C(O)(CH2) n4 R ii -(CH2) n3 NR ii C(O)NR gg (CH2) n4 R hh -(CH2) n3 NR ii C(O)O(CH2) n4 R hh -(CH2) n3 P(O)R gg (CH2) n4 R hh -O(CH2) n3 P(O)R gg (CH2) n4 R hh -(CH2)n3 C(=NR jj (CH2) n4 R hh -(CH2) n3 S(=NR jj (O) m (CH2) n4 R hh -(CH2) n3 C(=NR jj )NR gg (CH2) n4 R hh -(CH2) n3 NR ii C(=NR jj )NR gg (CH2) n4 R hh -(CH2) n3 NR hh S(O) m (CH2) n4 R ii -(CH2) n3 S(=O)R ii =N(CH2) n4 R hh -OC(R) hh R ii ) n3 (CH2) n4 R gg -NR hh (CH2) n3 R gg -CH=CH(CH2) n3 R gg -CH≡CH(CH2) n3 R gg -CH=CH(CH2) n3 NR gg R hh -CH=CH(CH2) n3 NR hh C(O)R ii -CH=CH(CH2) n3 NR ii C(O)NR gg R hh =N-OR hh or = CR gg R ii The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further divided by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =N-OR kk =CR ll R mm C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2- 6-Alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0032] Or R aa and R bb The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. p1 replace;

[0033] The H in the above CH2 can be optionally replaced by R H Replace; or any two Rs H The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. H1 replace;

[0034] Preferably, R n R aa R bb R cc P dd R eeR ff R H and R H1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0035] R q-1 R q-2、 R c2 R e3 R c4、 R p1 R gg、 R hh R ii R jj R kk R ll and R mmEach is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3, -SF5, =CF2, =CHF or =CH2, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, =CH2, or other C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0036] Preferably, R p1 R gg R hh R ii R jj R kk R ll and R mm Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0037] Or R gg and R ii The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. c1 replace;

[0038] Or R ll and R mm The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. c1 replace;

[0039] R c1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3, -SF5, =CF2 or =CHF, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0040] q3, x, y, w, n, n′, n1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0041] m is 1 or 2.

[0042] In certain embodiments of the invention, the compound is further represented as shown in formulas (II) to (XII):

[0043] in:

[0044] R a-1 and R a-3 The definition is the same as R a ;

[0045] L1, L2, L3, L4, R a R b R d M 11 M 12 、 Ring A″、 R 5 w, R 1 R 2 R 3 R 4 The definitions of x, y, ring B, and ring C are as described above.

[0046] In certain embodiments of the invention, the compound is further shown as of formulas (II-1) to (VI-1):

[0047] in:

[0048] Each ring D is independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl;

[0049] Cy5 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0050] R c5 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, =CH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted;

[0051] L6 is selected from a key, -(CH2) n3 -, -(CH2) n3 O(CH2) n4 -, -(CH2) n3 S(CH2) n4 -, -(CH2) n3 C(O)(CH2) n4 -, -(CH2) n3 C(O)O(CH2) n4 -, -(CH2) n3 S(O) m (CH2) n4 -, -(CH2) n3 NR gg (CH2) n4 -, -(CH2) n3 C(O)NR gg (CH2) n4 -, -(CH2) n3 NR ii C(O)NR gg (CH2) n4 -, -(CH2) n3 NR ii C(O)O(CH2) n4 -, -(CH2) n3 P(O)R gg (CH2) n4 -, -O(CH2) n3 P(O)R gg (CH2) n4 -, -(CH2) n3 C(=NR jj )(CH2) n4 -, -(CH2) n3 S(=NR jj )(O) m (CH2) n4 -, -(CH2) n3 C(=NR jj )NR gg (CH2) n4 -, -(CH2) n3 NR ii C(=NR jj )NR gg (CH2) n4 -, -(CH2) n3 NR hh S(O) m (CH2) n4 -, -(CH2) n3 S(=O)Rii =N(CH2) n4 -、-O(CR hh R ii ) n3 (CH2) n4 -、-NR hh (CH2) n3 -, -CH=CH(CH2) n3 -、-CH≡CH(CH2) n3 -, -CH=CH(CH2) n3 NR gg -, -CH=CH(CH2) n3 NR hh C(O)-, -CH=CH(CH2) n3 NR ii C(O)NR gg -、=NO- or=CR gg -;

[0052] X5 is independently selected from O, S, and NR. L Among them, R L Selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted;

[0053] q1 is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0054] q2 is independently selected from 0, 1, 2, 3, 4, or 5;

[0055] R a-1 and R a-3 The definition is the same as R a ;

[0056] z is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0057] L1, L2, L3, L4, R a Rb R d R gg R hh R jj R ii M 11 M 12 、 Ring A″、 R 5 w, m, n3, n4, R n R 2 R 3 R 4 The definitions of x, y, ring B, and ring C are as described above.

[0058] In some embodiments of the present invention, the compound is further shown below:

[0059] in:

[0060] R a′ and R a-3 The definition is the same as Ra;

[0061] Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0062] L5 molecules are independently selected from the bond and -(CH2). n -、-(CH2) n O(CH2) n′ -、-(CH2) n S(CH2) n′ -、-(CH2) n C(O)-、-(CH2) n C(O)O-、-(CH2) n S(O) m -、-(CH2) n NR bb -、-(CH2) n C(O)NR bb -、-(CH2) n NR bb C(O)-、-(CH2) n NR cc C(O)NR bb -、-(CH2) n P(O)R aa -、-O(CH2) n P(O)R aa -、-(CH2) n NR ccC(=NH)NR bb -、-(CH2) n NR bb S(O) m -、-(CH2) n S(=O)R cc =N-、-OC(R) aa R cc ) n (CH2) m -、-NR bb (CH2) n -, -CH=CH(CH2) n NR bb -, -CH=CH(CH2) n NR bb C(O), -CH=CH(CH2) n NR cc C(O)NR bb -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 Arene-ethylene or 5-14 membered heteroarylene-ethylene; wherein, the -(CH2) n -、-(CH2) n O-, -(CH2) n S、-(CH2) n C(O)-、-(CH2) n C(O)O-、-(CH2) n S(O) m -、-(CH2) n NR bb -、-(CH2) n C(O)NR bb -、-(CH2) n NR bb C(O)-、-(CH2) n NR cc C(O)NR bb -、-(CH2) n P(O)R aa -、-O(CH2) n P(O)R aa -、-(CH2) n NR cc C(=NH)NR bb -、-(CH2) n NR bb S(O) m -、-(CH2)n S(=O)R cc =N-、-OC(R) aa R cc ) n (CH2) m -、-NR bb (CH2) n -, -CH=CH(CH2) n NR bb -, -CH=CH(CH2) n NR bb C(O), -CH=CH(CH2) n NR cc C(O)NR bb -、C 1-6 Alkylene, C 1.6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 The arylene and 5-14 heteroarylene groups may be further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0063] Alternatively, each L5 may be independently selected from -(CH2). n C 2-6 alkenyl group, -(CH2) n C 2-6 Alynyl group, -(CH2) n C 3-12 Cycloalkylene, -(CH2) n 3-12 membered heterocyclic group, -(CH2) n C 6-14 aryl, -(CH2) n 5-14 heteroaryl groups, -O(CH2) n C 2-6 Alkenyl group, -O(CH2) n C 2-6 Alynyl group, -O(CH2) n C 3-12 Cycloalkylene, -O(CH2) n 3-12 membered heterocyclic group, -O(CH2) n C 6-14 aryl, -O(CH2) n 5-14 heteroaryl groups, -NH(CH2) n C 2-6 Alkenyl group, -NH(CH2) n C 2-6 Alynyl group, -NH(CH2) n C3- 12 Cycloalkylene, -NH(CH2) n 3-12 membered heterocyclic group, -NH(CH2) n C 6-14 aryl or -NH(CH2) n 5-14 heteroaryl groups, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0064] R a-2 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n3 R gg -O(CH2) n4 R hh -S(CH2) n4 R hh -C(O)(CH2) n4 R ii -C(O)O(CH2)n4 R ii 、-S(O) m (CH2) n4 R ii 、-NR gg (CH2) n4 R hh 、-C(O)NR gg (CH2) n4 R hh 、-NR hh C(O)(CH2) n4 R ii 、-NR ii C(O)NR gg (CH2) n4 R hh 、-NR ii C(O)O(CH2) n4 R hh 、-P(O)R gg (CH2) n4 R hh 、-O(CH2) n3 P(O)R gg R hh 、-C(=NR jj )(CH2) n4 R hh 、-S(=NR jj )(O) m (CH2) n4 R hh 、-C(=NR jj )NR gg (CH2) n4 R hh 、-NR cc C(=NR jj )NR gg (CH2) n4 R hh 、-NR hh S(O) m (CH2) n4 R ii 、-(CH2) n3 S(=O)R ii =N(CH2) n4 R hh 、-CH=CH(CH2) n3 NR gg R hh 、-CH=CH(CH2) n3 NR hh C(O)R ii 、-CH=CH(CH2)n3 NR ii C(O)NR gg R hh =N-OR hh or = CR gg R ii ; wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0065] Preferably, R a-2 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0066] Each ring D is independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl;

[0067] u is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0068] z is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0069] R aa R bb R cc R gg R hh R ii R jj ,m,n,n3,n4,L1,L2,L3,L4,R a R b R n R d M 11 M 12 、 Ring A″、 R 5 w, R 2 R 3 R 4 The definitions of x, y, ring B, and ring C are as described above.

[0070] In some embodiments of the invention, the compound is further shown as of formulas (II-1-1-1) to (II-1-1-8):

[0071] Among them, ring Q is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl;

[0072] v is 0, 1, 2, 3, 4, 5, or 6. ；

[0073] Ring H is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0074] R m0-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0075] Or any two Rm0-1 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c2 replace;

[0076] o can be 0, 1, 2, 3, 4, 5 or 6.

[0077] In some embodiments of the present invention, preferably, cyclic B is selected from thiophene group, Preferred Among them, M j M k M a M b M c M d M e M and M0 are each independently selected from C, N, or CH; M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; X4 independently selected from O, S, NR 2-1 or CR 2-2 R 2-3 ;R 2-1 R 2-2 and R 2-3 The definition is the same as R 2 .

[0078] In some embodiments of the present invention, ring B is selected from C. 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl or Preferably, ring B is selected from phenyl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, or... Preferably, ring B is selected from 5-6 member heteroaryl, 8-10 member heteroaryl, or... Among them, ring F is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl or 5-10 quinone heteroaryl; C is preferred 6-10 aryl or 5-10 heteroaryl, with ring G selected from C 5-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl or 5-10 quinone heteroaryl; C is preferred 5-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably, ring F is connected to L2 and ring G is connected to L3;

[0079] Preferably, ring B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridonel, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzobenzenethio, benzothiophenyl, benzotriazolyl, imidazopyridyl, imidazothiophenyl Azolyl, indazinyl, indoleyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindoleyl, isoquinolinyl, naphridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purine, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridinyl, acridineyl, benzoindoleyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, ketoxanyl, [The last part is incomplete and likely refers to a different group of groups, so it's left as is.] Preferably, ring B is selected from thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl, and others.

[0080] Preferably, ring B is selected from thiophene group, Preferred Among them, M j M k M a M b M c M d M e M and M0 are each independently selected from C, N, or CH; M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; X4 independently selected from O, S, NR 2-1 or CR 2-2 R 2-3 ;R 2-1 R 2-2 and R 2-3 The definition is the same as R 2 k1 and k2 are each independently 0, 1, 2, 3, 4, 5, or 6; k3 is 0, 1, or 2; M 31 and M 32 Each is independently selected from CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH;

[0081] Preferably, ring B is selected from thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl, and others. M6 is selected from CH or N; ring B1 and ring B2 are each independently selected from substituted or unsubstituted C. 4-12 Cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl or substituted or unsubstituted 5-10 heteroaryl groups; wherein the substitution refers to being replaced by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substitutions are made from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0082] Preferably, ring B is selected from

[0083] In some embodiments of the present invention, ring B is selected from... In some embodiments of the present invention, preferably, ring B is selected from... In certain embodiments of the present invention, preferably, cyclic B is selected from phenyl,

[0084] In some embodiments of the present invention, ring B is selected from...

[0085] In certain embodiments of the invention, the compound is further represented as shown in formulas (II-1-1-2) to (II-1-1-61), (IV-1-1-1) to (V-1-1-4), (VIII-1-1-1), (I′-1-1-1) to (I′-1-1-2) or (X-1-1-7).

[0086] in:

[0087] M 22 Selected from N or CH;

[0088] M j M k M a M b M c M d M e M0 and M0 are each independently selected from C, N, or CH;

[0089] X5 is independently selected from O, S, and NR. L Among them, R L Selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted;

[0090] X6 and X7 are each independently selected from O, S, N, NH, CH2 or CH;

[0091] X8 are each independently selected from bonds, O, S, NH or CH2;

[0092] X9 is independently selected from N or CH;

[0093] X 10 Each is independently selected from O, S, NH or CH2;

[0094] It can be a single bond or a double bond;

[0095] Ring H is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0096] Cy8 is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0097] R m0-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0098] Or any two R m0-1 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c2 replace;

[0099] a1 and a2 are each independently 0, 1, 2, 3, 4 or 5;

[0100] o can be 0, 1, 2, 3, 4, 5, or 6;

[0101] v1 is 0, 1, 2, 3, 4, 5, or 6;

[0102] t2, t3, t4, t5, t6 and t7 are each independently 0, 1, 2 or 3.

[0103] In certain embodiments of the invention, the compound is further shown as in formulas (IV-1) to (IV-121).

[0104] in:

[0105] Cy1 is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups;

[0106] Cy6 is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups;

[0107] M a M b M c M d M e M0 is selected from C, N, or CH;

[0108] M7 is selected from C, N, or CH;

[0109] M8 is selected from C, N, or CH;

[0110] M 23 Selected from N or CR5;

[0111] M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH;

[0112] M g Independently selected from N or CR n1 ;

[0113] M h Independently selected from N or CR n2 ;

[0114] R H-1 and R H-2 The definition is the same as R H ;

[0115] X9 is independently selected from N or CH;

[0116] X 10 Each is independently selected from O, S, NH or CH2;

[0117] X 11 Independently selected from N or CH;

[0118] L 5-1 and L 5-3 Each is independently selected from bonds, O, S, NH, and C. 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group, C 3- 12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0119] Cy10 is selected from C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene;

[0120] R L-1 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0121] t1 is 0, 1, 2, 3 or 4; t2, t3, t4 and t5 are each independently 0, 1, 2 or 3;

[0122] X4 is independently selected from O, S, and NR. 2-1 or CR 2-2 R 2-3 ;R 2-1 R 2-2 and R 2-3 The definition is the same as R 2 ;

[0123] X5 is independently selected from O, S, and NR. L Among them, R LSelected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted;

[0124] Ring Q is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl;

[0125] Ring I is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0126] R m4-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0127] y1 is 0, 1, 2, 3, 4, 5, or 6;

[0128] It can be a single bond or a double bond;

[0129] X1, X2, and X3 are each independently selected from CR m01 R m02 O, S, NR m03 CR m01 ,N,=N-,CO,SO,SO2 or POR m03 ;

[0130] M 24 Selected from C, N, CH or CO;

[0131] v is 0, 1, 2, 3, 4, 5, or 6;

[0132] t can be 0, 1, 2, 3, 4, 5, or 6;

[0133] R n1 and R n2 The definition is the same as R n ;

[0134] R m01 R m02 and R m03 The definition is the same as R m0 ;R m4 R 2 R H R n and R m0 The definition is as described above.

[0135] In some embodiments of the present invention, ring C is selected from C. 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, 5-6-membered heterocyclic 5-6-membered heteroaryl Preferably, ring C is selected from C 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, 5-6-membered heterocyclic 5-6-membered heteroaryl Among them, Cy2, Cy3, and Cy4 are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl; preferably, the ring C is selected from C 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, or 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably phenyl, More preferably phenyl, In some embodiments of the present invention, Selected from

[0136] In some embodiments of the present invention, R 1 Selected from the following group of substituent or unsubstituted groups: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 quinone heteroaryl, C 3-8 cycloalkyl, 4-8 membered heterocyclic, 5-6 membered heteroaryl, and C 4-6 Cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic, =N-OC 1-6 Alkyl or =CR aa R cc Preferably, R 1 Selected from the following group of substituent or unsubstituted groups: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl benzo[C] 4-6 Cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic, =N-OC1-6 Alkyl or =CR aa R cc ;

[0137] Or R 1 Selected from C(O)NR aa NR aa OR aa ;

[0138] Preferably, R 1 Selected from the following group (substituted or unsubstituted): thiophene, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl. methoxy Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, aziridine, oxacyclopentyl, piperazinyl, piperidinyl, oxacyclohexyl, vinyl, ethynyl

[0139] Preferably, R 1 Selected from the following group, whether substituted or unsubstituted: methoxy, NHCH3,

[0140] Preferably, R 1 Selected from the following group (substituted or unsubstituted): thiophene, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl. methoxy Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, oxacyclobutyl, azircyclopentyl, oxacyclopentyl, piperazinyl, piperidinyl, oxacyclohexyl, vinyl, ethynyl;

[0141] Wherein, the substitution refers to being replaced by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more groups selected from aryl, 5-14 heteroaryl, -SF3, or -SF5 are substituted, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups.

[0142] In some embodiments of the present invention, R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; preferably, R 1 It is selected from hydrogen, methyl, ethyl, isopropyl, CF3, CH2F, CHF2, methoxy, ethoxy, OCF3, OCH2F, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0143] In some embodiments of the present invention, R 1 Selected from More More preferably, R 1 Selected from

[0144] In some embodiments of the present invention, R aa Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 quinone heteroaryl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, preferably C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5-6 quinone heteroaryl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic groups.

[0145] In some embodiments of the present invention, L1 is selected from bond, CH2, CH2CH2, NH, O, S, CO, NHCO, CONH, NHCONH, NCH3, N(CH3)CO, NHCOO, N(CH3)COO, N(CH3)CONH or N(CH3)CON(CH3); preferably, L1 is selected from bond, CH2, CH2CH2, NH, O, S, CO, NHCO, CONH, NHCONH.

[0146] In some embodiments of the present invention, L2 is selected from bond or O; preferably, L2 is selected from bond.

[0147] In some embodiments of the present invention, L3 is selected from bond, O, S, C=O, C=S, NR. dd , C=O(CH2), C=S(CH2), (CH2)NR dd C=ONR dd (CH2), C 3-6 Cycloalkyl C=O, 4-6 membered heterocyclic C=O, C 1-3 Alkylene, C 2-4 Alkenyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl, 5-6 membered heterocyclic CH2, 5-6 membered heteroaryl CH2, 5-6 membered heterocyclic CH2CH2, 5-6 membered heteroaryl CH2CH2, 5-6 membered heterocyclic O, 5-6 membered heteroaryl O, 5-6 membered heterocyclic NH or 5-6 membered heteroaryl NH;

[0148] The H in the above CH2 can be optionally replaced by R H Instead, the C 3-6 cycloalkyl, 4-6 membered heterocyclic, C1-3 Alkylene, C 2-4 The alkenyl, 5-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C1-6 haloalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C1-6 haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents selected from substituted or unsubstituted 5-14 membered heteroaryl groups. In some embodiments of the invention, L3 is selected from the group consisting of aryl, CONH, CH2, CD2, CH2CH2, CONHCH2, NH, NHCH2, etc. Preferably, L3 is selected from the following: bond, CONH, CH2, CH2CH2, CONHCH2, NH, NHCH2, Preferably, L3 is selected from the following: bond, CONH, CH2, CH2CH2, CONHCH2, NH, NHCH2,

[0149] In some embodiments of the present invention, L4 is selected from bond, O, CH2, P(=O)R dd , SO2, CO, CONH, NHCO, NHCOO, S(=NH)O( ), NH, NHCONH, SO2NH or S(=NH)ONH ( Preferably, L4 is selected from bonds, P(=O)R dd SO2, CO, CONH, NHCO, NHCOO, S(=NH)O, preferably, L4 is selected from bond, CO, CONH, NHCO, NHCOO, S(=NH)O, preferably, L4 is selected from bond, CO, CONH, NHCO or NHCOO.

[0150] In some embodiments of the present invention, R 4 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF3, -SF5, R aa -O(CH2) n R aa -S(CH2) n′ R bb -C(O)(CH2) n′ R cc -C(O)O(CH2) n′ R cc -S(O) m (CH2) n′ R cc -NR aa (CH2) n′ R bb -C(O)NR aa (CH2) n′ R bb -NR bb C(O)(CH2) n′ R cc -NR cc C(O)NR aa (CH2) n′ R bb -NR cc C(O)O(CH2) n′ R bb -P(O)R aa (CH2) n′ R bb -O(CH2) n P(O)R aa R bb -C(=NR) ff )R bb -C(=NR) ff )NR aa R bb -NR cc C(=NR ff )NR aa R bb -NR bb S(O) m (CH2) n′ R cc -S(=O)R cc=N(CH2) n′ R bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally further divided by 1-6 R groups. n Replace; or R 4 Selected from S(=NR) ff (O) m R bb ;

[0151] Preferably, R 4 Selected from H, halogen, methyl, CD3, methoxy, CHF2, C2HF, CF3, -SF5, NH2, CF2Cl or Or R 4 Selected from Or R4 is selected from

[0152] In certain embodiments of the present invention, -L4-R 4 Selected from CONH2, NH2,

[0153] In some embodiments of the present invention, L5 is selected from bonds, S, O, NH, CO, and C. 1-3 Alkylene, C 2-4 imidene group, C 2- 4-ethynyl group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, (CH2)C 3-12 Cycloalkylene, (CH2)3-12-membered heterocyclic alkylene, (CH2)2C 3-12 Cycloalkylene, (CH2)23-12-membered heterocyclic group, -OC 3-12 Cycloalkylene, -O-3-12-membered heterocyclic alkylene, -O-(CH2)C 3-12 Cycloalkylene, -O-(CH2)3-12-membered heterocyclic alkylene, -O-(CH2)2C 3-12 Cycloalkylene, -O-(CH2)23-12-membered heterocyclic alkylene, -NH-C 3-12 Cycloalkylene, -NH-3-12-membered heterocyclic alkylene, -NH-(CH2)C 3-12 Cycloalkylene, -NH-(CH2)3-12-membered heterocyclic alkylene, -NH-(CH2)2C 3-12 Cycloalkylene, -NH-(CH2)23-12-membered heterocyclic alkylene, phenyl, 5-6-membered heteroaryl or 8-10-membered heteroaryl; wherein, the C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-12 Cycloalkylene, 3-12-membered heterocyclic phenylene, 5-6-membered heteroaryl, and 8-10-membered heteroaryl may be further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5; preferably L5 is selected from bond, S, O, NH, CO, C. 1-3 Alkylene, C 3-8 Cycloalkylene, 3-8-membered heterocyclic alkylene, 5-6-membered heteroaryl, or 8-10-membered heteroaryl; wherein, the C1-3 Alkylene, C 3-8 Cycloalkylene, 3-8-membered heterocyclic, 5-6-membered heteroaryl, and 8-10-membered heteroaryl groups may be further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0154] Preferably, L5 is selected from the following groups: -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CF2)(CF2)-, -(CF2)(CH2)-, -(CHF)(CHF)-, -(CD2)-, -(CF2)-, -(CHF)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferably, L5 is selected from -(CH2)-, S, O, -(CH2)(CH2)-,

[0155] In some embodiments of the present invention, L5 is selected from bonds, -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-, Preferred Where L 5-1 and L 5-3 Each is independently selected from bonds, O, S, NH, and C. 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0156] Cy10 is selected from C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene;

[0157] R L-1 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0158] t1 can be 0, 1, 2, 3 or 4.

[0159] In some embodiments of the present invention, the cyclic Cy10 is selected from C. 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene; preferably C 3-8 Cycloalkylene, 4-8 membered heterocyclic alkylene; more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0160] In some embodiments of the present invention, L 5-1 and L 5-3 Each is independently selected from the following: bond, -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CF2)(CF2)-, -(CF2)(CH2)-, -(CHF)(CHF)-, -(CD2)-, -(CF2)-, -(CHF)-.

[0161] In some embodiments of the present invention, ring E is selected from phenyl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-6 cycloalkylphenyl, 5-6 membered heterocyclic phenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably, ring E is selected from phenyl, 5-6-membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-6 cycloalkylphenyl, 5-6 membered heterocyclic phenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably, ring E is selected from phenyl, cyclohexyl, piperidinyl, piperazine, etc.

[0162] In some embodiments of the present invention, cycloE is selected from phenyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, pyrazinyl, pyridinyl, pyridoneyl, pyrimidinoneyl, etc.

[0163] In some embodiments of the present invention, ring D is selected from C. 3-6 Cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl fused C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocyclic; preferably, ring D is selected from 5-6-membered heteroaryl, 5-6-membered heterocyclic, and 5-6-membered heteroaryl-C. 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclic, preferably thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl,

[0164] In some embodiments of the present invention, ring D is selected from...

[0165] In some embodiments of the present invention, R a R b R c R a-2、 R m4 R 2 R 3 and R 5 Each group is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, SC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, -SF3 or -SF5, wherein the C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, SC1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally further divided by 1-6 R groups. n replace.

[0166] In some embodiments of the present invention, ring A′ is selected from 5-6 heteroaryl or 5-6 membered heterocyclic groups.

[0167] In some embodiments of the present invention, R a Selected from R aa -(CH2)R aa -(CH2)2R aa -OR aa -(CH2)NR aa R bb -(CH2)NR aa R bb (CH2)NR bb C(O)R cc The H in the above CH2 can be optionally replaced by R. H Replace; or any two Rs H The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. H1 Replace; more preferably R a Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, isopropyl,

[0168] In some embodiments of the present invention, R a-1 Selected from Among them, R a-4 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C1-6 haloalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1- 6-Haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 It is substituted by one or more substituents in the aryl group and substituted or unsubstituted 5-14 heteroaryl groups.

[0169] In some embodiments of the present invention, ring Q is selected from 4-6-membered cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic or 7-12-membered heterocyclic; preferably, ring Q is selected from 7-12-membered heterocyclic.

[0170] Preferably, Selected from Or preferably Selected from Or preferably Selected from Or preferably Selected from

[0171] Further preferred Selected from

[0172] Further preferred Selected from Further preferred Selected from Further preferred Selected from Further preferred Selected from

[0173] in, It can be a single bond or a double bond;

[0174] Among them, is a single bond or a double bond;

[0175] X1, X2, and X3 are each independently selected from CR m01 R m02 O, S, NR m03 CR m01 ,N,=N-,CO,SO,SO2 or POR m03 M 24 Selected from C, N, CH or CO; R m01 R m02 and R m03 The definition is the same as R m0 ;R m0 The definition is as described above;

[0176] Further preferred Selected from

[0177] Among them, M 24 Selected from C, N, CH or CO.

[0178] In some embodiments of the present invention, the ring I is selected from C. 3-14 Cycloalkyl, 3-8-membered heterocyclic, 5-6-membered heteroaryl or phenyl; preferably 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl or 6-membered heteroaryl;

[0179] Preferably, Selected from Preferably, Selected from Preferably, Selected from

[0180] In some embodiments of the present invention, Selected from In some embodiments of the present invention, Selected from In some embodiments of the present invention, Selected from

[0181] In some embodiments of the present invention, Selected from In some embodiments of the present invention, Selected from

[0182] In some embodiments of the present invention, Selected from

[0183] In some embodiments of the present invention, Selected from

[0184] In some embodiments of the present invention, Selected from

[0185] In some embodiments of the present invention, Selected from

[0186] In some embodiments of the present invention, Selected from

[0187] In some embodiments of the present invention, the ring H is selected from C. 4-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl or 5-10 membered heteroaryl; preferably 4-8 membered heterocyclic.

[0188] In some embodiments of the present invention, Selected from

[0189] L1 is selected from the bond; L5 is selected from the bond; ring E is selected from the...

[0190] In certain embodiments of the invention, the compound is further represented as shown in formula (II-1-1-5-1) or (II-1-1-5-10).

[0191] Where k is 0, 1 or 2;

[0192] It can be a single bond or a double bond;

[0193] X1, X2, and X3 are each independently selected from CR m01 R m02 O, S, NR m03 CR m01 ,N,=N-,CO,SO,SO2 or POR m03 ;

[0194] M 33 and M 34 Each is independently selected from CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH;

[0195] Cy7 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0196] a 3 and a 4 can be 0, 1, 2, 3, or 4 independently;

[0197] R m01 R m02 and R m03 The definition is the same as R m0 ;R c2 and R m0 The definition is as described above.

[0198] In some embodiments of the invention, the compound is further described as follows (II-1-1-5-1-1) to (II-1-1-5-1-15).

[0199] Where k is 0, 1, or 2; k3 is 0, 1, or 2;

[0200] M a M and M0 are each independently selected from C, N, or CH; M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; X4 independently selected from O, S, NR 2-1 or CR 2-2 R 2-3 ;R 2-1 R 2-2 and R 2- 3 The definition is the same as R 2 ;

[0201] M 31 M 32 M33 and M 34 Each is independently selected from CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH;

[0202] M g Independently selected from N or CR n1 ;

[0203] M h Independently selected from N or CR n2 ;

[0204] R n1 and R n2 The definition is the same as R n ;

[0205] R m0-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups;

[0206] o can be 0, 1, 2, 3, 4, 5 or 6.

[0207] In certain embodiments of the invention, the compound is further shown as in formulas (II-1-1-5-1-9-1) to (II-1-1-5-1-12-2).

[0208] In certain embodiments of the invention, the compound is further shown as of formulas (IV-1-1) to (IV-1-40).

[0209] The definitions of each substituent in the general formula are as described above.

[0210] In some embodiments of the present invention, L6 is selected from bonds, O, S, CO, NH, and CH2.

[0211] In some embodiments of the present invention, Cy5 is selected from C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; C is preferred 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, piperazineyl, In some embodiments of the present invention, Selected from

[0212] In some embodiments of the present invention, Cy6 is selected from C. 3-11 Cycloalkyl or 3-11 membered heterocyclic groups, more preferably Selected from

[0213] In some embodiments of the present invention, Cy8 is selected from C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; C is preferred 5-6 Cycloalkyl or 5-6 membered heterocyclic groups.

[0214] In some embodiments of the present invention, Cy8 is selected from C. 5-6 Cycloalkyl, 5-6 membered heterocyclic or 5-6 membered heteroaryl.

[0215] In some embodiments of the invention, B1 and ring B2 are each independently selected from substituted or unsubstituted C. 5-8Cycloalkyl, substituted or unsubstituted 5-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The aryl group is a substituted or unsubstituted 5-6 membered heteroaryl group; more preferably, ring B1 and ring B2 are each independently selected from substituted or unsubstituted 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups.

[0216] The present invention further relates to a compound as shown below, its nitrogen oxides, or a pharmaceutically acceptable salt thereof.

[0217] M6 is selected from CH or N;

[0218] L1, L2, L3, L4, L5, L6, R a M j M k M a M b M c M d M e M6, R 2 R 3 R 4 R n R c5 The definitions of q1, q2, x, y, ring Cy5, ring D, ring E, and ring C are as described above.

[0219] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound as described above, its nitrogen oxides or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0220] The present invention further relates to the use of the compounds described above, their nitrogen oxides or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described above in the preparation of calcitonin receptor and / or amylin receptor agonist pharmaceuticals.

[0221] This invention further relates to the use of the compounds described above, their nitrogen oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described above in the preparation of medicaments for treating endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative disorders, or cardiovascular disorders. Preferably, the diseases are selected from osteoporosis, Paget's disease, hypercalcemia, Sudeck's atrophy, multiple fibrous dysplasia, interclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or periodontal defects, osteolytic osteopathy, metastatic osteopathy, and bone loss due to malignant tumors. Autoimmune arthritis, fractures or breaks, bone disease pain, phantom limb pain, general pain, hyperalgesia, pain associated with diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, Syndrome X, complications of diabetes, primary or secondary hyperthyroidism, endocrine disorders, disorders related to inhibition of gastric acid secretion, gastrointestinal disorders, renal osteodystrophy, or male infertility.

[0222] The present invention further relates to methods of treating endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative disorders, or cardiovascular disorders with compounds, as described above, their nitrogen oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above.

[0223] The present invention also relates to a method for treating, preventing and / or treating endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative disorders or cardiovascular disorders, comprising administering to a patient a therapeutically effective dose of the compound as described above, its nitrogen oxides or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above.

[0224] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 90%, 85%, 80%, 75%, 70%, 60%, or 50%.

[0225] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0226] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to dysfunction associated with calcitonin receptors and / or amylin receptors.

[0227] The present invention also relates to methods for treating endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative disorders, or cardiovascular disorders in mammals, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0228] In some implementations, this method relates to the treatment of conditions such as endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative diseases, or cardiovascular diseases.

[0229] In some implementations, this method relates to osteoporosis, Paget's disease, hypercalcemia, Sudeck atrophy, multiple fibrous dysplasia, interclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or periodontal defects, osteolytic osteopathy, metastatic osteopathy, bone loss due to malignancy, autoimmune arthritis, fractures or breaks, osteopathic pain, phantom limb pain, general pain, hyperalgesia, pain associated with diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, Syndrome X, diabetic complications, primary or secondary hyperthyroidism, endocrine disorders, diseases related to inhibition of gastric acid secretion, gastrointestinal diseases, renal osteodystrophy, or male infertility.

[0230] Detailed description of the invention

[0231] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0232] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6 Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6 Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0233] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0234] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2- 8), 2 to 6 (C) 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3- 15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0235] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3- 15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0236] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6- 14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group described elsewhere herein or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group. In one embodiment, the cycloalkyl group is selected from C10. 3-6 Cycloalkylphenyl, C 3-6 cycloalkyl 5-6-membered heteroaryl or C 3-6 Cycloalkyl 3-6 membered heterocyclic groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms. Non-limiting examples include indenyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0237] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10(e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0238] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7- 10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0239] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0240] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. In one embodiment, the heterocyclic group is selected from 3-6-membered heterocyclic phenyl, 3-6-membered heterocyclic 5-6-membered heteroaryl, or 3-6-membered heterocyclic C3-6 cycloalkyl, wherein the heteroaryl group contains 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

[0241] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0242] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0243] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0244] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0245] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0246] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, a heteroaryl comprises 5 to 20, 5 to 14, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, a heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, a heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thiaphenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, gurttanyl,

[0247] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0248] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0249] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0250] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0251] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0252] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0253] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0254] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0255] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0256] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0257] The term "aminocarbonyl" refers to NH2-C(O)-. The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0258] The term "alkylamino" refers to an amino group in which one or both hydrogen atoms are replaced by an alkyl group, as defined above. The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0259] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotope-enriched analogs may be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures, wherein the hydrogen or hydrogen atom described in this patent comprises its isotopes (H) and / or mixtures thereof. 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof.

[0260] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0261] The term "substituted or unsubstituted" indicates that the modified substituent may optionally be further substituted by one or more of the following substituents, selected from alkyl, deuteralkyl, haloalkyl, alkenyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkoxy, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR bb S(O) m R cc -OC(R) aa R bb ) n (CH2) m Raa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc In one embodiment of the invention, the substitution in "substituted or unsubstituted" refers to the presence of hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substituents selected from aryl, 5-14 heteroaryl, -SF3 or -SF5.

[0262] In one embodiment of the present invention, S(=NH)O refers to

[0263] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0264] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0265] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0266] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0267] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0268] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0269] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0270] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0271] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0272] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0273] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0274] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0275] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0276] The compounds of this invention include all of their "stereoisomers", "stereoisomeric purity", "stereoisomeric enrichment", "enantiomeric purity", "optical activity", "enantiomeric activity" and "optical isomers". Detailed Implementation

[0277] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0278] Example

[0279] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0280] The determinations were performed using LC-MS with an Agilent 1200 Infinity Series mass spectrometer. The determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C). 18 150×4.6mm chromatographic column) and Waters 2695-2996 high-performance liquid chromatograph (Gimini C) 18 (150×4.6mm chromatographic column).

[0281] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0282] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0283] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0284] Example 1

[0285] Step 1: Synthesis of (R)-5-formyl-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0286] 5-Formylthiophene-2-carboxylic acid (957.51 mg, 6.13 mmol) and (R)-4-methoxy-2,3-dihydro-1H-indene-1-amine (1 g, 6.13 mmol) were mixed in DCM (15 mL), and TEA (2 mL) and HATU (2.8 g, 7.36 mmol) were added. The mixture was reacted at room temperature for 2 hours. A saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted three times with DCM. The combined organic phases were washed with saturated sodium chloride solution, and the separated organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (1.5 g, 81%). MS m / z (ESI): 302.1 [M+H] + .

[0287] Step 2: Synthesis of 3-imino-5-methylhexanoamide

[0288] Ethyl 5-methyl-3-carbonylhexanoate (3.7 g, 21.49 mmol) was dissolved in EtOH (10 mL), and 30% ammonia solution (10 mL, 176 mmol) was added. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (700 mg, 23%). MS m / z (ESI): 143.1 [M+H] +

[0289] Step 3: Synthesis of 5-(3-(4-fluorophenyl)propionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0290] 3-(4-fluorophenyl)propionic acid (1.68 g, 10 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.44 g, 10 mmol), and DMAP (2.44 g, 20 mmol) were mixed in DCM (30 mL), and DCC (2.06 g, 10 mmol) was added in portions. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed successively with 1N HCl aqueous solution (20 mL), water (20 mL), and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (2.88 g). MS m / z (ESI): 295.1 [M+H] + .

[0291] Step 4: Synthesis of ethyl 5-(4-fluorophenyl)-3-carbonylpentanoate

[0292] 5-(3-(4-fluorophenyl)propionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.88 g, 9.79 mmol) was dissolved in anhydrous EtOH (20 mL), and the mixture was refluxed for 5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (2.3 g). MS m / z (ESI): 239.1 [M+H] + .

[0293] Step 5: Synthesis of ethyl 5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-1,4-dihydropyridine-3-carboxylic acid ester

[0294] Ethyl 5-(4-fluorophenyl)-3-carbonylpentanoate (714.9 mg, 3 mmol), (R)-5-formyl-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (904.2 mg, 3 mmol), and 3-imino-5-methylhexanoamide (511.92 mg, 3.6 mmol) were mixed in 15 mL of EtOH and reacted overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (1.93 g). MS m / z (ESI): 646.3 [M+H] + .

[0295] Step 6: Synthesis of ethyl(R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid ester

[0296] Ethyl 5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-((((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-1,4-dihydropyridine-3-carboxylic acid ester (1.93 g, 3 mmol) and cerium ammonium nitrate (2.39 g, 4.5 mmol) were mixed in DCM (25 mL), and the reaction mixture was heated to reflux and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the DCM was separated from the water phase. The organic phase was then concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (695.3 mg, 36%). MS m / z (ESI): 644.3 [M+H] + .

[0297] Step 7: Synthesis of (R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid

[0298] Ethyl(R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid ester (695.3 mg, 1.08 mmol) and lithium chloride (228.91 mg, 5.4 mmol) were mixed in DMA (3 mL), and the mixture was heated to 150 °C and reacted for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the target compound (200 mg, 30%) was obtained by reversed-phase column chromatography. MS m / z (ESI): 616.2 [M+H] + .

[0299] Step 8: Synthesis of (R)-5-(2-(cyclopropylcarbonyl)hydrazine-1-carbonyl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophene-2-yl)nicotinamide

[0300] (R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid (200 mg, 0.32 mmol) and cyclopropionylhydrazine (35 mg, 0.35 mmol) were mixed in DCM (5 mL), and DIEA (129.24 mg, 1 mmol) and HATU (133.08 mg, 0.35 mmol) were added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the DCM was separated from the water phase by liquid chromatography. The organic phase was then concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (200 mg, 90%).

[0301] MS m / z (ESI): 698.3 [M+H] + .

[0302] Step 9: Synthesis of (R)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide

[0303] (R)-5-(2-(cyclopropylcarbonyl)hydrazide-1-carbonyl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (200 mg, 0.29 mmol) was dissolved in THF (60 mL), and p-toluenesulfonyl chloride (331.73 mg, 1.74 mmol) and TEA (176.07 mg, 1.74 mmol) were added. After nitrogen purging, the mixture was heated to 60 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, and DCM and water were separated. The organic phase was then concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (82 mg, 42%). MS m / z (ESI): 680.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.87 (d, J=8.4Hz, 1H), 7.88 (d, J=2.4Hz, 1H), 7.68 (d, J=4.0Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.12-7.02 (m, 4H), 6.92 (d, J=3.6Hz, 1H), 6.88-6.78 (m, 2H), 5.52-5.44 (m, 1H), 3.79(s, 3H), 3.09-3.03(m, 2H), 2.99-2.88(m, 3H), 2.76-2.64(m, 3H), 2.47-2.39(m, 1H), 2.34-2.25( m, 1H), 2.19-2.11 (m, 1H), 1.98-1.86 (m, 1H), 1.06-0.99 (m, 2H), 0.94 (d, J=6.8Hz, 6H), 0.67-0.61 (m, 2H).

[0304] The synthesis methods for Examples 2 to 4477 are the same as those for Example 1. The compounds of this invention are shown in Table 1.

[0305] Some compounds 1 The H NMR data are as follows:

[0306] Example 7 can also be prepared according to the following method

[0307] Step 1: Synthesis of N′-(3,4-dihydro-2H-pyrrolo-5-yl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine

[0308] 5-Methoxy-3,4-dihydro-2H-pyrrole (406.45 mg, 4.10 mmol) was added to a solution of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine (1.0 g, 3.73 mmol) in isopropanol (10 mL). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was evaporated to dryness, and the residue was separated by column chromatography to give a white solid N′-(3,4-dihydro-2H-pyrrole-5-yl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine (900 mg, 72%). MS m / z (ESI): 336.2 [M+H] + .

[0309] Step 2: Synthesis of 3-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

[0310] N′-(3,4-dihydro-2H-pyrrolo-5-yl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine (900 mg, 2.68 mmol) was added to a mixed solution of 2-pentanol (10 mL) and acetic acid (2 mL). The reaction solution was heated to 150 °C and reacted for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, evaporated to dryness, and the residue was purified by column chromatography to give a white solid 3-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (400 mg, 47.0%).

[0311] MS m / z (ESI): 318.2 [M+H] + .

[0312] Step 3: Synthesis of 1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-4-(4-fluorophenyl)butane-2-one

[0313] 3-((2-(4-fluorophenylethyl)-1,3-dioxapentane-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (400 mg, 1.26 mmol) was added to a mixture of formic acid (5 mL) and concentrated sulfuric acid (0.25 mL). The reaction mixture was heated to 50 °C and reacted for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, evaporated to dryness, and the residue was purified by column chromatography to give a white solid 1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-4-(4-fluorophenyl)butane-2-one (100 mg, 29.0%).

[0314] MS m / z (ESI): 274.1 [M+H] + .

[0315] Step 4: Synthesis of (R)-5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide

[0316] Ytterbium trifluoromethanesulfonate (17.49 mg, 28.21 μmol) was added to an ethanol (5 mL) solution of 3-imino-5-methylhexamamide (44 mg, 310 μmol), 5-formyl-N-[(1R)-4-methoxyindium-1-yl]thiophene-2-carboxamide (85 mg, 282 μmol), 1-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-4-(4-fluorophenyl)butane-2-one (77 mg, 282 μmol), and ammonium acetate (43 mg, 564 μmol). The reaction solution was heated to 100 °C and reacted for 16 hours. The reaction solution was then cooled to 50 °C, and cerium ammonium nitrate (370 mg, 698 μmol) was added to the reaction solution. The mixture was stirred for another 2 hours. The reaction solution was concentrated, washed twice with water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The residue was reverse-phase to prepare (R)-5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (9.5 mg, 4.8%). MS m / z (ESI): 679.3 [M+H] + .

[0317] Example 12 can also be prepared according to the following method

[0318] Step 1: Synthesis of methyl(R)-(5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)pyridin-3-yl)carbamate

[0319] Under a nitrogen atmosphere, MeOH (1 mL) was added to a 5 mL DMF solution of (R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid (50 mg, 0.08 mmol), diphenyl azide phosphate (26.82 mg, 0.10 mmol), and triethylamine (16.43 mg, 0.16 mmol). The mixture was heated to 100 °C and reacted for 1.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the target compound (9.2 mg, 17%). MS m / z (ESI): 645.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 8.85 (d, J = 8.4Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 4.0Hz, 1H), 7. 45(s, 1H), 7.29-7.23(m, 2H), 7.20(t, J=8.0Hz, 1H), 7.13-7.03(m, 3H), 6.89-6.82(m, 2H), 5.56-5. 44 (m, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 3.02-2.90 (m, 5H), 2.74-2.66 (m, 1H), 2.61 (d, J=7.2Hz, 2H), 2.48-2.41 (m, 1H), 2.25-2.16 (m, 1H), 1.98-1.88 (m, 1H), 1.35-1.18 (m, 1H), 0.88 (d, J=6.4Hz, 6H).

[0320] Example 27 can also be prepared according to the following method

[0321] Step 1: Preparation of tert-butyl(R)-(6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)carbamate

[0322] (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid was dissolved in a sealed tube containing tert-butanol (8 mL). Diphenyl azidophosphate (891.7 mg, 3.67 mmol, 700 μL) and triethylamine (618.2 mg, 6.11 mmol, 852 μL) were added. The reaction was bubbled with nitrogen gas, and then the tube was sealed and heated to 100 °C with stirring for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude tert-butyl(R)-(6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)carbamate (886 mg). MS m / z (ESI): 726.3 [M+H] + .

[0323] Step 2: Preparation of (R)-5-(3-amino-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0324] 886 mg (1.22 mmol) of tert-butyl(R)-(6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)carbamate (10 mL) was dissolved in dichloromethane, and trifluoroacetic acid (6.4 g, 56.00 mmol, 5 mL) was added. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate. The concentrate was then poured into 100 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (100 mL * 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated by column chromatography to give a yellow solid (R)-5-(3-amino-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (500 mg, 65.5%). MS m / z (ESI): 626.3 [M+H] + .

[0325] Step 3: Preparation of (R)-5-(3-bromo-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0326] (R)-5-(3-amino-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (500 mg, 799 μmol) was dissolved in acetonitrile (30 mL), and copper bromide (267.7 mg, 1.20 mmol), cuprous bromide (171.93 mg, 1.20 mmol), and tert-butyl nitrite (247.2 mg, 2.40 mmol, 285 μL) were added. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into 100 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 mL * 3). The organic phases were combined and concentrated under reduced pressure. The residue was separated by column chromatography to give a yellow solid, (R)-5-(3-bromo-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (225 mg, 49.9%). MS m / z (ESI): 691.1 [M+H] + .

[0327] Step 4: Preparation of Tributyl(1-Fluorovinyl)stanane

[0328] 1-Fluorovinylmethyl-diphenyl-silane (212 mg, 874.7 μmol, 0.2 mL) and tributyltin chloride (242.0 mg, 743.5 μmol, 202 μL) were dissolved in DMF (1 mL), and then CsF (120 mg, 790 μmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL * 3), the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain crude tributyl(1-fluorovinyl)tinane (150 mg, 60.2%), which was used directly in the next step.

[0329] Step 5: Preparation of (R)-5-(2-(4-fluorophenylethyl)-5-(1-fluorovinyl)-6-isobutyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0330] (R)-5-(3-bromo-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (25 mg, 36.3 μmol) and tributyl(1-fluorovinyl)stanane (60.7 mg, 181.3 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and tetrakis(triphenylphosphine)palladium (4.2 mg, 3.6 μmol) was added. The reaction mixture was heated to 100 °C and stirred for 6 hours. The reaction mixture was then poured into a 2M potassium fluoride aqueous solution (30 mL) and stirred for 10 minutes. The mixture was extracted with ethyl acetate (20 mL * 3), and the organic phases were combined and concentrated under reduced pressure. The concentrate was purified by reverse-phase extraction to give a white solid (R)-5-(2-(4-fluorophenylethyl)-5-(1-fluorovinyl)-6-isobutyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (1.6 mg, 6.5%). MS m / z (ESI): 655.2 [M+H] + .

[0331] 1 H NMR (400MHz, CDCl3) δ7.23-7.21 (m, 1H), 7.06 (dd, J=5.8, 8.0Hz, 2H), 6.98-6.86 (m, 4H), 6.79 (d, J =8.0Hz, 1H), 6.11 (d, J = 8.3Hz, 1H), 5.63 (q, J = 7.7Hz, 1H), 5.03 (dd, J = 3.5, 14.3Hz, 1H), 4.53 (d, J = 3.5Hz, 1H), 3.86 (s, 3H), 3.16-3.03 (m, 4H), 2.95 (d, J=6.8Hz, 2H), 2.86-2.78 (m, 1H), 2.73-2.62 (m , 1H), 2.41 (s, 3H), 2.36-2.29 (m, 1H), 1.96-1.87 (m, 1H), 1.64-1.59 (m, 1H), 0.99 (d, J=6.5Hz, 6H).

[0332] Example 38 can also be prepared according to the following method

[0333] Step 1: Preparation of methyl 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxylic acid

[0334] Under nitrogen protection, 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (3.6 g, 14.50 mmol), (R)-5-formyl-N-(4-methoxy-2,3-dihydro-1H-indene-1-yl)thiophene-2-carboxamide (4.37 g, 14.50 mmol) and methyl 3-imino-5-methylhexanoate (2.28 g, 14.50 mmol) were dissolved in ethanol (50 mL), and ammonium acetate (2.24 g, 29.0 mmol) and ytterbium trifluoromethanesulfonate (899.4 mg, 1.45 mmol) were added. The reaction was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, washed twice with water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give the crude product methyl 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxylic acid (9.3 g). MS m / z (ESI): 671.3 [M+H] + .

[0335] Step 2: Preparation of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid methyl ester

[0336] Under nitrogen protection, cerium ammonium nitrate (14.7 g, 27.73 mmol) was added to ethanol (50 mL) containing crude product 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((R)-4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxylic acid methyl ester (9.3 g, 13.86 mmol), and the mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), dried and concentrated, and the residue was separated by column chromatography to obtain (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid methyl ester (2.8 g, 30.2%). MS m / z (ESI): 669.2 [M+H] + .

[0337] 1H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.4Hz, 1H), 7.69 (d, J=3.9Hz, 1H), 7.18 (t, J= 7.8Hz, 1H), 7.13-7.00(m, 4H), 6.90(d, J=3.9Hz, 1H), 6.87-6.78(m, 2H), 5.46(q , J=7.9Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.05-2.85 (m, 5H), 2.76-2.64 (m, 3H), 2.48-2.39(m, 4H), 2.25-2.11(m, 1H), 1.99-1.85(m, 1H), 0.91(d, J=6.6Hz, 6H).

[0338] Step 3: Preparation of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid

[0339] Under nitrogen protection, methyl (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid (2.8 g, 4.19 mmol) and lithium chloride (1.77 g, 41.87 mmol) were dissolved in N,N-dimethylacetamide (30 mL) and reacted at 120 °C with stirring for 16 hours. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was dried and concentrated to give the crude product (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid (2.7 g). MS m / z (ESI): 655.2 [M+H] + .

[0340] Step 4: Preparation of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinyl chloride

[0341] Under nitrogen protection, (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid (200 mg, 0.305 mmol) and (chloromethylene)dimethylammonium chloride (78.2 mg, 0.611 mmol) were dissolved in dichloromethane (5 mL) and the mixture was stirred at 20 °C for 0.5 hours. After the reaction was complete, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was dried and concentrated. The residue was separated by column chromatography to obtain (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinic acid chloride (130 mg, 63.2%). MS m / z (ESI): 673.2 [M+H] + Step 5: Preparation of (R)-5-(3-acetyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0342] Under nitrogen protection, (R)-5-(3-acetyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (30 mg, 44.56 μmol) was dissolved in tetrahydrofuran (2 mL), and methyl magnesium bromide (2.5 M, 53.2 μL) was added dropwise. The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The organic phase was dried and concentrated, and the residue was separated by column chromatography to obtain (16 mg, 55.0%). MS m / z (ESI): 653.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.91 (d, J=8.4Hz, 1H), 7.71 (d, J=3.9Hz, 1H), 7.18 (t, J=7.8H z, 1H), 7.14-7.01 (m, 4H), 6.90 (d, J = 3.9Hz, 1H), 6.88-6.80 (m, 2H), 5.46 (q, J = 7.9Hz, 1H), 3.79 (s, 3H), 3.05-2.88 (m, 5H), 2.74-2.66 (m, 1H), 2.61 (d, J=7.2Hz, 2H), 2.48-2 .38(m, 4H), 2.25-2.14(m, 1H), 2.12(s, 3H), 1.96-1.84(m, 1H), 0.91(d, J=6.6Hz, 6H).

[0343] Example 46 can also be prepared according to the following method

[0344] Step 1: Synthesis of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)-N-(2-carbonylcyclopentyl)acetamide

[0345] 2-Aminocyclopentane-1-one hydrochloric acid (1.07 g, 7.87 mmol) was added to a mixture of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetic acid (2 g, 7.87 mmol), HATU (4.45 g, 11.8 mmol), and triethylamine (1.59 g, 15.73 mmol) in DMF (20 mL). The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with saturated brine, extracted three times with ethyl acetate (60 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (1.6 g, 61%). MS m / z (ESI): 336.2 [M+H] + .

[0346] Step 2: Synthesis of 2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-5,6-dihydro-4H-cyclopentadien[d]oxazole

[0347] Triphenylphosphine (938.5 mg, 3.58 mmol) and carbon tetrachloride (1.83 g, 11.93 mmol) were dissolved in DCM (5 mL) and stirred at 5 °C for 30 min. Then, 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)-N-(2-carbonylcyclopentyl)acetamide (400 mg, 1.19 mmol) and triethylamine (1.21 g, 11.93 mmol) were added, and the reaction mixture was stirred at 50 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with saturated brine, extracted three times with dichloromethane (15 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (120 mg, 32%). MS m / z (ESI): 318.1 [M+H] +

[0348] Step 3: Synthesis of 1-(5,6-dihydro-4H-cyclopentadieno[d]oxazol-2-yl)-4-(4-fluorophenyl)butane-2-one

[0349] Sulfuric acid (0.1 mL) was added to formic acid (2 mL) containing 2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-5,6-dihydro-4H-cyclopentadieno[d]oxazole (120 mg, 0.38 mmol). The reaction mixture was stirred at 50 °C for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, washed with saturated brine, extracted three times with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (80 mg, 77%). MS m / z (ESI): 274.1 [M+H] + .

[0350] Step 4: Synthesis of 5-(5,6-dihydro-4H-cyclopentadieno[d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-1,4-dihydropyridine-3-carboxamide

[0351] 1-(5,6-dihydro-4H-cyclopentadieno[d]oxazol-2-yl)-4-(4-fluorophenyl)butane-2-one (50 mg, 0.18 mmol), (R)-5-formyl-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (55.13 mg, 0.18 mmol), 3-imino-5-methylhexanoamide (26.01 mg, 0.18 mmol), ammonium acetate (15.51 mg, 0.20 mmol), and ytterbium trifluoromethanesulfonate (11.68 mg, 0.02 mmol) were mixed in EtOH (2 mL) and reacted at 50 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (120 mg). MS m / z (ESI): 681.3 [M+H] + .

[0352] Step 5: Synthesis of (R)-5-(5,6-dihydro-4H-cyclopentadieno[d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide

[0353] 5-(5,6-dihydro-4H-cyclopentadieno[d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-1,4-dihydropyridine-3-carboxamide (120 mg, 0.18 mmol) and cerium ammonium nitrate (193.25 mg, 0.35 mmol) were mixed in EtOH (3 mL), and the reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with saturated brine, extracted three times with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to obtain the target compound (17.2 mg, 14%). MS m / z (ESI): 679.3 [M+H] + .

[0354] 1H NMR (400MHz, DMSO-d6) δ8.81 (d, J=8.4Hz, 1H), 7.86 (s, 1H), 7.65 (d, J=4.0Hz, 1H), 7.55 (s, 1H), 7.18 (t, J=7 .6Hz, 1H), 7.14-7.09 (m, 2H), 7.08-7.02 (m, 2H), 6.95 (d, J=4.0Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 6.81 (d, J=7. 6Hz, 1H), 5.53-5.39 (m, 1H), 3.79 (s, 3H), 3.03-2.86 (m, 5H), 2.75-2.65 (m, 3H), 2.64-2.56 (m, 2H), 2.45-2. 38(m, 2H), 2.33-2.23(m, 1H), 2.00-1.85(m, 1H), 1.38(s, 2H), 0.92(d, J=6.4Hz, 6H), 0.88(d, J=8.0Hz, 1H).

[0355] Example 69 can also be prepared according to the following method

[0356] Step 1: Synthesis of 3-ethoxycyclohepta-2-en-1-one

[0357] At room temperature, p-toluenesulfonic acid (341 mg, 1.98 mmol) was added to a chloroform (50 mL) solution of cycloheptane-1,3-dione (5 g, 39.63 mmol) and ethanol (4.56 g, 99.09 mmol). The reaction mixture was heated to 90 °C, and water was separated using a water separator. The reaction was allowed to proceed for 4 hours. The reaction mixture was evaporated to dryness and then separated by direct column chromatography to obtain a colorless liquid, 3-ethoxycycloheptane-2-en-1-one (3.18 g, 52.1%). MS m / z (ESI): 155.1 [M+H] + .

[0358] Step 2: Synthesis of 3-ethoxycyclohepta-2-ene-1-one oxime

[0359] Hydroxylamine hydrochloride (1.08 g, 15.55 mmol) was added to an ethanol (30 mL) solution of 3-ethoxycyclohepta-2-en-1-one (2.18 g, 14.14 mmol), and the reaction mixture was heated to 100 °C for 2 hours. Direct concentration yielded a brown oily substance, 3-ethoxycyclohepta-2-en-1-one oxime (2.38 g, 99.5%). MS m / z (ESI): 170.2 [M+H] + .

[0360] Step 3: Synthesis of 4-ethoxy-5,6,7,8-tetrahydroacoxine-2(1H)-one

[0361] Triethylamine (897 mg, 8.86 mmol) was added to a solution of 3-ethoxycyclohepta-2-en-1-one oxime (500 mg, 2.95 mmol) and p-toluenesulfonyl chloride (845 mg, 4.43 mmol) in 15 mL of tetrahydrofuran at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, evaporated to dryness, and separated by column chromatography to obtain a brown solid, 4-ethoxy-5,6,7,8-tetrahydroacoxine-2(1H)-one (77 mg, 15.4%). MS m / z (ESI): 170.1 [M+H] + .

[0362] Step 4: Synthesis of acrylonitrile-2,4-dione

[0363] Concentrated hydrochloric acid (2 mL) was added to a solution of 4-ethoxy-5,6,7,8-tetrahydroacocine-2(1H)-one (77 mg, 455 μmol) in acetone (6 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated to dryness to obtain a brown oily substance, acrylonitrile-2,4-dione (88 mg, crude product), which was used directly in the next step of the reaction. MS m / z (ESI): 141.9 [M+H]+.

[0364] Step 5: Synthesis of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-imine

[0365] Ammonium acetate (1.41 g, 18.23 mmol) was added to a toluene (15 mL) solution of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (1 g, 3.65 mmol). The reaction mixture was heated to 110 °C and reacted for 16 hours. The reaction mixture was concentrated to dryness and separated by column chromatography to obtain a white solid 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-imine (455 mg, 45.7%). MS m / z (ESI): 273.9 [M+H] + .

[0366] Step 6: Synthesis of (R)-5-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-5-carbonyl-5,6,7,8,9,10-hexahydropyrido[3,2-c]acoxine-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide

[0367] Ytterbium trifluoromethanesulfonate (17.49 mg, 28.21 μmol) was added to an ethanol (5 mL) solution of acrylonitrile-2,4-dione (44 mg, 310 μmol), 5-formyl-N-[(1R)-4-methoxyindium-1-yl]thiophene-2-carboxamide (85 mg, 282 μmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-imine (77 mg, 282 μmol), and ammonium acetate (43 mg, 564 μmol). The reaction solution was heated to 100 °C and reacted for 16 hours. The reaction solution was then cooled to 50 °C, and cerium ammonium nitrate (370 mg, 698 μmol) was added to the reaction solution. The mixture was stirred for another 2 hours. The reaction solution was concentrated, washed twice with ethyl acetate and water, and the organic phase was dried and concentrated. (R)-5-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-5-carbonyl-5,6,7,8,9,10-hexahydropyrido[3,2-c]acoxine-4-yl)-N-(4-methoxy-2,3-dihydro-1H-inden-1-yl)thiophene-2-carboxamide (10.8 mg, 5.5%) was prepared by prep-HPLC. MS m / z (ESI): 678.2 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=8.4Hz, 1H), 8.29 (s, 1H), 7.66 (d, J=4.0Hz, 1H), 7.19 (t, J=7.6Hz, 1H ), 7.12-6.99 (m, 4H), 6.88-6.78 (m, 3H), 5.48 (q, J=8.0Hz, 1H), 3.79 (s, 3H), 3.22 (d, J=14.8Hz, 1H), 3.1 5-3.03(m, 3H), 2.99-2.80(m, 5H), 2.75-2.64(m, 1H), 2.48-2.40(m, 1H), 2.20-2.08(m, 2H), 1.96-1.88 (m, 1H), 1.83-1.75 (m, 1H), 1.58-1.42 (m, 2H), 1.08-0.99 (m, 2H), 0.76-0.69 (m, 1H), 0.65-0.57 (m, 1H).

[0369] Example 71 can also be prepared according to the following method

[0370] Step 1: Synthesis of methyl 7-((3,4-difluorophenylmethyl)amino)thiopheno[2,3-c]pyridine-2-carboxylic acid ester

[0371] Methyl 7-bromothiopheno[2,3-c]pyridine-2-carboxylic acid ester (2.72 g, 10 mmol) and (3,4-difluorophenyl)methylamine (1.43 g, 10 mmol) were mixed in dioxane (30 mL), followed by the addition of cesium carbonate (6.52 g, 20 mmol) and Xantphos Pd G4 (481 mg, 0.5 mmol). After nitrogen purging, the mixture was heated to 105 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, and saturated sodium chloride aqueous solution (100 mL) was added. The mixture was extracted three times with DCM, and the organic phases were combined and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (2.5 g, 75%). MS m / z (ESI): 335.1 [M+H] + .

[0372] Step 2: Synthesis of (7-((3,4-difluorobenzyl)amino)thiopheno[2,3-c]pyridin-2-yl)methanol

[0373] Methyl 7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridine-2-carboxylic acid ester (1.67 g, 5 mmol) was dissolved in THF (30 mL). The reaction solution was cooled to 0 °C, and LAH (240 mg, 6 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched dropwise with saturated ammonium chloride aqueous solution. The organic phase was extracted with DCM, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (1.4 g, 91%). MS m / z (ESI): 307.1 [M+H] + .

[0374] Step 3: Synthesis of 7-((3,4-difluorobenzyl)amino)thiopheno[2,3-c]pyridine-2-carboxaldehyde

[0375] (7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)methanol (1.23 g, 4 mmol) was dissolved in DCE (30 mL), and manganese dioxide (3.48 g, 40 mmol) was added. The mixture was heated to 50 °C and reacted for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (1.1 g, 90%). MS m / z (ESI): 305.1 [M+H] + .

[0376] Step 4: Synthesis of 5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0377] 7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridine-2-carboxaldehyde (304.3 mg, 1 mmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (274.3 mg, 1 mmol), and 3-imino-5-methylhexamamide (170.6 mg, 1.2 mmol) were mixed in EtOH (6 mL) and reacted at 100 °C for 12 h. The reaction mixture was cooled to room temperature, and cerium ammonium nitrate (1.06 g, 2 mmol) was added. The mixture was then heated to 50 °C and reacted for 2 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with DCM, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed from the organic phase under reduced pressure. The residue was purified by preparative chromatography to obtain the target compound (260 mg, 38%). MS m / z (ESI): 683.2 [M+H] + .

[0378] 1 H NMR (400MHz, DMSO-d6) δ7.92-7.85 (m, 2H), 7.59 (s, 1H), 7.51 (t, J=6.0Hz, 1H) , 7.38-7.28 (m, 2H), 7.23 (s, 1H), 7.17-7.01 (m, 6H), 4.64 (d, J=5.7Hz, 2H), 3.2 0-3.10 (m, 2H), 3.02-2.94 (m, 2H), 2.75 (d, J=7.2Hz, 2H), 2.36-2.26 (m, 1H), 2 .07-1.97(m, 1H), 0.95(d, J=6.6Hz, 6H), 0.84-0.78(m, 2H), 0.37-0.31(m, 2H).

[0379] Example 241 can also be prepared according to the following method

[0380] Step 1: Preparation of benzyl 5-formylthiophene-2-carboxylic acid ester

[0381] 5-Formylthiophene-2-carboxylic acid (8 g, 51.23 mmol) and benzyl alcohol (6.65 g, 61.48 mmol) were dissolved in dichloromethane (100 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.73 g, 76.84 mmol) and DMAP (3.13 g, 25.61 mmol) were added with stirring at room temperature. The reaction mixture was stirred at 20 °C for 4 hours. The reaction mixture was diluted with dichloromethane, and the organic phase was washed with dilute hydrochloric acid and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography to obtain benzyl 5-formylthiophene-2-carboxylic acid ester (12 g, 95%). MS m / z (ESI): 247.0 [M+H] + .

[0382] Step 2: Preparation of benzyl 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridin-4-yl)thiophene-2-carboxylic acid ester

[0383] 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (1.5 g, 5.47 mmol), benzyl 5-formylthiophene-2-carboxylic acid ester (1.35 g, 5.47 mmol), 5-methyl-3-carbonylhexanoate (777 mg, 5.47 mmol), and ammonium acetate (843 mg, 10.94 mmol) were dispersed in ethanol (30 mL). Ytterbium trifluoromethanesulfonate (339 mg, 0.65 mmol) was added to the reaction solution with stirring at room temperature, and the mixture was heated to 55 °C and stirred for 12 hours. The reaction solution was used directly in the next step without further processing. MS m / z (ESI): 627.2 [M+H] + .

[0384] Step 3: Preparation of benzyl 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid ester

[0385] In the previous step, benzyl 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridin-4-yl)thiophene-2-carboxylic acid ester (3.43 g, 5.47 mmol) was reacted with cerium ammonium nitrate (8.70 g, 16.42 mmol) in 30 mL of ethanol. The reaction mixture was stirred at 55 °C for 4 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography to obtain benzyl 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid ester (2 g, 58%). MS m / z (ESI): 625.2 [M+H] + .

[0386] Step 4: Preparation of 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid

[0387] Benzyl 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid ester (2 g, 3.20 mmol) was dissolved in methanol (30 mL). Pd / C (681 mg, 0.64 mmol) was added with stirring at room temperature, and hydrogen was purged three times. The reaction mixture was stirred at 20 °C for 1 hour. The solution was filtered and concentrated to obtain 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid (1.7 g, 99%), which was used directly in the next step. MS m / z (ESI): 535.2 [M+H] + .

[0388] Step 5: Preparation of 5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(5-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)thiophene-2-yl)nicotinamide

[0389] 5-(3-carbamoyl-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)thiophene-2-carboxylic acid (53 mg, 0.10 mmol), 5-methoxy-1,2,3,4-tetrahydroisoquinoline (20.0 mg, 0.10 mmol), and HATU (45 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). N,N-diisopropylethylamine (64 mg, 0.50 mmol) was added with stirring at room temperature. The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was separated by high performance liquid chromatography to obtain 5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(5-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)thiophene-2-yl)nicotinamide (16.2 mg, 24%). MS m / z (ESI): 680.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.89 (d, J=2.4Hz, 1H), 7.63 (d, J=2.4Hz, 1H), 7.45 (d, J=3 .8Hz, 1H), 7.19 (t, J=7.9Hz, 1H), 7.14-6.93 (m, 5H), 6.86-6.79 (m, 2H), 4.75 (s, 2 H), 3.82-3.79(m, 5H), 3.08(t, J=8.8Hz, 2H), 2.96(t, J=8.8Hz, 2H), 2.78-2.72(m , 4H), 2.37-2.27(m, 1H), 2.25-2.08(m, 1H), 1.00-0.93(m, 8H), 0.67-0.63(m, 2H).

[0390] Example 244 can also be prepared according to the following method

[0391] Step 1: Synthesis of ethyl 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetate

[0392] Ethyl 5-(4-fluorophenyl)-3-carbonylpentanoate (20.0 g, 83.94 mmol) and ethylene glycol (15.63 g, 251.83 mmol) were dissolved in anhydrous DCE (200 mL). Trimethylchlorosilane (27.36 g, 251.83 mmol) was added to the reaction solution. The reaction was heated to 85 °C and reacted for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (17.7 g, 75%). MS m / z (ESI): 283.1 [M+H] + .

[0393] Step 2: Synthesis of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetic acid

[0394] Ethyl 2-(2-(4-fluorophenylethyl)-1,3-dioxapentane-2-yl)acetate (26.5 g, 93.87 mmol) was dissolved in methanol (250 mL) and water (50 mL). Sodium hydroxide (11.26 g, 281.61 mmol) was added to the reaction solution, and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and aqueous solution (100 mL) was added to the reaction solution. The pH was adjusted to 5 with dilute hydrochloric acid, and the solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, and the separated organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure to obtain the crude target compound (23.8 g). MS m / z (ESI): 255.1 [M+H] + .

[0395] Step 3: Synthesis of N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)cyclopropionylhydrazine

[0396] At room temperature, diisopropylethylamine (15.25 g, 118 mmol) was added to a solution of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetic acid (10 g, 39.3 mmol), cyclopropionyl hydrazine (7.88 g, 78.7 mmol), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (17.95 g, 47.2 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 50 °C and reacted for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried and the solvent was removed under reduced pressure. The residue was slurried with tert-butyl methyl ether (100 mL) to give N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)cyclopropionylhydrazine (9.1 g, 68.8%). MS m / z (ESI): 337.1 [M+H]+.

[0397] Step 4: Synthesis of 2-cyclopropyl-5-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-1,3,4-oxadiazole

[0398] At room temperature, p-toluenesulfonyl chloride (6.19 g, 32.5 mmol) was added to a solution of N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)cyclopropanehydrazine (9.1 g, 27.1 mmol) and triethylamine (3.56 g, 35.2 mmol) in 100 mL of dichloromethane. The reaction mixture was heated to 30 °C and stirred for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried and the solvent was removed under reduced pressure. The residue was separated by column chromatography to give 2-cyclopropyl-5-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-1,3,4-oxadiazole (3 g, 34.8%). MS m / z (ESI): 319.1 [M+H]+.

[0399] Step 5: Synthesis of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one

[0400] Sulfuric acid (46.2 mg, 471 μmol) was added to a solution of 2-cyclopropyl-5-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-1,3,4-oxadiazole (1.5 g, 4.71 mmol) in formic acid (5 mL). The reaction mixture was heated to 45 °C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried and the solvent was removed under reduced pressure. The residue was separated by column chromatography to give 1-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-4-(4-fluorophenyl)butane-2-one (875 mg, 67.7%). MS m / z (ESI): 275.1 [M+H]+.

[0401] Step 6: Synthesis of 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile

[0402] 2-Carbonyl-2,3-dihydrobenzo[d]oxazol-6-carboxaldehyde (500 mg, 3.07 mmol) and 4-(bromomethyl)-2-fluorobenzonitrile (719.9 mg, 3.38 mmol) were mixed in DMF (10 mL), and potassium carbonate (1.06 g, 7.68 mmol) was added. The mixture was heated to 75 °C and reacted for 2 hours. After cooling to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, and the separated organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target compound (489 mg, 54%). MS m / z (ESI): 297.1 [M+H] + .

[0403] Step 7: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide

[0404] 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (100 mg, 0.36 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (106.6 mg, 0.36 mmol), and 3-imino-5-methylhexamamide (61.1 mg, 0.43 mmol) were mixed in EtOH (5 mL), and ytterbium trifluoromethanesulfonate (22.3 mg, 0.036 mmol) and ammonium acetate (55.5 mg, 0.72 mmol) were added. The mixture was heated to 50 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (345.5 mg). MS m / z (ESI): 677.3 [M+H] + .

[0405] Step 8: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0406] 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (345.5 mg, 0.36 mmol) and cerium ammonium nitrate (394.7 mg, 0.72 mmol) were mixed in ethanol (5 mL), and the reaction mixture was heated to 55 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (27.8 mg, 11%). MS m / z (ESI): 675.2 [M+H] + .

[0407] 1H NMR (400MHz, DMSO-d6) δ7.97 (t, J=7.4Hz, 1H), 7.77 (s, 1H), 7.63-7.58 (m, 1H), 7.49-7.45 (m , 1H), 7.41 (dd, J=8.1, 1.5Hz, 1H), 7.21 (d, J=8.2Hz, 1H), 7.17-7.14 (m, 1H), 7.12-7.01 (m, 4H ), 6.88 (dd, J=8.1, 1.5Hz, 1H), 5.17 (s, 2H), 3.10-3.02 (m, 2H), 2.97-2.90 (m, 2H), 2.72 (d, J =7.1Hz, 2H), 2.35-2.24 (m, 1H), 2.08-1.96 (m, 1H), 0.94 (d, J = 6.6Hz, 6H), 0.90-0.82 (m, 4H).

[0408] Examples 290 and 291 can also be prepared according to the following method

[0409] Step 1: Synthesis of 2-(4-fluorophenylethyl)-N-(2-hydroxypropyl)-6-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)pyridine-3,5-dicarboxamide

[0410] A mixture of (R)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinic acid (110 mg, 0.18 mmol), HATU (101.1 mg, 0.27 mmol), and triethylamine (36.16 mg, 0.36 mmol) in DMF (3 mL) was stirred for 30 minutes. Then, 1-aminopropane-2-ol (67.09 mg, 0.89 mmol) was added, and the reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, and extracted three times with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (90 mg, 75%). MS m / z (ESI): 673.3 [M+H] + .

[0411] Step 2: Synthesis of 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((((R)-4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)-5-((R)-5-methyl-4,5-dihydrooxazol-2-yl)nicotinamide and 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((((R)-4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)-5-((S)-5-methyl-4,5-dihydrooxazol-2-yl)nicotinamide

[0412] Under a nitrogen atmosphere, DIAD (30.05 mg, 0.15 mmol) was added to 1 mL of a mixture of 2-(4-fluorophenylethyl)-N-(2-hydroxypropyl)-6-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)pyridine-3,5-dicarboxamide (50 mg, 0.07 mmol) and triphenylphosphine (38.98 mg, 0.15 mmol). The mixture was reacted at 5 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was chirally separated to obtain target compounds P1 (5.1 mg, 21%) and P2 (5.1 mg, 21%).

[0413] P1: MS m / z (ESI): 655.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=8.4Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=4.0Hz, 1H), 7.54 (s, 1H), 7.28 -7.16 (m, 3H), 7.13-7.03 (m, 3H), 6.84 (dd, J=12.4, 7.6Hz, 2H), 5.55-5.45 (m, 1H), 4.70-4.59 (m, 1H), 3.94 (dd, J=14.4, 9.6Hz, 1H), 3.79 (s, 3H), 3.08-2.91 (m, 5H), 2.76-2.64 (m, 3H), 2.47-2.40 (m, 1H), 2 .28-2.19 (m, 1H), 1.99-1.90 (m, 1H), 1.27-1.19 (m, 1H), 1.07 (d, J = 6.0Hz, 3H), 0.90 (d, J = 6.8Hz, 6H).

[0414] P2: MS m / z (ESI): 655.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.87 (d, J=8.4Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=4.0Hz, 1H), 7.54 (s, 1H), 7.28 -7.16 (m, 3H), 7.13-7.03 (m, 3H), 6.84 (dd, J=12.4, 7.6Hz, 2H), 5.55-5.45 (m, 1H), 4.70-4.59 (m, 1H), 3.94 (dd, J=14.4, 9.6Hz, 1H), 3.79 (s, 3H), 3.08-2.91 (m, 5H), 2.76-2.64 (m, 3H), 2.47-2.40 (m, 1H), 2 .28-2.19 (m, 1H), 1.99-1.90 (m, 1H), 1.27-1.19 (m, 1H), 1.07 (d, J = 6.0Hz, 3H), 0.90 (d, J = 6.8Hz, 6H).

[0415] Example 305 can also be prepared according to the following method

[0416] Step 1: Synthesis of 3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propionic acid

[0417] At 0 °C, formic acid (96.50 g, 2.10 mol) was added to a solution of triethylamine (85.32 g, 843.15 mmol), followed by the addition of 2,2-difluorobenzo[d][1,3]dioxazol-4-carboxaldehyde (12.85 g, 69.04 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (10.95 g, 75.95 mmol). The reaction mixture was heated to 100 °C and reacted for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (300 mL x 3). The organic phase was dried, evaporated to dryness, and separated by column chromatography to obtain a white solid 3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propionic acid (12 g, 75.5%). MS m / z (ESI): 231.0 [M+H] + .

[0418] Step 2: Synthesis of 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-one

[0419] Trifluoromethanesulfonic acid (9.78 g, 65.17 mmol) was added to a solution of 3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propionic acid (5.0 g, 21.72 mmol) in 100 mL of dichloromethane. The reaction mixture was heated to 40 °C and reacted for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane (30 mL x 3). The organic phase was dried, evaporated to dryness, and separated by column chromatography to obtain a colorless oily substance, 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-one (1.3 g, 28.2%). MS m / z (ESI): 213.0 [M+H] + .

[0420] Step 3: Synthesis of (R,E)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-ylidene)-2-methylpropane-2-sulfinamide

[0421] At 20 °C, 1.2 g (5.66 mmol) of 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-one was added to a tetrahydrofuran (50 mL) solution of tetraethyl titanate (2.58 g, 11.31 mmol) and (R)-2-methylpropane-2-sulfinamide (959.78 mg, 7.92 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The organic phase was dried, evaporated to dryness, and separated by column chromatography to obtain a white solid (R,E)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-ylidene)-2-methylpropane-2-sulfinamide (1.3 g, 72.9%). MS m / z (ESI): 316.1 [M+H]+.

[0422] Step 4: Synthesis of (R)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)-2-methylpropane-2-sulfinamide

[0423] Sodium borohydride (311.92 mg, 8.25 mmol) was added to a solution of (R,E)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)-2-methylpropane-2-sulfinamide (1.3 g, 4.12 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solution was evaporated to dryness and separated by column chromatography to obtain a white solid (R)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)-2-methylpropane-2-sulfinamide (1.1 g, 84.1%). MS m / z (ESI): 318.1 [M+H] + .

[0424] Step 5: Synthesis of 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-amine

[0425] A solution of dioxane hydrochloride (4 M, 2.63 mL) was added to a solution of (R)-N-(2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)-2-methylpropane-2-sulfinamide (1.1 g, 3.51 mmol) in dichloromethane (10 mL). The reaction mixture was reacted at 20 °C for 1 hour. The solution was then directly concentrated to give a white solid, 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-amine (500 mg, crude). MS m / z (ESI): 214.1 [M+H] + .

[0426] Step 6: Synthesis of 4-(5-((2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide

[0427] 5-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiophene-2-carboxylic acid (50 mg, 98.32 μmol) was added to a solution of 2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-amine (25.15 mg, 117.98 μmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (25.15 mg, 117.98 μmol), and N,N-diisopropylethylamine (25.41 mg, 196.63 μmol) in N,N-dimethylformamide (2 mL). The reaction mixture was reacted at 20 °C for 1 hour. The reaction solution was reverse-phase to prepare 4-(5-((2,2-difluoro-7,8-dihydro-6H-indeno[4,5-d][1,3]dioxazol-6-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (30.0 mg, 43.4%). MS m / z (ESI): 704.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.88 (d, J=8.1Hz, 1H), 7.90 (d, J=2.2Hz, 1H), 7.65-7.60 (m, 2 H), 7.23 (d, J=8.1Hz, 1H), 7.15-7.00 (m, 5H), 6.95 (d, J=3.9Hz, 1H), 5.46 (q, J=7.8Hz, 1H), 3.12-3.05 (m, 1H), 2.96 (s, 3H), 2.93-2.87 (m, 1H), 2.73 (d, J=7.1Hz, 2H), 2.55-2 .48(m, 2H), 2.40(s, 3H), 2.36-2.25(m, 1H), 2.10-1.99(m, 1H), 0.94(d, J=6.6Hz, 6H).

[0428] Example 391 can also be prepared according to the following method

[0429] Step 1: Synthesis of (R)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide

[0430] Diisopropylethylamine (50 mg, 389 μmol) was added to a solution of 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-6-isobutyl-4-[5-[[(1R)-4-methoxyindium-1-yl]carbamoyl]-2-thienyl]pyridine-3-carboxylic acid (80 mg, 130 μmol), hydrazine dihydrochloride (15 mg, 143 μmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (81 mg, 156 μmol) in N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, evaporated to dryness, and the residue was separated by column chromatography to give a white solid (R)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (80 mg, 97.7%). MS m / z (ESI): 630.1 [M+H] + .

[0431] Step 2: Synthesis of (R)-5-(2-(cyclopropylaminomethylthioyl)hydrazine-1-carbonyl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophene-2-yl)nicotinamide

[0432] Cyclopropyl isothiocyanate (8 mg, 82 μmol) was added to an ethanol (5 mL) solution of (R)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (40 mg, 63 μmol), and the reaction solution was heated to 80 °C and reacted for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, evaporated to dryness, and the residue was purified by column chromatography to give a yellow solid (R)-5-(2-(cyclopropylaminomethylthioyl)hydrazine-1-carbonyl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophene-2-yl)nicotinamide (45 mg, 97.2%). MS m / z (ESI): 729.1 [M+H] + .

[0433] Step 3: Synthesis of (R)-5-(5-(cyclopropylamino)-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide

[0434] p-Toluenesulfonyl chloride (35 mg, 1 μmol) was added to a tetrahydrofuran (5 mL) solution of (R)-5-(2-(cyclopropylaminomethylthioyl)hydrazine-1-carbonyl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (45 mg, 61 μmol) and pyridine (14.65 mg, 185 μmol). The reaction solution was heated to 60 °C and reacted for 3 hours. The reaction mixture was directly concentrated to dryness, and the resulting white solid (R)-5-(5-(cyclopropylamino)-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (6.4 mg, 14.6%) was prepared by prep-HPLC. MS m / z (ESI): 695.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.85 (d, J=8.4Hz, 1H), 7.93 (d, J=2.4Hz, 1H), 7.87 (d, J=2.4Hz, 1H), 7.70 (d, J=4.0H z, 1H), 7.58 (s, 1H), 7.22-7.12 (m, 3H), 7.09-7.02 (m, 2H), 6.98 (d, J=4.0Hz, 1H), 6.84 (dd, J=17.2, 8.0Hz, 2H ), 5.48 (q, J=8.0Hz, 1H), 3.79 (s, 3H), 3.08-3.01 (m, 2H), 2.99-2.89 (m, 3H), 2.71 (d, J=7.2Hz, 2H), 2.47-2.3 9(m, 3H), 2.31-2.25(m, 1H), 1.95-1.89(m, 1H), 0.93(d, J=6.4Hz, 6H), 0.62-0.55(m, 2H), 0.38-0.31(m, 2H).

[0435] Example 392 can also be prepared according to the following method

[0436] Step 1: Synthesis of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(2-(oxobutylcyclo-3-carbonyl)hydrazine-1-carbonyl)nicotinamide

[0437] Diisopropylethylamine (24.63 mg, 190 μmol) was added to a solution of (R)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)nicotinamide (40 mg, 63.5 μmol), oxobutylcyclo-3-carboxylic acid (8 mg, 76.2 μmol), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (36 mg, 95.3 μmol) in N,N-dimethylformamide (5 mL). The reaction mixture was heated to 50 °C and reacted for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate (30 mL x 3), dried over an evaporator, and then evaporated to dryness. The residue was purified by column chromatography to give a yellow solid (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(2-(oxobutylcyclo-3-carbonyl)hydrazine-1-carbonyl)nicotinamide (56 mg, crude). MS m / z (ESI): 712.2 [M+H] + .

[0438] Step 2: Synthesis of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(5-(oxobutylcyclo-3-yl)-1,3,4-oxadiazol-2-yl)nicotinamide

[0439] p-Toluenesulfonyl chloride (44.9 mg, 235 μmol) was added to a solution of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)-5-(2-(oxobutylcyclo-3-carbonyl)hydrazine-1-carbonyl)nicotinamide (56 mg, crude) and triethylamine (23.8 mg, 235 μmol) in dichloromethane (5 mL). The reaction mixture was heated to 40 °C and reacted for 16 hours. The reaction solution was directly concentrated to dryness, and (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(oxobutylcyclo-3-yl)-1,3,4-oxadiazol-2-yl)nicotinamide was prepared as a white solid (4.4 mg, 7.6%) by prep-HPLC. MS m / z (ESI): 696.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.85 (d, J=8.4Hz, 1H), 7.90 (s, 1H), 7.68 (d, J=4.0Hz, 1H), 7.62 (s, 1H), 7.21-7.1 0 (m, 3H), 7.05 (t, J=8.8Hz, 2H), 6.98 (d, J=4.0Hz, 1H), 6.85 (d, J=8.0Hz, 1H), 6.78 (d, J=7.6Hz, 1H), 5.46 (q, J=8.0Hz, 1H), 4.85-4.77 (m, 2H), 4.54-4.41 (m, 3H), 3.79 (s, 3H), 3.09 (t, J=7.6Hz, 2H), 3.02-2.89 (m , 3H), 2.76-2.66 (m, 3H), 2.44-2.39 (m, 1H), 2.34-2.28 (m, 1H), 1.93-1.85 (m, 1H), 0.94 (d, J=6.4Hz, 6H).

[0440] Example 428 can also be prepared according to the following method

[0441] Step 1: Preparation of 1-methoxycyclopropyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetyl)hydrazine-1-carboxylic acid ester

[0442] Under nitrogen protection, 2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetylhydrazine (2.4 g, 8.95 mmol) and 1-methoxycyclopropane-1-carboxylic acid (1.25 g, 10.73 mmol) were dissolved in N,N-dimethylformamide (50 mL), and 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.06 g, 13.42 mmol) and triethylamine (1.81 g, 17.89 mmol) were added. The mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 1-methoxycyclopropyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetyl)hydrazine-1-carboxylic acid ester (3.0 g, 91.5%). MS m / z (ESI): 383.2 [M+H] + .

[0443] Step 2: Preparation of 2-((2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)methyl)-5-(1-methoxycyclopropyl)-1,3,4-oxadiazole

[0444] Under nitrogen protection, 1-methoxycyclopropyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetyl)hydrazine-1-carboxylic acid ester (3 g, 8.19 mmol) was dissolved in dichloromethane (50 mL), and p-toluenesulfonyl chloride (4.68 g, 24.56 mmol) and triethylamine (2.49 g, 24.56 mmol) were added. The mixture was stirred at 40 °C for 3 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was dried and concentrated. The residue was separated by column chromatography to give 2-((2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)methyl)-5-(1-methoxycyclopropyl)-1,3,4-oxadiazole (2.4 g, 84.1%). MS m / z (ESI): 349.1 [M+H] + .

[0445] Step 3: Preparation of 4-(4-fluorophenyl)-1-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)but-2-one

[0446] Under nitrogen protection, 2-((2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)methyl)-5-(1-methoxycyclopropyl)-1,3,4-oxadiazole (2.4 g, 6.89 mmol) was dissolved in formic acid (10 mL), and 5 drops of concentrated sulfuric acid were added. The mixture was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 4-(4-fluorophenyl)-1-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazole-2-yl)but-2-one (1.7 g, 81.1%). MS m / z (ESI): 305.1 [M+H] + .

[0447] Step 4: Preparation of 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide

[0448] Under nitrogen protection, 4-(4-fluorophenyl)-1-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)but-2-one (100 mg, 0.328 mmol), (R)-5-formyl-N-(4-methoxy-2,3-dihydro-1H-indene-1-yl)thiophene-2-carboxamide (99.03 mg, 0.328 mmol) and 3-imino-5-methylhexamamide (46.73 mg, 0.328 mmol) were dissolved in ethanol (3 mL), and ammonium acetate (50.66 mg, 0.657 mmol) and ytterbium trifluoromethanesulfonate (20.38 mg, 0.033 mmol) were added. The reaction was stirred at 50 °C for 16 hours. The reaction solution was concentrated, washed twice with water, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to give the crude product 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-(((R)-4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (233 mg). MS m / z (ESI): 712.3 [M+H] + .

[0449] Step 5: Preparation of (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)nicotinamide

[0450] Under nitrogen protection, cerium ammonium nitrate (347.1 mg, 0.654 mmol) was added to 3 mL of ethanol containing the crude product 6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((R)-4-methoxy-2,3-dihydro-1H-indene-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (233 mg, 0.327 mmol), and the mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), dried and concentrated, and then reversed to prepare (R)-6-(4-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-(1-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)nicotinamide (66 mg, 28.4%). MS m / z (ESI): 710.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.88 (d, J=8.5Hz, 1H), 7.91 (d, J=2.4Hz, 1H), 7.69 (d, J=3.8Hz, 1H), 7.63 (s, 1H) , 7.19 (t, J=7.8Hz, 1H), 7.14-7.02 (m, 4H), 6.95 (d, J=3.8Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 6.78 (d, J=7.5H z, 1H), 5.47 (q, J=8.1Hz, 1H), 3.79 (s, 3H), 3.21 (s, 3H), 3.15-3.06 (m, 2H), 3.02-2.87 (m, 3H), 2.77-2.6 3(m, 3H), 2.50-2.38(m, 1H), 2.35-2.24(m, 1H), 1.98-1.84(m, 1H), 1.31-1.21(m, 2H), 0.99-0.91(m, 8H).

[0451] Example 509 can also be prepared according to the following method

[0452] Step 1: Synthesis of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine

[0453] A solution of methyl 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetate (15 g, 55.91 mmol) and hydrazine hydrate (8.96 g, 279.56 mmol) in ethanol (150 mL) was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction was quenched with saturated brine, and the mixture was extracted three times with ethyl acetate (600 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (10.8 g, 72.0%). MS m / z (ESI): 269.1 [M+H] + .

[0454] Step 2: Synthesis of N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)-1-hydroxycyclopropane-1-formylhydrazine

[0455] To a DMF (40 mL) solution of 1-hydroxycyclopropane-1-carboxylic acid (1.52 g, 14.91 mmol), HATU (8.44 g, 22.36 mmol), and triethylamine (3.02 g, 29.82 mmol), 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetylhydrazine (4 g, 14.91 mmol) was added, and the reaction mixture was stirred at 50 °C for 12 h. After the reaction was complete, the mixture was washed with saturated brine (80 mL), extracted three times with ethyl acetate (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (3.2 g, 60.9%). MS m / z (ESI): 353.1 [M+H] + .

[0456] Step 3: Synthesis of 1-((tert-butyldimethylsilyl)oxo)-N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)cyclopropane-1-formylhydrazine

[0457] To a DMF (30 mL) solution of N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)-1-hydroxycyclopropane-1-formylhydrazine (2.9 g, 8.23 ​​mmol) and 1H-imidazolium-4-carboxylic acid (1.85 g, 16.46 mmol), tert-butylchlorodimethylsilane (1.49 g, 9.88 mmol) was added. The reaction mixture was heated to 40 °C and stirred for 4 hours. After the reaction was complete, the mixture was washed with saturated brine (60 mL), extracted three times with ethyl acetate (90 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (3.0 g, 78.1%). MS m / z (ESI): 467.2 [M+H] + .

[0458] Step 4: Synthesis of 2-(1-((tert-butyldimethylsilyl)oxo)cyclopropyl)-5-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-1,3,4-oxadiazole

[0459] To a DCM solution of 1-((tert-butyldimethylsilyl)oxo)-N′-(2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetyl)cyclopropane-1-carboxylhydrazine (3 g, 6.43 mmol) and triethylamine (1.95 g, 19.29 mmol) in 30 mL, p-toluenesulfonyl chloride (3.68 g, 19.29 mmol) was added, and the mixture was heated to 40 °C and stirred for 12 hours. After the reaction was complete, the mixture was extracted three times successively with water (30 mL) and dichloromethane (90 mL), washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound (1.5 g, 52.0%). MS m / z (ESI): 449.2 [M+H] + .

[0460] Step 5: Synthesis of 4-(4-fluorophenyl)-1-(5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)butane-2-one

[0461] Sulfuric acid (920 mg, 9.38 mmol) was added to a formic acid (15 mL) solution of 2-(1-((tert-butyldimethylsilyl)oxo)cyclopropyl)-5-((2-(4-fluorophenylethyl)-1,3-dioxopentyl-2-yl)methyl)-1,3,4-oxadiazole (1.5 g, 3.34 mmol). The reaction mixture was heated to 50 °C and stirred for 1.5 h. After the reaction was complete, the mixture was washed with saturated brine (40 mL), extracted three times with ethyl acetate (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (310 mg, 31.9%). MS m / z (ESI): 291.1 [M+H] + .

[0462] Step 6: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-5-(5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide

[0463] 4-(4-fluorophenyl)-1-(5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)butane-2-one (97.90 mg, 0.34 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (100 mg, 0.34 mmol), 3-imino-5-methylhexamamide (48.00 mg, 0.34 mmol), ammonium acetate (28.62 mg, 0.37 mmol), and ytterbium trifluoromethanesulfonate (21.54 mg, 0.03 mmol) were mixed in EtOH (3 mL), and the reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was completed, the crude target compound (230 mg) was concentrated under reduced pressure. MS m / z (ESI): 693.3 [M+H] + .

[0464] Step 7: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-5-(5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)-2-isobutylnicotinamide

[0465] 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-5-(5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (230 mg, 0.33 mmol) and cerium ammonium nitrate (364.05 mg, 0.66 mmol) were mixed in EtOH (3 mL), and the reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with saturated brine (10 mL), extracted three times with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to obtain the target compound (24.2 mg, 10.3%). MS m / z (ESI): 691.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.95 (t, J=7.6Hz, 1H), 7.76 (s, 1H), 7.60 (d, J=10.0Hz, 1H), 7.4 6 (s, 1H), 7.40 (d, J=8.0Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.17-7.09 (m, 3H), 7.05 (t, J=8. 8Hz, 2H), 6.92 (d, J=8.0Hz, 1H), 6.69 (s, 1H), 5.16 (s, 2H), 3.10-3.01 (m, 2H), 2.99-2.9 1 (m, 2H), 2.72 (d, J=7.2Hz, 2H), 2.34-2.23 (m, 1H), 0.94 (d, J=6.8Hz, 8H), 0.60 (s, 2H).

[0466] Example 516 can also be prepared according to the following method

[0467] Step 1: Synthesis of methyl 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylic acid ester

[0468] Methyl 5-(4-fluorophenyl)-3-carbonylpentanoate (340.6 mg, 1.52 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (450 mg, 1.52 mmol), 3-imino-5-methylhexanoamide (216 mg, 1.52 mmol), ammonium acetate (234.17 mg, 3.04 mmol), and ytterbium trifluoromethanesulfonate (96.95 mg, 0.15 mmol) were mixed in EtOH (10 mL), and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature, and the organic solvent was removed by vacuum concentration to obtain the crude target compound (950 mg). MS m / z (ESI): 627.2 [M+H] + .

[0469] Step 2: Synthesis of methyl 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid ester

[0470] Methyl 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylic acid ester (950 mg, 1.52 mmol) and cerium ammonium nitrate (1.67 g, 3.04 mmol) were mixed in EtOH (10 mL), and the reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (250 mg, 26%). MS m / z (ESI): 625.2 [M+H] + .

[0471] Step 3: Synthesis of 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid

[0472] Methyl 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid ester (280 mg, 0.45 mmol) and lithium chloride (95.02 mg, 2.24 mmol) were mixed in DMA (3 mL), and the mixture was heated to 150 °C and microwaved for 4 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 5–6 with dilute hydrochloric acid. The reaction solution was washed with saturated brine (10 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (150 mg, 55%). MS m / z (ESI): 611.2 [M+H] + .

[0473] Step 4: Synthesis of cyclopropyl (5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylpyridin-3-yl)carbamate

[0474] 5-Carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid (100 mg, 0.16 mmol), diphenyl azidophosphate (54.08 mg, 0.20 mmol), and triethylamine (33.14 mg, 0.33 mmol) were dissolved in DMF (5 mL), and cyclopropanol (95.12 mg, 1.64 mmol) was added. The reaction mixture was reacted at 100 °C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was separated by high performance liquid chromatography to obtain the target compound (25.8 mg, 23%). MS m / z (ESI): 666.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 7.97 (t, J=8.4Hz,, 1H), 7.74 (s, 1H), 7. 63(d, J=10.4Hz, 1H), 7.45(d, J=8.4Hz, 1H), 7.32-7.22(m, 5H), 7.12-7.03(m , 3H), 5.19 (s, 2H), 3.86-3.71 (m, 1H), 2.94 (s, 4H), 2.61 (d, J=7.2Hz, 2H), 2. 26-2.16 (m, 1H), 0.89 (d, J=6.4Hz, 6H), 0.58-0.41 (m, 2H), 0.37-0.09 (m, 2H).

[0475] Example 784 can also be prepared according to the following method

[0476] Step 1: Synthesis of 4-aminodihydrofuran-3(2H)-one

[0477] At room temperature, tert-butyl(4-carbonyltetrahydrofuran-3-yl)carbamate (500 mg, 2.49 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid / dioxane (3 mL) was added. The reaction was carried out at room temperature for 1 hour. The organic solvent was concentrated under reduced pressure, and the resulting residue (251 mg) was used directly in the next reaction step. MS m / z (ESI): 102.0 [M+H] + .

[0478] Step 2: Synthesis of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)-N-(4-carbonyltetrahydrofuran-3-yl)acetamide

[0479] 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetic acid (635 mg, 2.50 mmol) and 4-aminodihydrofuran-3(2H)-one (251 mg, 2.49 mmol) were mixed in DMF (5 mL), and triethylamine (757.5 mg, 7.5 mmol) and HATU (1.24 g, 3.25 mmol) were added. The mixture was reacted at room temperature for 12 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum concentration. The residue was purified by column chromatography to obtain the target compound (387.0 mg, 49%). MS m / z (ESI): 338.1 [M+H] + .

[0480] Step 3: Synthesis of 2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-4,6-dihydrofurano[3,4-d]oxazole

[0481] Triphenylphosphine (903.9 mg, 3.45 mmol) was dissolved in dichloromethane (8 mL), and carbon tetrachloride (1.77 g, 11.5 mmol) was added. The reaction was carried out at room temperature for 30 minutes. Triethylamine (1.16 g, 11.5 mmol) was added, followed by dropwise addition of a solution of 2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)-N-(4-carbonyltetrahydrofuran-3-yl)acetamide (387 mg, 1.15 mmol) dissolved in dichloromethane (2 mL). The mixture was heated to 50 °C and reacted for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum concentration. The residue was purified by column chromatography to obtain the target compound (315.0 mg, 86%). MS m / z (ESI): 320.1 [M+H] + .

[0482] Step 4: Synthesis of 1-(4,6-dihydrofurano[3,4-d]oxazol-2-yl)-4-(4-fluorophenyl)butane-2-one

[0483] 2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)-4,6-dihydrofurano[3,4-d]oxazole (315.0 mg, 0.99 mmol) was dissolved in formic acid (5 mL), and 2 drops of sulfuric acid were added. The mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete, the organic solvent was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound (195.0 mg, 72%). MS m / z (ESI): 276.1 [M+H] + .

[0484] Step 5: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(4,6-dihydrofurano[3,4-d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide

[0485] 1-(4,6-dihydrofurano[3,4-d]oxazol-2-yl)-4-(4-fluorophenyl)butane-2-one (65 mg, 0.24 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (71.1 mg, 0.24 mmol), and 3-imino-5-methylhexamamide (34.1 mg, 0.24 mmol) were mixed in EtOH (5 mL), and ytterbium trifluoromethanesulfonate (14.9 mg, 0.024 mmol) and ammonium acetate (37.0 mg, 0.48 mmol) were added. The mixture was heated to 50 °C and reacted for 12 h. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (222.1 mg). MS m / z (ESI): 678.2 [M+H] + .

[0486] Step 6: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(4,6-dihydrofurano[3,4-d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0487] 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(4,6-dihydrofurano[3,4-d]oxazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (222.1 mg, 0.24 mmol) and cerium ammonium nitrate (263.1 mg, 0.48 mmol) were mixed in ethanol (5 mL), and the reaction mixture was heated to 55 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (6.1 mg, 4%). MS m / z (ESI): 676.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.94 (t, J=7.4Hz, 1H), 7.77 (s, 1H), 7.59 (d, J=10.2Hz, 1H), 7.45-7.4 3 (m, 1H), 7.40 (d, J=8.1Hz, 1H), 7.29-7.24 (m, 1H), 7.19-7.16 (m, 1H), 7.15-7.09 (m, 3H), 7.07 (d, J=9.0Hz, 1H), 6.90 (dd, J=8.2, 1.6Hz, 1H), 5.15 (s, 2H), 4.69-4.57 (m, 4H), 3.02 (d, J=7.6H z, 2H), 2.96 (d, J=7.7Hz, 2H), 2.71 (d, J=7.1Hz, 2H), 2.35-2.26 (m, 1H), 0.94 (d, J=6.7Hz, 6H).

[0488] Example 1732 can also be prepared according to the following method

[0489] Step 1: Synthesis of methyl N-(2-bromothiazolyl-5-yl)-N-tert-butoxycarbonyl-carbamate

[0490] Under ice bath conditions, sodium hydride (172 mg, 4.30 mmol, 60% purity) was added to a tetrahydrofuran (20 mL) solution of tert-butyl 2-bromothiazolium-5-carbamate (1 g, 3.58 mmol). The reaction mixture was stirred for 30 minutes. Dimethyl dicarbonate (624 mg, 4.66 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain methyl N-(2-bromothiazolium-5-yl)-N-tert-butoxycarbonyl-carbamate (550 mg, 45%). MS m / z (ESI): 337.0 [M+H] + .

[0491] Step 2: Synthesis of methyl 2-bromothiazole-5-carbamate

[0492] At room temperature, 1.5 mL of trifluoroacetic acid was added to a solution of methyl N-(2-bromothiazol-5-yl)-N-tert-butoxycarbonyl-carbamate (550 mg, 1.63 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude methyl 2-bromothiazol-5-carbamate (367 mg), which was used directly in the next step. MS m / z (ESI): 236.9 [M+H] + .

[0493] Step 3: Synthesis of methyl N-(2-bromothiazolyl-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate

[0494] Under ice bath conditions, sodium hydride (74 mg, 1.86 mmol, 60% purity) was added to a solution of methyl 2-bromothiazol-5-carbamate (367 mg, 1.55 mmol) in N,N-dimethylformamide (30 mL). After stirring for 30 minutes, 4-(bromomethyl)-2-fluorobenzonitrile (364 mg, 1.70 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain methyl N-(2-bromothiazol-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate (500 mg, 87%). MS m / z (ESI): 370.0 [M+H] + .

[0495] Step 4: Synthesis of methyl N-(2-bromothiazolyl-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate

[0496] [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (79 mg, 108 μmol) was added to a solution of methyl N-(2-bromothiazo-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate (400 mg, 1.08 mmol), potassium ethylene trifluoroborate (217 mg, 1.62 mmol), and potassium carbonate (373 mg, 2.70 mmol) in 1,4-dioxane (10 mL) / water (2 mL). The mixture was microwaved at 110 °C for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain methyl N-(2-bromothiazol-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate (177 mg, 51%). MS m / z (ESI): 318.1 [M+H] + .

[0497] Step 5: Synthesis of methyl N-[(4-cyano-3-fluoro-phenyl)methyl]-N-(2-formylthiazolyl-5-yl)carbamate

[0498] Potassium osmium tetroxide dihydrate (16.4 mg, 55.7 μmol) was added to a 1,4-dioxane (5 mL) / water (1 mL) solution of methyl N-(2-bromothiazol-5-yl)-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate (177 mg, 557 μmol). The reaction mixture was stirred at room temperature for 10 minutes. Sodium periodate (357 mg, 1.67 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain methyl N-[(4-cyano-3-fluoro-phenyl)methyl]-N-(2-formylthiazol-5-yl)carbamate (170 mg, 95%). MS m / z (ESI): 320.0 [M+H] + .

[0499] Step 6: Synthesis of methyl N-[2-[5-carbamoyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-[2-(4-fluorophenyl)ethyl]-6-isobutyl-4-pyridyl]thiazolyl-5-yl]-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate

[0500] Ytterbium trifluoromethanesulfonate hydrate (14.7 mg, 23.7 μmol) was added to an ethanol (10 mL) solution of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (65 mg, 237 μmol), methyl N-[(4-cyano-3-fluoro-phenyl)methyl]-N-(2-formylthiazolyl-5-yl)carbamate (83 mg, 260 μmol), 3-amino-5-methyl-hex-2-enamide (33.70 mg, 237 μmol), and ammonium acetate (36.5 mg, 474 μmol). The reaction solution was reacted at 60 °C for 16 hours. After cooling, cerium ammonium nitrate (250 mg, 456 μmol) was added to the reaction solution, and the reaction was continued at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to prep-HPLC to prepare methyl N-[2-[5-carbamoyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-[2-(4-fluorophenyl)ethyl]-6-isobutyl-4-pyridyl]thiazolyl-5-yl]-N-[(4-cyano-3-fluoro-phenyl)methyl]carbamate (43.7 mg, 26.2%). MS m / z (ESI): 698.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.07-7.99 (m, 1H), 7.94 (t, J=7.2Hz, 1H), 7.68 (d, J=2.4Hz, 1H) , 7.49 (d, J=10.0Hz, 1H), 7.42 (s, 1H), 7.30 (dd, J=8.0, 1.6Hz, 1H), 7.12-6.99 (m, 4H), 5 .17 (s, 2H), 3.83 (s, 3H), 3.10 (dd, J=8.8, 6.4Hz, 2H), 2.94 (t, J=7.6Hz, 2H), 2.74 (d, J= 7.2Hz, 2H), 2.35-2.23(m, 1H), 2.10-2.00(m, 1H), 0.98-0.87(m, 8H), 0.60-0.48(m, 2H).

[0501] Example 1763 can also be prepared according to the following method

[0502] Step 1: Synthesis of 4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-6-isobutyl-5-nitro-1,4-dihydropyridin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0503] 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (926 mg, 3.38 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (1 g, 3.38 mmol), 4-methyl-1-nitropentane-2-one (490 mg, 3.38 mmol), and ammonium acetate (780 mg, 10.13 mmol) were mixed in acetic acid (10 mL), and the reaction solution was heated to 100 °C and reacted for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure to obtain the crude target compound (2 g, 87.3%). MS m / z (ESI): 679.2 [M+H] + .

[0504] Step 2: Synthesis of 4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-6-isobutyl-5-nitropyridin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0505] 4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-6-isobutyl-5-nitro-1,4-dihydropyridin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile (2 g, 2.95 mmol) and cerium ammonium nitrate (3.23 g, 5.89 mmol) were mixed in ethanol (30 mL), and the reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the organic solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the target compound (750 mg, 37.6%). MS m / z (ESI): 677.2 [M+H] + .

[0506] Step 3: Synthesis of 4-((6-(3-amino-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylpyridin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0507] 4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(4-fluorophenylethyl)-6-isobutyl-5-nitropyridin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile (750 mg, 1.11 mmol) and 10% palladium on carbon catalyst (200 mg) were mixed in methanol (10 mL). The reaction system was purged under a hydrogen atmosphere, and the reaction mixture was heated to 50 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography to obtain the target compound (661 mg, 92.2%). MS m / z (ESI): 647.3 [M+H] + .

[0508] 1 H NMR (400MHz, DMSO-d6) δ=7.90 (t, J=7.2Hz, 1H), 7.51 (d, J=10.4Hz, 1H), 7.35 (d, J=8.0H z, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.12 (s, 1H), 6.96 (d, J = 7.2Hz, 4H), 6.76 (d, J = 8.0Hz, 1H), 5.13 (d, J=4.4Hz, 2H), 4.68 (s, 2H), 2.89-2.73 (m, 4H), 2.62 (d, J=6.8Hz, 2H), 2.18-2.13 (m, 1H), 1.96-1.88 (m, 1H), 0.90 (d, J=6.4Hz, 6H), 0.83-0.76 (m, 2H), 0.35-0.27 (m, 2H).

[0509] Example 2036 can also be prepared according to the following method

[0510] Step 1: Synthesis of 2-((3-(2-toluenesulfonylhydrazinyl)cyclobutane-1-carbonyl)oxo)ethane-1-onium

[0511] Ethyl 3-carbonylcyclobutane-1-carboxylic acid ester (1.42 g, 10 mmol) and 4-methylbenzenesulfonylhydrazine (1.86 g, 10 mmol) were mixed in EtOH (20 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure to obtain the crude target compound (3 g). MS m / z (ESI): 311.1 [M+H] + .

[0512] Step 2: Synthesis of ethyl 3-(4-fluorophenyl)cyclobutane-1-carboxylic acid ester

[0513] 2-((3-(2-toluenesulfonylhydrazinyl)cyclobutane-1-carbonyl)oxo)ethane-1-onium (2.48 g, 8 mmol), (4-fluorophenyl)boronic acid (1.12 g, 8 mmol), and cesium carbonate (5.21 g, 16 mmol) were mixed in a 35 mL solution of dioxane and reacted at 110 °C for 5 hours. The reaction mixture was cooled to room temperature, and the reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with DCM, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed from the organic phase under reduced pressure. The residue was separated by column chromatography to obtain the target compound (700 mg, 39%). MS m / z (ESI): 223.1 [M+H] + .

[0514] Step 3: Synthesis of 3-(4-fluorophenyl)cyclobutane-1-carboxylic acid

[0515] Ethyl 3-(4-fluorophenyl)cyclobutane-1-carboxylic acid ester (666.9 mg, 3 mmol) was mixed in THF (10 mL) and water (10 mL), and NaOH (400 mg, 10 mmol) was added. The mixture was reacted at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was extracted three times with DCM, and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (620 mg). MS m / z (ESI): 195.1 [M+H] + .

[0516] Step 4: Synthesis of 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(3-(4-fluorophenyl)cyclobutyl)ethane-1-one

[0517] 3-(4-fluorophenyl)cyclobutane-1-carboxylic acid (388.4 mg, 2 mmol) and N,N′-carbonyldiimidazole (389.2 mg, 2.4 mmol) were mixed in DMA (6 mL) and stirred at room temperature for 0.5 h. Potassium 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetate (618.6 mg, 3 mmol) and magnesium chloride (190.4 mg, 2 mmol) were added, and the mixture was heated to 50 °C and reacted for 12 h. After the reaction, the mixture was washed with saturated sodium chloride solution, extracted three times with DCM, and the resulting organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to obtain the target compound (500 mg, 83%). MS m / z (ESI): 301.1 [M+H] + .

[0518] Step 5: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-((1r,3r)-3-(4-fluorophenyl)cyclobutyl)-2-isobutylnicotinamide

[0519] 7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridine-2-carboxaldehyde (296.3 mg, 1 mmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (300.3 mg, 1 mmol), and 3-imino-5-methylhexamethylene (170.6 mg, 1.2 mmol) were mixed in EtOH (6 mL) and reacted at 100 °C for 12 h. The reaction mixture was cooled to room temperature, and cerium ammonium nitrate (1.06 g, 2 mmol) was added. The mixture was then heated to 50 °C and reacted for 2 h. After the reaction was complete, the mixture was washed with saturated sodium chloride solution, extracted three times with DCM, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain the target compound (112 mg, 16%). MS m / z (ESI): 701.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.99-7.93 (m, 1H), 7.81 (s, 1H), 7.60 (d, J=10.2Hz, 1H), 7.49 (s, 1H), 7. 42(d, J=8.1Hz, 1H), 7.35-7.33(m, 2H), 7.22-7.18(m, 2H), 7.16-7.10(m, 2H), 6.95-6.90(m, 1H), 5.16 (s, 2H), 3.77-3.66 (m, 2H), 2.81 (d, J=7.1Hz, 2H), 2.77-2.68 (m, 2H), 2.47-2.40 (m, 1H), 2. 40-2.30 (m, 2H), 2.11-2.03 (m, 1H), 1.02 (d, J=6.6Hz, 6H), 0.95-0.89 (m, 2H), 0.52-0.46 (m, 2H).

[0520] Example 2041 can also be prepared according to the following method

[0521] Step 1: Preparation of methyl 6-(2-toluenesulfonylhydrazide)spiro[3.3]heptane-2-carboxylic acid ester

[0522] Methyl 6-carbonylspiro[3.3]heptane-2-carboxylic acid ester (7.85 g, 46.67 mmol) and 4-methylbenzenesulfonylhydrazine (9.13 g, 49.01 mmol) were dissolved in methanol (100 mL), and the reaction solution was heated to 50 °C and stirred for 3 hours. The reaction solution was then directly concentrated under reduced pressure to obtain crude methyl 6-(2-toluenesulfonylhydrazine derivative)spiro[3.3]heptane-2-carboxylic acid ester (15.7 g). MS m / z (ESI): 337.1 [M+H] + Step 2: Preparation of methyl 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylic acid ester

[0523] Methyl 6-(2-toluenesulfonylhydrazide)spiro[3.3]heptane-2-carboxylate (15.7 g, 46.67 mmol) and (4-fluorophenyl)boronic acid (9.80 g, 70.00 mmol) were dissolved in dioxane (250 mL), followed by the addition of cesium carbonate (30.41 g, 93.34 mmol). The reaction mixture was heated to 110 °C and stirred for 12 hours. The reaction mixture was then directly concentrated and purified by rapid silica gel column chromatography to obtain methyl 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylate (520 mg, 4.49%). 1H NMR (400MHz, CDCl3) δ7.15-7.08 (m, 2H), 6.93 (br s, 2H), 3.68 (s, 3H), 3.41-3.31 (m, 1H), 3.09-3.01 (m, 1H), 2.52-2.34 (m, 4H), 2.26-2.06 (m, 4H).

[0524] Step 3: Preparation of 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylic acid

[0525] Methyl 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylic acid ester (660 mg, 2.66 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2.5 mL), methanol (2.5 mL), and water (2.5 mL). Lithium hydroxide monohydrate (334.64 mg, 7.97 mmol) was then added, and the reaction mixture was heated to 45 °C and stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure. The concentrate was diluted with 100 mL of ethyl acetate, and 100 mL of 1 N hydrochloric acid aqueous solution was added. After stirring for 5 minutes, the mixture was separated and extracted with 300 mL of ethyl acetate (100 mL * 3). The organic phases were combined and concentrated under reduced pressure to obtain crude 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylic acid (500 mg). MS m / z (ESI): 233.1 [MH] - .

[0526] Step 4: Preparation of 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)ethane-1-one

[0527] 6-(4-fluorophenyl)spiro[3.3]heptane-2-carboxylic acid (500 mg, 2.13 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and then N,N′-carbonyldiimidazole (460.86 mg, 3.20 mmol) was added. After stirring for 1 hour, potassium 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetate (660.28 mg, 3.20 mmol) and magnesium chloride (406.42 mg, 4.27 mmol) were added. The reaction was carried out at 50 °C with stirring for 12 hours. The reaction solution was poured into water (300 mL), extracted with 600 mL of ethyl acetate (200 mL * 3), the organic phases were combined, concentrated under reduced pressure, and purified by rapid silica gel column chromatography to obtain 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)ethane-1-one (550 mg, 75.7%). MS m / z (ESI): 341.2 [M + H] + .

[0528] Step 5: Preparation of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide

[0529] 2-Fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (100 mg, 338 μmol), 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)ethane-1-one (115 mg, 338 μmol), 3-imino-5-methylhexamamide (48 mg, 338 μmol) and ammonium acetate (52 mg, 675 μmol) were dissolved in ethanol (10 mL), and then ytterbium trifluoromethanesulfonate (21 mg, 34 μmol) was added. The reaction solution was heated to 90 °C and stirred for 3 hours. The reaction solution was then poured into water (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined and concentrated under reduced pressure to obtain 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (250 mg, 99.7%). MS m / z (ESI): 743.2 [M+H] + .

[0530] Step 6: Preparation of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)-2-isobutylnicotinamide

[0531] 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(6-(4-fluorophenyl)spiro[3.3]heptane-2-yl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (250 mg, 337 μmol) was dissolved in ethanol (10 mL), and then cerium ammonium nitrate (535 mg, 1 mmol) was added. The reaction mixture was heated to 35 °C and stirred for 2 hours. The reaction mixture was then poured into water (50 mL), extracted with 150 mL of ethyl acetate (50 mL * 3), the organic phases were combined, and the residue was concentrated under reduced pressure. The residue was then reversed to prepare (68.6 mg, 27.1%). MS m / z (ESI): 741.3 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ7.96 (t, J=7.4Hz, 1H), 7.75 (s, 1H), 7.60 (d, J=10.4 Hz, 1H), 7.45-7.40 (m, 2H), 7.24-7.17 (m, 4H), 7.10-7.06 (m, 2H), 6.90 (d, J= 8.4Hz, 1H), 5.15(s, 2H), 3.58-3.54(m, 1H), 2.79-2.69(m, 2H), 2.46-2.44(m , 2H), 2.37-2.28(m, 4H), 2.12-1.98(m, 5H), 0.98-0.92(m, 8H), 0.51(s, 2H).

[0532] Example 2065 can also be prepared according to the following method

[0533] Step 1: Preparation of 6-bromo-3-iodopyrazolo[1,5-a]pyridine

[0534] N-iodosuccinimide (11.42 g, 50.76 mmol) was added to a solution of 6-bromopyrazolo[1,5-a]pyridine (10.0 g, 50.76 mmol) in acetonitrile (150 mL), and the reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid 6-bromo-3-iodopyrazolo[1,5-a]pyridine (14.94 g, 90.0%). MS m / z (ESI): 323.0 [M+H] + .

[0535] Step 2: Preparation of 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile

[0536] Under nitrogen protection, 6-bromo-3-iodopyrazolo[1,5-a]pyridine (2.0 g, 6.19 mmol) and isopropyl magnesium chloride-lithium chloride (1.3 M, 5.71 mL) were dissolved in tetrahydrofuran (50 mL), and 2-fluoro-4-carboxybenzonitrile (1.39 g, 9.29 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered after cooling. The filtrate was extracted with ethyl acetate (30 mL x 3), the organic phase was dried and concentrated, and the residue was separated by column chromatography to obtain a yellow solid 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile (1.20 g, 55.9%). MS m / z (ESI): 346.0 [M+H] + .

[0537] Step 3: Synthesis of 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile

[0538] At 20°C, 5 mL of trifluoroacetic acid was added to a solution of 1.2 g (3.47 mmol) of 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile in 20 mL of dichloromethane. Triethylsilane (1.6 g, 13.87 mmol) was then added to the reaction mixture. The mixture was stirred at 20°C for 2 hours, then poured into water and extracted with DCM (50 mL x 3). The organic phase was dried, and the solvent was removed under reduced pressure. The residue was separated by column chromatography to obtain a white solid, 1.0 g (87.37%), of 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile. MS m / z (ESI): 330.0 [M+H] + .

[0539] Step 4: Synthesis of 2-fluoro-4-((2-fluoro-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile

[0540] Dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium (221.41 mg, 0.30 mmol) was added to a mixed solution of 4-((6-bromopyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile (1.0 g, 3.03 mmol), potassium vinyl fluoroborate (0.608 g, 4.54 mmol), and potassium carbonate (1.25 g, 9.09 mmol) in dioxane (20 mL) / water (2 mL). The reaction mixture was stirred at 100 °C for 2 hours. The solution was evaporated to dryness, and the residue was separated by column chromatography to obtain a white solid 2-fluoro-4-((2-fluoro-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (0.6 g, 71.44%). MS m / z (ESI): 278.1 [M+H] + .

[0541] Step 5: Synthesis of 2-fluoro-4-((6-formylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile

[0542] Potassium osmium tetroxide dihydrate (80 mg, 216.40 μmol) was added to a mixture of 2-fluoro-4-((2-fluoro-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (0.6 g, 2.16 mmol) in dioxane (40 mL) / water (10 mL). The reaction mixture was stirred at 20 °C for 0.5 h. Sodium periodate (1.85 g, 8.66 mmol) was then added to the reaction mixture. The mixture was stirred at 20 °C for 2 h, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica column chromatography to give a white solid, 2-fluoro-4-((6-formylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (0.5 g, 82.74%). MS m / z (ESI): 280.1 [M+H] + .

[0543] Step 6: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)pyrazolo[1,5-a]pyridin-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0544] Ytterbium trifluoromethanesulfonate (19.22 mg, 31.0 μmol) was added to an ethanol (5 mL) solution of 3-imino-5-methylhexamamide (44 mg, 310 μmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (85 mg, 310 μmol), 2-fluoro-4-((6-formylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (86 mg, 310 μmol) and ammonium acetate (47 mg, 620 μmol). The reaction solution was heated to 100 °C and reacted for 2 hours. The reaction solution was then cooled to 50 °C, and cerium ammonium nitrate (679 mg, 1.24 mmol) was added to the reaction solution. The mixture was stirred for another 2 hours. The reaction solution was concentrated, washed twice with ethyl acetate and water, and the organic phase was dried and concentrated. 4-(3-(4-cyano-3-fluorobenzyl)pyrazolo[1,5-a]pyridin-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (30 mg, 14.74%) was prepared by prep-HPLC. MS m / z (ESI): 658.3 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ8.42 (t, J=1.2Hz, 1H), 8.05 (s, 1H), 7.89-7.80 (m, 2H), 7.65 (dd, J=9.2, 1.0Hz, 1H), 7.57 (d, J=2.4Hz, 1H), 7.48 (dd, J=10.6, 1.5Hz, 1H), 7.34 (dd, J=8.0, 1.6Hz, 1H), 7.14-7.00 (m, 4H ), 6.80 (dd, J=9.2, 1.6Hz, 1H), 4.20 (s, 2H), 3.12 (t, J=7.6Hz, 2H), 2.97 (t, J=7.6Hz, 2H), 2.74 (d, J=7. 1Hz, 2H), 2.25-2.37(m, 1H), 1.91-2.08(m, 1H), 0.95(d, J=6.6Hz, 6H), 0.83-0.75(m, 2H), 0.28(s, 2H).

[0545] Example 2365 can also be prepared according to the following method

[0546] Step 1: Preparation of 2-fluoro-4-(1-hydroxybut-2-yn-1-yl)benzonitrile

[0547] 2-Fluoro-4-carboxybenzonitrile (25 g, 167.65 mmol) was added to a solution of 1-propyne magnesium bromide (0.5 M, 402.36 mL) in tetrahydrofuran (500 mL) under ice bath conditions, and the mixture was stirred for 2 hours under ice bath conditions. The reaction solution was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL × 2). The combined organic phases were washed with saturated brine (1000 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give a colorless oily substance, 2-fluoro-4-(1-hydroxybut-2-yn-1-yl)benzonitrile (26.0 g, 81.9%). MS m / z (ESI): 190.1 [M+H] + .

[0548] Step 2: Preparation of 4-(but-2-ynyl)-2-fluorobenzonitrile

[0549] To a solution of 2-fluoro-4-(1-hydroxybut-2-yn-1-yl)benzonitrile (26 g, 137.43 mmol) in dichloromethane (500 mL), manganese dioxide (47.83 g, 549.73 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid, 4-(but-2-ynyl)-2-fluorobenzonitrile (22.0 g, 85.53%). MS m / z (ESI): 188.0 [M+H] + .

[0550] Step 3: Preparation of 3-bromopyridine-1-onium-1-amineiodide

[0551] Under ice bath conditions, a solution of amino-2,4,6-trimethylbenzenesulfonate (34 g, 157.94 mmol) in dichloromethane (100 mL) was added to a solution of 3-bromopyridine (24.95 g, 157.94 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 12 hours. Hydroiodic acid (20.13 g, 100.00 mmol) was added to the mixture and stirred for 30 minutes. The resulting solution was stored in a refrigerator and crystallized to give an orange solid, 3-bromopyridine-1-onthium-1-amineiodide (32.0 g, 57.4%). MS m / z (ESI): 173.0 [M] + .

[0552] Step 4: Preparation of 4-(6-bromo-2-methylpyrazolo[1,5-a]pyridine-3-carbonyl)-2-fluorobenzonitrile

[0553] Potassium carbonate (19.54 g, 141.57 mmol) was added to a solution of 3-bromopyridin-1-onthium-1-amine iodide (10.0 g, 28.31 mmol) and 4-(but-2-ynyl)-2-fluorobenzonitrile (5.30 g, 28.31 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid 4-(6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-carbonyl)-2-fluorobenzonitrile (3.2 g, 31.5%). MS m / z (ESI): 358.0 [M+H] + .

[0554] Step 5: Preparation of 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile

[0555] Sodium borohydride (676.03 mg, 17.87 mmol) was added to a methanol (50 mL) solution of 3.2 g (8.93 mmol) of 4-(6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-carbonyl)-2-fluorobenzonitrile (8.93 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile (83.9%). MS m / z (ESI): 360.0 [M+H] + .

[0556] Step 6: Synthesis of 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile

[0557] At room temperature, 2 mL of trifluoroacetic acid was added to a solution of 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)(hydroxy)methyl)-2-fluorobenzonitrile (2.7 g, 7.50 mmol) in 20 mL of dichloromethane. Triethylsilane (2.61 g, 22.49 mmol) was then added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, then poured into water and extracted with DCM (150 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid, 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile (2.0 g, 77.5%). MS m / z (ESI): 344.0 [M+H] + .

[0558] Step 7: Synthesis of 2-fluoro-4-((2-methyl-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile

[0559] Dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium (424.78 mg, 581.09 μmol) was added to a mixture of 4-((6-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)-2-fluorobenzonitrile (2.0 g, 5.81 mmol), potassium vinyl fluoroborate (1.17 g, 8.72 mmol), and potassium carbonate (2.41 g, 17.43 mmol) in dioxane (40 mL) / water (4 mL). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid, 2-fluoro-4-((2-methyl-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (1.2 g, 70.9%). MS m / z (ESI): 292.1 [M+H] + .

[0560] Step 8: Synthesis of 2-fluoro-4-((6-formyl-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile

[0561] Potassium osmium tetroxide dihydrate (151.75 mg, 411.92 μmol) was added to a mixture of 2-fluoro-4-((2-methyl-6-vinylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (1.2 g, 4.12 mmol) in dioxane (80 mL) / water (20 mL). The reaction mixture was stirred at room temperature for 0.5 hours. Sodium periodate (3.52 g, 16.48 mmol) was then added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give a white solid, 2-fluoro-4-((6-formyl-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (0.8 g, 66.2%). MS m / z (ESI): 294.1 [M+H] + .

[0562] Step 9: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-methylpyrazolo[1,5-a]pyridin-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0563] Ytterbium trifluoromethanesulfonate (16.91 mg, 27.28 μmol) was added to an ethanol (5 mL) solution of 3-imino-5-methylhexamamide (38.79 mg, 272.76 μmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (74.82 mg, 272.76 μmol), 2-fluoro-4-((6-formyl-2-methylpyrazolo[1,5-a]pyridin-3-yl)methyl)benzonitrile (80 mg, 272.76 μmol), and ammonium acetate (38.19 mg, 545.53 μmol). The reaction solution was reacted at 100 °C for 2 hours. The reaction solution was cooled to 50°C, and cerium ammonium nitrate (470.95 mg, 818.29 μmol) was added to the reaction solution. Stirring was continued for 2 hours. The reaction solution was concentrated, and the residue was subjected to prep-HPLC to prepare 4-(3-(4-cyano-3-fluorobenzyl)-2-methylpyrazolo[1,5-a]pyridin-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (45 mg, 24.6%). MS m / z (ESI): 672.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 7.63-7.55 (m, 2H), 7.35-7.26 (m, 2H), 7.10 (d, J=10.6, 1H), 6.98 (d, J=8.0, 1H), 6.90-6.76 (m, 4H), 6.50 (d, J=9.1, 1H), 3.91 (s, 2H) , 2.89-2.82(m, 2H), 2.77-2.66(m, 2H), 2.49(d, J=7.1Hz, 2H), 2.09(s, 3H), 2.07-1. 99 (m, 1H), 1.83-1.72 (m, 1H), 0.71 (d, J=6.6Hz, 6H), 0.61-0.53 (m, 2H), 0.08 (s, 2H).

[0564] Example 2542 can also be prepared according to the following method

[0565] Step 1: Synthesis of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(thiazolyl-5-yl)butane-2-one

[0566] N,N′-carbonyldiimidazole (1.03 g, 6.36 mmol) was added to a tetrahydrofuran (10 mL) solution of 3-(thiazol-5-yl)propionic acid (1.0 g, 6.36 mmol), and the reaction mixture was stirred at 20 °C for 1 hour. Magnesium chloride (1.03 g, 6.36 mmol) and potassium 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetate (1.03 g, 6.36 mmol) were then added to the reaction mixture, and the mixture was stirred at 60 °C for 13 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to yield compound 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(thiazol-5-yl)butane-2-one (500 mg, 29.9%). MS m / z (ESI): 264.1 [M+H] + .

[0567] Step 2: Synthesis of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-isobutyl-6-(2-(thiazolyl-5-yl)ethyl)nicotinamide

[0568] Ytterbium trifluoromethanesulfonate (21.80 mg, 35.16 μmol) was added to an ethanol (5 mL) solution of 3-imino-5-methylhexamamide (50 mg, 351.62 μmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(thiazolyl-5-yl)butane-2-one (92.59 mg, 351.62 μmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (104.17 mg, 351.62 μmol), and ammonium acetate (49.23 mg, 703.24 μmol). The reaction solution was heated to 100 °C and reacted for 2 hours. The reaction solution was cooled to 50°C, and cerium ammonium nitrate (770.75 mg, 1.41 mmol) was added. Stirring continued for 2 hours. The reaction solution was concentrated, washed with saturated brine (50 mL × 2), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried, and concentrated. The filtrate was used to prepare 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-isobutyl-6-(2-(thiazol-5-yl)ethyl)nicotinamide (30 mg, 12.9%) by prep-HPLC. MS m / z (ESI): 664.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.87 (d, J=0.8Hz, 1H), 8.00-7.90 (m, 1H), 7.87-7.76 (m, 2H), 7.6 7-7.53 (m, 2H), 7.48-7.37 (m, 2H), 7.24-7.14 (m, 2H), 6.89 (dd, J=8.0, 1.6Hz, 1H), 5.16 ( s, 2H), 3.29 (d, J=7.4Hz, 2H), 3.11 (t, J=7.3Hz, 2H), 2.72 (d, J=7.1Hz, 2H), 2.41-2.21 (m , 1H), 2.09-1.97 (m, 1H), 0.94 (d, J=6.6Hz, 6H), 0.91-0.84 (m, 1H), 0.41 (d, J=4.3Hz, 2H).

[0569] Examples 2545 and 2546 can also be prepared according to the following method.

[0570] Step 1: Preparation of (R)-1-(4-bromo-3-fluorophenyl)-2-(2-methylmorpholino)ethane-1-one

[0571] To a tetrahydrofuran (50 mL) solution of 2-bromo-1-(4-bromo-3-fluorophenyl)ethane-1-one (3.0 g, 10.14 mmol), (R)-2-methylmorpholine (3.08 g, 30.41 mmol) and DIEA (1.31 g, 10.14 mmol, 1.77 mL) were added, and the reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow solid (R)-1-(4-bromo-3-fluorophenyl)-2-(2-methylmorpholine)ethane-1-one (3.6 g, crude). MS m / z (ESI): 316.0 [M+H] + .

[0572] Step 2: Preparation of 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethane-1-ol

[0573] Sodium borohydride (861.50 mg, 22.77 mmol) was added to a solution of (R)-1-(4-bromo-3-fluorophenyl)-2-(2-methylmorpholino)ethane-1-one (3.6 g, 11.39 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated and diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to give compound 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethane-1-ol (2.8 g, 77.3%). MS m / z (ESI): 318.0 [M+H] + .

[0574] Step 3: Synthesis of 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl methanesulfonate

[0575] At 20°C, methanesulfonic anhydride (3.07 g, 17.60 mmol) was added to a solution of 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethane-1-ol (2.8 g, 8.80 mmol) in 50 mL of dichloromethane. Triethylamine (2.67 g, 26.40 mmol, 3.68 mL) was added to the reaction mixture. The reaction mixture was stirred at 20°C for 2 hours, then poured into water and extracted with DCM (50 mL x 3). The organic phase was dried, evaporated to dryness, and separated by column chromatography to obtain 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl methanesulfonate (3.3 g, 94.6%). MS m / z (ESI): 398.0 [M+H] + .

[0576] Step 4: Synthesis of 3-(1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-carboxaldehyde

[0577] 1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl methanesulfonate (3.1 g, 7.82 mmol) was added to a solution of 2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-carboxaldehyde (1.28 g, 7.82 mmol) and potassium carbonate (2.16 g, 15.65 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to yield 3-(1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-carboxaldehyde (1.6 g, 44.1%). MS m / z (ESI): 465.1 [M+H] + .

[0578] Step 5: Synthesis of 2-fluoro-4-(1-(6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)benzonitrile

[0579] 3-(1-(4-bromo-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-carboxaldehyde (1.0 g, 2.16 mmol) was added to a solution of tetrakis(triphenylphosphine)palladium (249.30 mg, 215.84 μmol) and zinc cyanide (1.26 g, 10.79 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 130 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. Concentrated column chromatography yielded 2-fluoro-4-(1-(6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)-2-((R)-2-methylmorpholino)ethyl)benzonitrile (300 mg, 33.9%). MS m / z (ESI): 410.1 [M+H] + .

[0580] Step 6: Synthesis of 4-(3-(1-(4-cyano-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0581] Ytterbium trifluoromethanesulfonate (22.60 mg, 36.46 μmol) was added to 3-imino-5-methylhexamamide (51.84 mg, 364.58 μmol), 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (100 mg, 364.58 μmol), and 2-fluoro-4-(1-(6-formyl-2-carbonylbenzo[d]oxazol-3-( In a 5 mL ethanol solution of 2H)-yl)-2-((R)-2-methylmorpholino)ethyl)benzonitrile (149.62 mg, 364.58 μmol) and ammonium acetate (51.04 mg, 729.16 μmol), the reaction solution was heated to 100 °C and reacted for 2 hours. The reaction solution was then cooled to 50 °C, and cerium ammonium nitrate (599.37 mg, 1.09 mmol) was added to the reaction solution. The mixture was stirred for another 2 hours. The reaction solution was concentrated, and the residue was prepared chirally to yield 4-(3(S)-(1-(4-cyano-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (30 mg, 20.9%) and 4-(3(R)-(1-(4-cyano-3-fluorophenyl)-2-((R)-2-methylmorpholino)ethyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (30 mg, 20.9%). MS m / z (ESI): 788.3 [M+H] + .

[0582] Examples 2545 and 2546: 1 H NMR (400MHz, DMSO-d6) δ8.01 (s, 1H), 7.80-7.70 (m, 2H), 7.54 (d, J=8.4Hz, 2H), 7.46 (s, 1H), 7.18 (s, 1H), 7.12-7.03 (m, 4H), 6.87 (d, J=8.2Hz, 1H), 3.68 (s, 2H) , 3.03 (d, J = 7.5Hz, 3H), 2.95 (d, J = 7.5Hz, 3H), 2.72 (d, J = 7.3Hz, 3H), 2.34-2.24 (m, 1H), 2.01 (s, 3H), 1.25 (s, 1H), 1.08-0.90 (m, 8H), 0.86 (s, 4H), 0.43 (s, 3H).

[0583] Example 2564 can also be prepared according to the following method

[0584] Step 1: Preparation of 4-((5-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzonitrile

[0585] Potassium carbonate (1.63 g, 11.85 mmol), 5-bromo-2-methyl-1H-benzo[D]imidazole (1 g, 4.74 mmol), and 4-cyano-3-fluorobenzyl bromide (1.20 g, 5.61 mmol) were added separately to DMF (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL), filtered, and the filter cake was dried under reduced pressure and separated by silica gel column chromatography to give a mixture of the title compound and its isomers (1.23 g, 61.3%). MS m / z (ESI): 344.0 [M+H] + .

[0586] Step 2: Preparation of 2-fluoro-4-((2-methyl-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile

[0587] A mixture of 4-((5-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-fluorobenzonitrile and its isomers (1 g, 2.91 mmol), potassium ethylene trifluoroborate (584 mg, 4.36 mmol), Pd(dpp)Cl2 (204 mg, 291 μmol), and K2CO3 (802 mg, 5.81 mmol) were added to a mixed solvent of 1,4-epoxyhexacyclohexane (20 mL) and water (4 mL). The mixture was heated to 100 °C and stirred for 2.5 hours under nitrogen protection. The reaction mixture was separated, the organic layer was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain a mixture of the title compound and its isomers (595 mg, 70.3%). MS m / z (ESI): 292.2 [M+H] + .

[0588] Step 3: Preparation of 2-fluoro-4-((5-formyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile

[0589] At room temperature, NaIO4 (1.75 g, 8.17 mmol) was added in portions to a mixture of 2-fluoro-4-((2-methyl-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile and its isomers (0.595 g, 2.04 mmol) and K2OsO4·2H2O (63.5 mg, 204 μmol) in 20 mL of 1,4-dioxane and 20 mL of H2O. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a mixture of the title compound and its isomers (333 mg, 55.6%).

[0590] MS m / z (ESI): 294.1 [M+H] + .

[0591] Step 4: Preparation of 4-(1-(4-cyano-3-fluorobenzyl)-2-methyl-1H-benzimidazol-5-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0592] A solution of 1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-4-(4-fluorophenyl)butane-2-one (308 mg, 1.13 mmol), a mixture of 2-fluoro-4-((5-formyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile and its isomers (0.33 g, 1.13 mmol), and 3-imino-5-methylhexamamide (160 mg, 1.13 mmol) in EtOH (10 mL) was sealed and heated to 100 °C and stirred for 3 hours. The reaction solution was cooled, and cerium ammonium nitrate (1.23 g, 2.25 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), washed with water (10 mL), concentrated under reduced pressure, and separated by preparative HPLC to give the title compound (68 mg, 8.9%). MS m / z (ESI): 672.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.93 (t, J=7.4Hz, 1H), 7.72-7.67 (m, 1H), 7.39-7.26 ( m, 4H), 7.14-6.99 (m, 5H), 6.88-6.81 (m, 1H), 5.59 (s, 2H), 3.11-3.03 (m, 2H), 3.00-2.92(m, 2H), 2.76-2.69(m, 2H), 2.56-2.52(m, 3H), 2.39-2.24(m, 1H), 1 .99-1.88(m, 1H), 0.95(d, J=6.6Hz, 6H), 0.80-0.73(m, 2H), 0.24-0.09(m, 2H).

[0593] Example 3069 can also be prepared according to the following method

[0594] Step 1: (5-Carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylpyridin-3-yl) tert-butyl carbamate

[0595] 5-Carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid (100 mg, 0.16 mmol), diphenyl azide phosphate (54.08 mg, 0.20 mmol), and triethylamine (33.14 mg, 0.33 mmol) were dissolved in DMF (5 mL), and tert-butanol (121.3 mg, 1.64 mmol) was added. The reaction mixture was reacted at 100 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give the target compound (26.8 mg, 24.0%). MS m / z (ESI): 682.3 [M+H] + .

[0596] Step 2: Synthesis of 5-amino-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0597] At room temperature, 1.5 mL of trifluoroacetic acid was added to a solution of tert-butyl carbamate (26.8 mg, 39.31 μmol) in 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the target compound (16.6 mg, 72.6%). MS m / z (ESI): 582.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.00-7.93 (m, 1H), 7.67-7.60 (m, 1H), 7.49-7.43 (m, 2H), 7.36-7.29 (m, 3H), 7.25 (d, J=1.5Hz, 1H), 7.12-7.04 (m, 4H) ), 5.19 (d, J = 4.3Hz, 2H), 4.33 (s, 2H), 3.04-2.96 (m, 2H), 2.96-2.89 (m, 2H), 2.47 (d, J = 7.0Hz, 2H), 2.19-2.07 (m, 1H), 0.87 (d, J = 6.6Hz, 6H).

[0598] Example 3099 can also be prepared according to the following method.

[0599] Preparation of 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0600] Methyl 5-carbamoyl-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinate (70 mg, 0.112 mmol) was dissolved in N-methylpyrrolidone (2 mL), and LiCl (95.02 mg, 2.24 mmol) was added. The mixture was microwaved at 200 °C for 3 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to Pre-HPLC column chromatography to obtain 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (8.0 mg, 12.6%). MS m / z (ESI): 567.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.99-7.91 (m, 1H), 7.73 (s, 1H), 7.64 (d, J=9.4Hz, 1H), 7.50-7.39 (m, 3H), 7.34-7.22 (m, 4H) , 7.13-7.03 (m, 3H), 5.19 (s, 2H), 3.07-2.96 (m, 4H), 2.65 (d, J=7.2Hz, 2H), 2.31-2.16 (m, 1H), 0.89 (d, J=6.6Hz, 6H).

[0601] Example 3186-1 can also be prepared according to the following method.

[0602] Step 1: 4-Chloro-5-cyano-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0603] 4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (5 g, 28.15 mmol) was dissolved in ethyl acetate (120 mL), and m-chloroperoxybenzoic acid (15.77 g, 70.39 mmol, 77% purity) was added. The reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and 200 mL of petroleum ether was added. After stirring for 10 minutes, the mixture was filtered, and the filter cake was collected and purified by slurrying with 100 mL of methyl tert-butyl ether to obtain 4-chloro-5-cyano-1H-pyrrolo[2,3-b]pyridine-7-oxide (3.83 g, 70.27%). MS m / z (ESI): 194.2 [M+H] + .

[0604] Step 2: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0605] Under ice bath conditions, 4-chloro-5-cyano-1H-pyrrolo[2,3-b]pyridine-7-oxide (3.83 g, 19.78 mmol) was dissolved in N-methylpyrrolidone (40 mL), and phosphine oxychloride (6.58 g, 42.91 mmol, 4 mL) was slowly added. The reaction was stirred at 0 °C for 1 hour. The reaction solution was slowly poured into a stirred ice water solution (300 mL), stirred for 5 minutes, filtered, and the filter cake was collected and purified by slurry mixing with a mixture of petroleum ether and methyl tert-butyl ether (5:1) (50 mL) to obtain 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile (3.8 g, 90.59%). MS m / z (ESI): 212.0 [M+H] + .

[0606] Step 3: 6-Chloro-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0607] 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (2.7 g, 12.73 mmol) was dissolved in methanol (40 mL), and then sodium methoxide methanol solution (5.4 M, 10.61 mL) was added. The reaction mixture was stirred at 70 °C for 12 hours. The reaction solution was slowly poured into 2 M citric acid aqueous solution (500 mL), stirred for 10 minutes, filtered, and the filter cake was collected and concentrated under reduced pressure to obtain 6-chloro-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (2.63 g, crude). MS m / z (ESI): 207.0 [M+H] + .

[0608] Step 4: 4-Methoxy-6-(2-methylprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0609] 6-Chloro-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (2 g, 9.63 mmol) and (2-methylprop-1-en-1-yl)boronic acid (2.89 g, 28.90 mmol) were dissolved in a mixed solvent of dioxane (50 mL) and water (10 mL). Then, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (786.68 mg, 963.32 μmol) and cesium carbonate (9.42 g, 28.90 mmol) were added. The reaction solution was heated to 100 °C and stirred for 2 hours. The reaction solution was filtered, and the filtrate was purified by reverse-phase column chromatography (C18, 120 g; water (1% formic acid): acetonitrile = 5%–85%) to give 4-methoxy-6-(2-methylprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylon (2.15 g, 98.21%). MS m / z (ESI): 228.2 [M+H] + .

[0610] Step 5: 6-Isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0611] 4-Methoxy-6-(2-methylprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (2 g, 8.80 mmol) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and methanol (50 mL), and then wet palladium on carbon (936.54 mg, 880.04 μmol, 10% purity) was added. The reaction was carried out under vacuum, and the system was purged with hydrogen three times. The reaction solution was heated to 45 °C and stirred for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 6-isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (2 g, 99.12%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 11.75 (br s, 1H), 6.79 (d, J = 3.6, 1H), 4.57 (s, 3H), 2.94 (d, J = 7.6, 2H), 2.30-2.23 (m, 1H), 1.04 (d, J = 6.8, 6H).

[0612] Step 6: 3-(4-fluorophenyl)cyclobutane-1-ol

[0613] 3-(4-fluorophenyl)cyclobutane-1-one (3 g, 18.27 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and methanol (10 mL), and then sodium borohydride (1.38 g, 36.55 mmol) was added. The reaction mixture was stirred at room temperature (25 °C) for 1 hour. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (200 mL * 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give 3-(4-fluorophenyl)cyclobutane-1-ol (2.6 g, 85.62%). MS m / z (ESI): 167.1 [M + H] + Step 7: 1-(3-bromocyclobutyl)-4-fluorobenzene

[0614] 3-(4-fluorophenyl)cyclobutane-1-ol (1.75 g, 10.53 mmol) was dissolved in tetrahydrofuran (100 mL), followed by the addition of triphenylphosphine (10.19 g, 38.86 mmol), zinc bromide (2.96 g, 13.16 mmol), and diisopropyl azodicarbonate (7.86 g, 38.86 mmol, 7.65 mL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. After concentration under reduced pressure, the residue was purified by rapid silica gel column chromatography to give 1-(3-bromocyclobutyl)-4-fluorobenzene (1.46 g, 6.37 mmol, 60.52%).

[0615] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.19-7.15 (m, 2H), 7.03-6.98 (m, 2H), 4.64-4.58 (m, 1H), 3.99 (q, J = 8.0Hz, 1H), 2.88-2.75 (m, 4H).

[0616] Step 8: 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0617] 6-Isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (500 mg, 2.18 mmol) and 1-(3-bromocyclobutyl)-4-fluorobenzene (549.55 mg, 2.40 mmol) were dissolved in N-methylpyrrolidone (10 mL), and then cesium carbonate (1.42 g, 4.36 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by rapid silica gel column chromatography to obtain 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (500 mg, 60.74%). MS m / z (ESI): 378.2 [M+H] + .

[0618] Step 9: 1-(3-(4-fluorophenyl)cyclobutyl)-4-hydroxy-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0619] 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile (500.00 mg, 1.32 mmol) and lithium chloride (561.58 mg, 13.25 mmol) were dissolved in N-methylpyrrolidone (10 mL), and then p-toluenesulfonic acid (345.01 mg, 6.62 mmol) was added. The reaction was stirred at 180 °C for 1 hour. The reaction solution was poured into 100 mL of water, extracted with ethyl acetate (100 mL * 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by rapid silica gel column chromatography to obtain 1-(3-(4-fluorophenyl)cyclobutyl)-4-hydroxy-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile (250 mg, 51.93%). MS m / z (ESI): 364.2 [M+H] + .

[0620] Step 10: 4-Chloro-1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0621] 1-(3-(4-fluorophenyl)cyclobutyl)-4-hydroxy-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (210.00 mg, 577.83 μmol) was dissolved in dichloromethane (15 mL), and then (chloromethylene)dimethylammonium chloride (369.81 mg, 2.89 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into water, extracted with dichloromethane (40 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-chloro-1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (220 mg, 99.70%).

[0622] Step 11: 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile

[0623] 4-Chloro-1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylonitrile (220.00 mg, 576.11 μmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzo[d]oxazol-2(3H)-one (225.62 mg, 864.16 μmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). Then, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (42.15 mg, 57.61 μmol) and sodium carbonate (122.12 mg, 1.15 mmol) were added. The reaction solution was heated to 110 °C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography to give 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile (270 mg, 97.53%). MS m / z (ESI): 481.1 [M+H] + .

[0624] Step 12: 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0625] 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxynitrile (270.00 mg, 561.88 μmol) was dissolved in a mixed solvent of ethanol (3 mL) and water (3 mL), and then the (dimethylphosphonic acid)platinum(II) hydrogenated complex (Parkins' Catalyst) (605.77 mg, 1.40 mmol) was added. The reaction solution was heated to 100 °C and stirred for 2 hours. The reaction solution was poured into 50 mL of water and extracted with 150 mL of ethyl acetate (3 x 50 mL). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (280 mg, crude). MS m / z (ESI): 499.2 [M+H] + .

[0626] Step 13: 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1-(trans-3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0627] 1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-4-(2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (280.00 mg, 561.63 μmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (232.86 mg, 1.68 mmol) and 4-(bromomethyl)-2-fluorobenzonitrile (170.00 mg, 794.27 μmol) were added, and the reaction was heated to 70 °C and stirred for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was then purified by HPLC to obtain 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-1-(3-(4-fluorophenyl)cyclobutyl)-6-isobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (200 mg, 56.38%). MS m / z (ESI): 632.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ=7.97 (t, J=7.4Hz, 1H), 7.74 (d, J=3.4Hz, 1H), 7.67 (d, J=10.0Hz, 1H), 7.57-7.57 (m, 1H), 7.54-7.46 (m, 4H), 7.37-7.31 (m, 3 H), 7.17 (t, J=8.8Hz, 2H), 6.21 (d, J=3.4Hz, 1H), 5.21-5.14 (m, 3H), 3.43- 3.39 (m, 1H), 2.95-2.75 (m, 6H), 2.35-2.25 (m, 1H), 0.93 (d, J=6.8Hz, 6H).

[0628] Example 3194 can also be prepared according to the following method.

[0629] Step 1: Synthesis of N-(2-cyclopropyl-2-carbonylethyl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetamide

[0630] Diisopropylethylamine (2.44 g, 18.88 mmol) was added to a solution of 2-(2-(4-fluorophenylethyl)-1,3-dioxapentane-2-yl)acetic acid (1.2 g, 4.72 mmol), 2-amino-1-cyclopropyl-ethyl ketone hydrochloride (959 mg, 7.08 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (2.67 g, 7.08 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 50 °C and reacted for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, and the solvent was removed under reduced pressure. The residue was separated by column chromatography to give N-(2-cyclopropyl-2-carbonylethyl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetamide (1.4 g, 88.5%). MS m / z (ESI): 336.2 [M+H] + .

[0631] Step 2: Synthesis of 5-cyclopropyl-2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)oxazole

[0632] Burgess reagent (1.99 g, 8.35 mmol) was added to a tetrahydrofuran (30 mL) solution of N-(2-cyclopropyl-2-carbonylethyl)-2-(2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)acetamide (1.4 g, 4.17 mmol). The reaction mixture was heated to 65 °C and reacted for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The organic phase was dried, and the solvent was removed under reduced pressure. The residue was separated by column chromatography to give 5-cyclopropyl-2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)oxazole (720 mg, 54.4%). MS m / z (ESI): 318.1 [M+H] + .

[0633] Step 3: Synthesis of 1-(5-cyclopropyloxazol-2-yl)-4-(4-fluorophenyl)butane-2-one

[0634] Concentrated sulfuric acid (22 mg, 226 μmol) was added to a solution of 5-cyclopropyl-2-((2-(4-fluorophenylethyl)-1,3-dioxopentane-2-yl)methyl)oxazole (720 mg, 2.27 mmol) in formic acid (5 mL). The reaction mixture was heated to 50 °C and reacted for 3 hours. The reaction mixture was then slowly poured into saturated sodium bicarbonate, extracted with ethyl acetate (30 mL x 3), and the organic phase was dried and concentrated. The residue was separated by column chromatography to obtain 1-(5-cyclopropyloxazol-2-yl)-4-(4-fluorophenyl)butane-2-one (450 mg, 72.6%). MS m / z (ESI): 274.1 [M+H] + .

[0635] Step 4: Synthesis of 5-(5-cyclopropyloxazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide

[0636] Ytterbium trifluoromethanesulfonate (22 mg, 36.6 μmol) was added to an ethanol (10 mL) solution of 1-(5-cyclopropyloxazol-2-yl)-4-(4-fluorophenyl)butane-2-one (100 mg, 365 μmol), 7-[(3,4-difluorophenyl)methylamino]thieno[2,3-c]pyridine-2-carboxaldehyde (111.35 mg, 365 μmol), 3-amino-5-methyl-hex-2-enamide (52 mg, 365 μmol), and ammonium acetate (56.41 mg, 731 μmol). The reaction solution was heated to 60 °C and reacted for 16 hours. The reaction solution was concentrated to obtain 5-(5-cyclopropyloxazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (250 mg, 99%), which was used directly in the next step of the reaction. MS m / z (ESI): 684.3 [M+H] + .

[0637] Step 5: Synthesis of 5-(5-cyclopropyloxazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide

[0638] Cerium ammonium nitrate (387 mg, 731 μmol) was added to an ethanol (10 mL) solution of 5-(5-cyclopropyloxazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-1,4-dihydropyridine-3-carboxamide (250 mg, 365 μmol), and the reaction mixture was heated to 60 °C and stirred for 1 hour. The reaction solution was concentrated to dryness, poured into water, and extracted with ethyl acetate (30 mL x 3). After drying and concentrating the organic phase, the residue was subjected to prep-HPLC to prepare 5-(5-cyclopropyloxazol-2-yl)-4-(7-((3,4-difluorobenzyl)amino)thieno[2,3-c]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutylnicotinamide (43.8 mg, 17.2%). MS m / z (ESI): 682.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.91-7.82 (m, 2H), 7.54 (s, 1H), 7.44 (t, J=6.0Hz, 1H), 7.37-7.27 (m, 2 H), 7.21 (s, 1H), 7.17-7.09 (m, 3H), 7.05 (t, J=8.8Hz, 2H), 7.00 (d, J=5.6Hz, 1H), 6.96 (s, 1H), 4.63 (d, J=6.0Hz, 2H), 3.11 (t, J=8.0Hz, 2H), 2.93 (t, J=8.0Hz, 2H), 2.72 (d, J=7.2Hz, 2H), 2.3 1-2.25 (m, 1H), 1.79-1.71 (m, 1H), 0.94 (d, J=6.8Hz, 6H), 0.65-0.58 (m, 2H), 0.20-0.13 (m, 2H).

[0639] Example 3198 can also be prepared according to the following method.

[0640] Step 1: Synthesis of ethyl 2,2-difluorospiro[3.5]nonane-7-carboxylate

[0641] Ethyl 2-carbonylspiro[3.5]nonane-7-carboxylate (1.0 g, 4.8 mmol) was dissolved in dichloromethane (10 mL) under ice bath conditions. Bis(2-methoxyethyl)aminosulfur trifluoride (3.2 g, 14.4 mmol) was added dropwise, and the mixture was gradually brought to room temperature and stirred for 10 h. The reaction mixture was added dropwise to an ice-water mixture and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to obtain the target compound (858.0 mg, 77%). MS m / z (ESI): 233.1 [M+H] + .

[0642] Step 2: Synthesis of 2,2-difluorospiro[3.5]nonane-7-carboxylic acid

[0643] Ethyl 2,2-difluorospiro[3.5]nonane-7-carboxylate (858.0 mg, 3.7 mmol) was dissolved in THF / MeOH / H2O (3 / 3 / 3 mL), and lithium hydroxide (444.0 mg, 18.5 mmol) was added. The reaction mixture was reacted at room temperature for 1 h. The pH of the reaction mixture was adjusted to 5 by adding dilute hydrochloric acid, and the mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude target compound (667.0 mg). MS m / z (ESI): 205.1 [M+H]+ Step 3: Synthesis of 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(2,2-difluorospiro[3.5]nonane-7-yl)ethane-1-one

[0644] 2,2-Difluorospiro[3,5]nonane-7-carboxylic acid (667.0 mg, 3.27 mmol) was dissolved in DMAc (5 mL), and CDI (635.4 mg, 3.92 mmol) was added. The reaction was carried out at room temperature for 1 h. Potassium 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetate (1.01 g, 4.91 mmol) and magnesium chloride (622.6 mg, 6.54 mmol) were then added to the reaction solution, and the reaction was carried out at 55 °C for 5 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography to give the target compound (357.0 mg, 35%). MS m / z (ESI): 311.1 [M+H] + .

[0645] Step 4: Synthesis of 4-((6-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-(2,2-difluorospiro[3.5]nonane-7-yl)-3-carbonylprop-1-en-1-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0646] 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(2,2-difluorospiro[3.5]nonane-7-yl)ethane-1-one (150.0 mg, 0.48 mmol) was dissolved in toluene (5 mL), and piperidine (12.3 mg, 0.144 mmol) and acetic acid (8.6 mg, 0.144 mmol) were added. The mixture was heated to 120 °C and reacted for 10 h. The organic solvent was removed under reduced pressure, and the residue was extracted with saturated sodium bicarbonate solution (150 mL × 3) and ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude target compound (256.0 mg). MS m / z (ESI): 589.2 [M + H] + .

[0647] Step 5: Synthesis of 4-((6-((9aS)-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(2,2-difluorospiro[3.5]nonane-7-yl)-5-carbonyl-1,5,7,8,9,9a-hexahydro-4H-pyrido[2,3-a]pyrrolizin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0648] 4-((6-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-(2,2-difluorospiro[3.5]nonane-7-yl)-3-carbonylprop-1-en-1-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile (256.0 mg, 0.44 mmol), (S)-tetrahydro-1H-pyrrolidone-1,3(2H)-dione (61.2 mg, 0.44 mmol), and ammonium acetate (67.8 mg, 0.88 mmol) were mixed in EtOH (5 mL) and reacted at 120 °C for 12 h. The reaction solution was cooled to room temperature, and the organic solvent was removed under reduced pressure to obtain the crude target compound (311.5 mg). MS m / z (ESI): 709.3 [M+H] + .

[0649] Step 6: Synthesis of (S)-4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(2,2-difluorospiro[3.5]nonane-7-yl)-5-carbonyl-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0650] 4-((6-((9aS)-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(2,2-difluorospiro[3.5]nonane-7-yl)-5-carbonyl-1,5,7,8,9,9a-hexahydro-4H-pyrido[2,3-a]pyrrolizin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile (311.5 mg, 0.44 mmol) and cerium ammonium nitrate (482.4 mg, 0.88 mmol) were mixed in ethanol (5 mL), and the reaction mixture was heated to 55 °C and stirred for 2 hours. After cooling to room temperature, the organic solvent was removed under reduced pressure, and the residue was separated by high performance liquid chromatography to obtain the target compound (32.1 mg, 10%). MS m / z (ESI): 707.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.98-7.92 (m, 1H), 7.60 (d, J=10.2Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.33-7.28 (m, 1H), 7.1 8(d, J=8.2Hz, 1H), 6.91-6.85(m, 1H), 5.18(s, 2H), 4.89-4.80(m, 1H), 3.55-3.49(m, 1H), 3.29-3.21(m, 1H), 2.6 2-2.54(m,1H),2.44-2.36(m,2H),2.33-2.28(m,2H),2.27-2.21(m,2H),2.16-2.10(m,1H),2.04-1.95(m,1H),1 .77-1.69(m, 4H), 1.68-1.62(m, 2H), 1.48-1.36(m, 3H), 1.00-0.94(m, 2H), 0.64-0.57(m, 1H), 0.57-0.50(m, 1H).

[0651] Examples 3772 and 3786 can also be prepared according to the following method.

[0652] Step 1: Preparation of 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)ethane-1-one

[0653] 5-Fluoro-2,3-dihydro-1H-indene-2-carboxylic acid (1.8 g, 9.99 mmol) was dissolved in N,N-dimethylacetamide (30 mL), and N,N′-carbonyldiimidazole (1.78 g, 10.99 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Potassium 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetate (3.09 g, 14.99 mmol) and magnesium chloride (951 mg, 9.99 mmol) were added to the reaction mixture, and the mixture was then stirred at 50 °C for 12 hours. The reaction solution was diluted with ethyl acetate. The organic phase was washed with saturated ammonium chloride and sodium chloride aqueous solutions, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)ethane-1-one (2.5 g, 87%). MS m / z (ESI): 287.1 [M+H] + .

[0654] Step 2: Preparation of 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)ethane-1-imine

[0655] 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-indene-2-yl)ethane-1-one (2.1 g, 7.33 mmol) was dissolved in toluene (50 mL), and ammonium acetate (2.83 g, 36.6 mmol) was added with stirring at room temperature. The reaction mixture was stirred at 11 °C for 2 hours. After concentration, the solution was separated by silica gel column chromatography to obtain 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-indene-2-yl)ethane-1-imine (1.2 g, 57%). MS m / z (ESI): 287.1 [M+H] + .

[0656] Step 3: Preparation of ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1,4-dihydropyridine-3-carboxylic acid ester

[0657] 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)ethane-1-imine (720 mg, 2.52 mmol) and 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (747 mg, 2.52 mmol) were dissolved in ethanol (15 mL). Tert-butyl(S)-2-(3-ethoxy-3-carbonylpropionyl)pyrrolidine-1-carboxylic acid ester (720 mg, 2.52 mmol) was added with stirring at room temperature. The reaction mixture was stirred at 120 °C for 12 hours. Crude ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1,4-dihydropyridine-3-carboxylic acid ester (2 g, crude). MS m / z (ESI): 831.3 [M+H] + .

[0658] Step 4: Preparation of ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)nicotinic acid ester

[0659] Ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1,4-dihydropyridine-3-carboxylic acid ester (2 g, 2.41 mmol) was dissolved in ethanol (15 mL), and cerium ammonium nitrate (5.10 g, 9.63 mmol) was added with stirring at room temperature. The reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)nicotinic acid ester (1.9 g, crude product). MS m / z (ESI): 829.3 [M+H] + .

[0660] Step 4: Preparation of ethyl 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-2-((S)-pyrrolidine-2-yl)nicotinic acid ester

[0661] Ethyl 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-yl)-4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)nicotinic acid ester (1.9 g, 2.29 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added with stirring at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to give ethyl 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-2-((S)-pyrrolidine-2-yl)nicotinic acid ester (1.6 g, crude product). MS m / z (ESI): 729.3 [M+H] + .

[0662] Step 5: Preparation of 4-((6-((9aS)-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-carbonyl-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0663] Ethyl 4-(3-(4-cyano-3-fluorobenzyl)-2-carbonyl-2,3-dihydrobenzo[d]oxazol-6-yl)-5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-2-((S)-pyrrolidine-2-yl)nicotinic acid ester (1.6 g, 2.20 mmol) was dissolved in dichloromethane (16 mL), and TEA (8 mL) was added with stirring at room temperature. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the crude product of the target product. The crude product was separated by chiral column chromatography to obtain the title compound P1 (102.5 mg, 13.5%) and P2 (110 mg, 14.5%). P1 and P2 MS m / z (ESI): 683.2 [M+H] + .

[0664] P1: 1H NMR (400MHz, DMSO-d6) δ7.97 (t, J=7.4Hz, 1H), 7.62 (d, J=10.2Hz, 1H), 7.42 (d, J=8.1Hz , 1H), 7.35(s, 1H), 7.24-7.19(m, 2H), 7.09-7.01(m, 1H), 7.00-6.89(m, 2H), 5.20(s, 2H ), 4.85-4.80(m, 1H), 3.99-3.85(m, 1H), 3.57-3.50(m, 1H), 3.46-3.06(m, 5H), 2.36-2. 18(m, 3H), 2.14-2.08(m, 1H), 1.45-1.37(m, 1H), 1.01-0.81(m, 2H), 0.63-0.47(m, 2H).

[0665] P2: 1 H NMR (400MHz, DMSO-d6) δ7.97 (t, J=7.4Hz, 1H), 7.62 (d, J=10.2Hz, 1H), 7.42 (d, J=8.1Hz , 1H), 7.35(s, 1H), 7.24-7.19(m, 2H), 7.09-7.01(m, 1H), 7.00-6.89(m, 2H), 5.20(s, 2H ), 4.85-4.80(m, 1H), 3.99-3.85(m, 1H), 3.57-3.50(m, 1H), 3.46-3.06(m, 5H), 2.36-2. 18(m, 3H), 2.14-2.08(m, 1H), 1.45-1.37(m, 1H), 1.01-0.81(m, 2H), 0.63-0.47(m, 2H).

[0666] Example 4358 can also be prepared according to the following method.

[0667] Synthesis of (R)-4-((6-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-(2,2-difluorospiro[3.5]nonane-7-yl)-5-carbonyl-7,8,10,10a-tetrahydro-5H-pyrido[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazin-4-yl)-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)-2-fluorobenzonitrile

[0668] 2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-(2,2-difluorospiro[3.5]nonane-7-yl)ethane-1-one (400 mg, 1.29 mmol) was added to a solution of tert-butyl(S)-3-(3-ethoxy-3-carbonylpropionyl)morpholine-4-carboxylic acid ester (466.07 mg, 1.55 mmol), 2-fluoro-4-((6-formyl-2-carbonylbenzo[d]oxazol-3(2H)-yl)methyl)benzonitrile (381.84 mg, 1.29 mmol) and ammonium acetate (198.49 mg, 2.58 mmol) in acetic acid (10 mL). The reaction mixture was heated to 120 °C and reacted for 4 hours. The reaction mixture was concentrated, and ethanol (10 mL) and cerium ammonium nitrate (2.05 g, 3.87 mmol) were added. The mixture was stirred for another 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chiral column chromatography to give the target compound (150 mg, 16.1%). MS m / z (ESI): 723.2 [M+H] + .

[0669] 1 H NMR (400MHz, DMSO-d6) δ8.01-7.93 (m, 1H), 7.62 (d, J = 10.2, 1H), 7.42 (d, J = 8.1, 1H), 7.34 (s, 1H), 7.19 (d, J = 8.1Hz, 1H), 6.90 (d, J=8.1, 1H), 5.19 (s, 2H), 4.80 (dd, J=10.5, 4.6Hz, 1H), 4.47 (dd, J=10.9, 4.6Hz, 1H), 4.08-3.99 (m, 1H) , 3.97-3.89 (m, 1H), 3.33-3.20 (m, 2H), 3.16 (t, J=10.8Hz, 1H), 2.64-2.55 (m, 1H), 2.41 (t, J=13.1Hz, 2H), 2.30 (t, J =13.1Hz, 2H), 2.20-2.05(m, 1H), 1.74-1.67(m, 6H), 1.49-1.35(m, 2H), 1.04-0.94(d, J=8.3, 2H), 0.63-0.55(m, 2H).

[0670] Biological test evaluation

[0671] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0672] I. Determination of the ability of the compounds of this invention to stimulate cAMP production in human amylin AMY3 receptor-stabilized cell lines

[0673] 1. Experimental Objective: The purpose of this test case is to assess the ability of the compound to activate the human amylin-AMY3 receptor on the cell surface. Activation of this receptor stimulates the production of cAMP in ECs. 50 The activation ability of the compound on the human AMY3 receptor was characterized.

[0674] In this experiment, the compound and cells were co-incubated for 30 minutes.

[0675] 2. Experimental reagents and instruments

[0676] 2.1 Experimental Apparatus:

[0677] Microplate reader (PerkinElmer EnVision)

[0678] Pipettes (Eppendorf & Rainin)

[0679] 2.2 Experimental Reagents

[0680] Ham's F-12K (Kaighn's) medium was purchased from Gibco, catalog number 21127022.

[0681] Casein was purchased from Sigma, product number C3400.

[0682] The 384-well plate was purchased from Sigma, part number CLS4514.

[0683] IBMX purchased from Sigma, part number I7018

[0684] The HTRF cAMP Gs Detection Kit was purchased from revvity.

[0685] 3. Experimental methods:

[0686] The frozen human AMY3 receptor stable cell line was removed from the liquid nitrogen tank and rapidly thawed in a 37°C water bath. The cells were resuspended in F-12K medium, centrifuged, washed once, and resuspended in experimental buffer (F-12K medium containing 0.1% casein). After centrifugation, the cell density was adjusted with experimental buffer, and 10 μL of the cells were seeded into each well of a 384-well plate. Then, 10 nL of IBMX working solution (prepared in buffer to a final concentration of 0.5 mM) and serially diluted compound samples (starting at 1000, 3-fold dilution) were added to each well. Criterion curves were prepared by diluting cAMP standard samples at different concentrations and added to each blank well (10 μL per well). The plates were centrifuged at 1000 rpm for 1 minute and incubated at 37°C for 0.5 hours. Detection was performed using the HTRF cAMP Gs Detection Kit. cAMP-d2 and Anti-cAMP-Eu3+-Cryptate were diluted 20-fold with cAMP Lysis & Detection Buffer and mixed thoroughly. Add 5 μL of diluted cAMP-d2 solution to each well, centrifuge at 1000 rpm for 1 minute, vortex for 30 seconds to mix, then add 5 μL of diluted Anti-cAMP-Eu3+-Cryptate solution, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature in the dark for 1 hour. Fluorescence signals are read using a PerkinElmer EnVision microplate reader with excitation wavelength of 320 nm and emission wavelengths of 615 nm and 665 nm.

[0687] 4. Experimental data processing methods:

[0688] The signal ratio (665nm / 615nm) was calculated and substituted into the experimental standard curve in GraphPad Prism 10 to obtain the cAMP concentration. This cAMP concentration was then nonlinearly fitted with a four-parameter equation against the sample concentration to obtain the EC50 concentration. 50 value.

[0689] 5. Experimental Conclusion:

[0690] Based on the above methods, in the experiment where the compound of this invention stimulated the hAMY3R stable cell line to produce cAMP for 0.5 hours, the EC50 of the generated cAMP was obtained. 50 value.

[0691] The compounds of this invention have ECG effects on cAMP 50 Less than about 100 nM, preferably less than about 10 nM, more preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM or even less than about 0.01 nM among the compounds listed in this invention. Test results for some compounds are as follows:

[0692] Conclusion: The compounds of this invention have a good ability to activate human amylin AMY3 receptors on the cell surface.

[0693] II. Determination of the ability of the compounds of this invention to stimulate cAMP production in human calcitonin receptor hCTR stable cell lines

[0694] 1. Experimental Objective: The purpose of this test case is to test the ability of the compound to activate the human calcitonin receptor on the cell surface. Activation stimulates ECMO (electrode cytokines) to produce cAMP. 50 The ability of the compound to activate human calcitonin receptors was characterized.

[0695] In this experiment, the compound and cells were co-incubated for 30 minutes.

[0696] 2. Experimental reagents and instruments

[0697] 2.1 Experimental Apparatus:

[0698] Microplate reader (PerkinElmer EnVision)

[0699] Pipettes (Eppendorf & Rainin)

[0700] 2.2 Experimental Reagents

[0701] Ham's F-12K (Kaighn's) medium was purchased from Gibco, catalog number 21127022.

[0702] Casein was purchased from Sigma, product number C3400.

[0703] The 384-well plate was purchased from Sigma, part number CLS4514.

[0704] IBMX purchased from Sigma, part number I7018

[0705] The HTRF cAMP Gs Detection Kit was purchased from revvity.

[0706] 3. Experimental methods:

[0707] The frozen human calcitonin receptor stable cell line was removed from the liquid nitrogen tank and rapidly thawed in a 37°C water bath. The cells were resuspended in F-12K medium, centrifuged, washed once, and resuspended in experimental buffer (F-12K medium containing 0.1% casein). After centrifugation, the cell density was adjusted with experimental buffer, and the cells were seeded at 10 μL per well in a 384-well plate. Then, 10 nL of IBMX working solution (prepared in buffer to a final concentration of 0.5 mM) and serially diluted compound samples (starting at 1000, 3-fold dilution) were added to each well. Criterion curves were prepared by diluting cAMP standard samples at different concentrations and added to blank wells (10 μL per well). The plates were centrifuged at 1000 rpm for 1 minute and incubated at 37°C for 0.5 hours. Detection was performed using the HTRF cAMP Gs Detection Kit. cAMP-d2 and Anti-cAMP-Eu3+-Cryptate were diluted 20-fold with cAMP Lysis & Detection Buffer and mixed thoroughly. Add 5 μL of diluted cAMP-d2 solution to each well, centrifuge at 1000 rpm for 1 minute, vortex for 30 seconds to mix, then add 5 μL of diluted Anti-cAMP-Eu3+-Cryptate solution, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature in the dark for 1 hour. Fluorescence signals are read using a PerkinElmer EnVision microplate reader with excitation wavelength of 320 nm and emission wavelengths of 615 nm and 665 nm.

[0708] 4. Experimental data processing methods:

[0709] The signal ratio (665nm / 615nm) was calculated and substituted into the experimental standard curve in GraphPad Prism 10 to obtain the cAMP concentration. This cAMP concentration was then nonlinearly fitted with a four-parameter equation against the sample concentration to obtain the EC50 concentration. 50 value.

[0710] 5. Experimental Conclusion:

[0711] Based on the above scheme, in the experiment where the compound of the present invention stimulated human calcitonin receptor hCTR stable cell line to produce cAMP for 30 minutes, the EC50 of the generated cAMP was obtained. 50 value.

[0712] The compounds of this invention are effective for ECs that generate cAMP. 50 Less than about 100 nM, preferably less than about 10 nM, more preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM or even less than about 0.01 nM among the compounds listed in this invention. Test results for some compounds are as follows:

[0713] Conclusion: The compounds of this invention have a good ability to activate human calcitonin receptors on the cell surface.

Claims

1. A compound of general formula (I′), (I′′) or (I″′), its nitrogen oxides or a pharmaceutically acceptable salt thereof: in, M1, M2, and M3 are each independently selected from O, C=O, C=S, N, S, and CR. a R c CR a or NR b ; Or M1 does not exist; M4 and M5 are each independently selected from N or CR. a ; M 11 and M 12 each independently is selected from C, N or CR d ; Ring A′ is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Ring A″ is selected from C 5-14 Cycloalkyl, 5-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; Ring C is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; L1, L2, L3, and L4 are each independently selected from the bond, -(CH2). n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2 -、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NR ee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2 -、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Alynyl group; wherein the -(CH2) group is... n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2 -、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NR ee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2 -、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide and C 1-6 Alynyl group, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, COOH, COOCH3, COOCHCH3, CONH2, CONHCH3, CON(CH3)2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Alternatively, L1, L2, L3, and L4 can each be independently selected from -(CH2). n1 S(=NH)O(CH2) n2 -、-(CH2) n1 S(=NH)ONR ee (CH2) n2 -、C 3-12 cycloalkylene L L 3-12-membered subheterocyclic L L C 6-14 Aspartic L L 5-14 methyl methacrylate L L C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene, 5-14 methylarylene or Optional further substitution with hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; L L Each is independently selected from -(CH2) n1 -(CH2) n1 O(CH2) n2 -、-(CH2) n1 S(CH2) n2 -、-(CH2) n1 C=O(CH2) n2 -、-(CH2) n1 C = S(CH2) n2 -、-(CH2) n1 C = OO(CH2) n2 -、-(CH2) n1 NR dd (CH2) n2 -、-(CH2) n1 CONR dd (CH2) n2 -、-(CH2) n1 NR dd CONR ee (CH2) n2 -、-(CH2) n1 NR dd C(=NH)NR ee (CH2) n2 -、-(CH2) n1 POR dd (CH2) n2 -、-O(CH2) n1 POR dd (CH2) n2 -、-(CH2) n1 SO(CH2) n2 -、-(CH2) n1 SO2(CH2) n2 -、-(CH2) n1 SONR dd (CH2) n2 -、-(CH2) n1 SO2NR dd (CH2) n2 -、C 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group; Cy9is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; R a R b R c R d R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n O(CH2) n′ R bb -O(CH2) n R aa -(CH2) n S(CH2) n′ R bb -(CH2) n C(O)(CH2) n′ R cc -(CH2) n C(O)O(CH2) n′ R cc -(CH2) n S(O) m (CH2) n′ R cc -(CH2) n NR aa (CH2) n′ R bb -(CH2) n C(O)NR aa (CH2) n′ R bb -(CH2) n NR bb C(O)(CH2) n′ R cc -(CH2) n NR cc C(O)NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(O)O(CH2) n′ R bb 、-(CH2) n P(O)R aa (CH2) n′ R bb 、-O(CH2) n P(O)R aa (CH2) n′ R bb 、-(CH2) n C(=NR ff )(CH2) n′ R bb 、-(CH2) n S(=NR ff )(O) m (CH2) n′ R bb 、-(CH2) n C(=NR ff )NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(=NR ff )NR aa (CH2) n′ R bb 、-(CH2) n NR bb S(O) m (CH2) n′ R cc 、-(CH2) n S(=O)R cc =N(CH2) n′ R bb 、-OC(R aa R cc ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH≡CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further divided by 1-6 R groups n replace; Preferably, R a R b R c R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n O(CH2) n′ R bb -O(CH2) n R aa -(CH2) n S(CH2) n′ R bb -(CH2) n C(O)(CH2) n′ R cc -(CH2) n C(O)O(CH2) n′ R cc -(CH2) n S(O) m (CH2) n′ R cc -(CH2) n NR aa (CH2) n′ R bb -(CH2) n C(O)NR aa (CH2) n′ R bb -(CH2) n NR bb C(O)(CH2) n′ R cc -(CH2) n NR cc C(O)NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(O)O(CH2) n′ R bb 、-(CH2) n P(O)R aa (CH2) n′ R bb 、-O(CH2) n P(O)R aa (CH2) n′ R bb 、-(CH2) n C(=NR ff )(CH2) n′ R bb 、-(CH2) n C(=NR ff )NR aa (CH2) n′ R bb 、-(CH2) n NR cc C(=NR ff )NR aa (CH2) n′ R bb 、-(CH2) n NR bb S(O) m (CH2) n′ R cc 、-(CH2) n S(=O)R cc =N(CH2) n′ R bb 、-OC(R aa R cc ) n (CH2) m R aa 、-NR bb (CH2) n R aa 、-CH=CH(CH2) n R aa 、-CH≡CH(CH2) n R aa 、-CH=CH(CH2) n NR aa R bb 、-CH=CH(CH2) n NR bb C(O)R cc 、-CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally further divided by 1-6 R groups n replace; Or R a R b R c R 1 R 2 R 3 R 4 With R 5 Any two links form a substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 5-12 Cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m0 replace; Or R a R b Or R c and R 1 The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 5-12 Cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m1 replace; Or R a R b Or R c and R 4 The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, preferably substituted or unsubstituted C groups. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. m4 replace; R m0 R m1 and R m4 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2.6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n -、-(CH2) n R aa -(CH2) n OR bb -O(CH2) n R aa -(CH2) n SR bb -(CH2) n C(O)R cc -(CH2) n C(O)OR cc -(CH2) n S(O) m R cc -(CH2) n NR aa R bb -(CH2) n C(O)NR aa R bb -(CH2) n NR bb C(O)R cc -(CH2) n NR cc C(O)NR aa R bb -(CH2) n P(O)R aa R bb -O(CH2) n P(O)R aa R bb -(CH2) n NR cc C(=NH)NR aa R bb -(CH2) n NR bb S(O) m R cc -(CH2) n S(=O)R cc =NR bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =NR bb =N-OR bb or = CR aa R cc The C mentioned therein 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C1-6 haloalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C1-6 haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 one or more substituents selected from the group consisting of halogen, -CN, -N3, -N02, -NHOH, -NHORe, -OH, -ORe, -OCN, -SRe, -SCN, -SH, -NH Or any two R m0 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c2 replace; or any two R m1 substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-14 aryl or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substitution means being substituted with 1-6 R c3 substituted; or any two R m4 to form a substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-14 aryl or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substitution means being substituted with 1-6 R c4 substituted; R n R aa R bb R cc R dd R ee R ff R H and R H1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n3 -、-(CH2) n3 R gg -(CH2) n3 O(CH2) n4 R hh -O(CH2) n3 R gg -(CH2) n3 S(CH2) n4 R hh -(CH2) n3 C(O)(CH2) n4 R ii -(CH2) n3 C(O)O(CH2) n4 R ii -(CH2) n3 S(O) m (CH2) n4 R ii -(CH2) n3 NR gg (CH2) n4 R hh -(CH2) n3 C(O)NR gg (CH2) n4 R hh -(CH2) n3 NR hh C(O)(CH2) n4 R ii -(CH2) n3 NR ii C(O)NR gg (CH2) n4 R hh 、-(CH2) n3 NR ii C(O)O(CH2) n4 R hh 、-(CH2) n3 P(O)R gg (CH2) n4 R hh 、-O(CH2) n3 P(O)R gg (CH2) n4 R hh 、-(CH2) n3 C(=NR jj )(CH2) n4 R hh 、-(CH2) n3 S(=NR jj )(O) m (CH2) n4 R hh 、-(CH2) n3 C(=NR jj )NR gg (CH2) n4 R hh 、-(CH2) n3 NR ii C(=NR jj )NR gg (CH2) n4 R hh 、-(CH2) n3 NR hh S(O) m (CH2) n4 R ii 、-(CH2) n3 S(=O)R ii =N(CH2) n4 R hh 、-OC(R hh R ii ) n3 (CH2) n4 R gg 、-NR hh (CH2) n3 R gg 、-CH=CH(CH2) n3 R gg 、-CH≡CH(CH2) n3 R gg 、-CH=CH(CH2) n3 NR gg R hh -CH=CH(CH2) n3 NR hh C(O)R ii -CH=CH(CH2) n3 NR ii C(O)NR gg R hh =N-OR hh or = CR gg R ii The C mentioned therein 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further divided by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =N-OR kk =CR ll R mm C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Haloalkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or R aa and R bb The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. p1 replace; The H in the above CH2 can be optionally replaced by R H Replace; or any two Rs H The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. H1 Replacement; preferably, R n R aa R bb R cc R dd R ee R ff R H and R H1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 6-alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 one or more substituents selected from the group consisting of halogen, -CN, -N3, -N02, -NHOH, -NHORe, -OH, -ORe, -OCN, -SRe, -SCN, -SH, -NH R q-1、 R q-2、 R c2 R c3 R c4、 R p1 R gg、 R hh R ii R jj R kk R ll and R mm Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3, -SF5, =CF2, =CHF or =CH2, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, =CH2, or other C groups. 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2- 6-Alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, R p1 R gg R hh R ii R jj R kk R ll and R mm Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; or R gg and R ii together with the atom to which they are attached form a substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-14 aryl and substituted or unsubstituted 5-14 membered heteroaryl, wherein the substitution refers to substitution with 1-6 R c1 substituents; or R ll and R mm together with the atom to which they are attached form a substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-14 aryl and substituted or unsubstituted 5-14 membered heteroaryl, wherein the substitution refers to substitution with 1-6 R c1 substituents; R c1 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3, -SF5, =CF2 or =CHF, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; q3, x, y, w, n, n′, n1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6; m is 1 or 2.

2. The compound of claim 1, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in equation (II): in: R a-1 is defined as R a ; L1, L2, L3, L4, R a , R 1 , R 2 , R 3 , R 4 , x, y, ring B and ring C are as defined in claim 1.

3. The compound as described in claim 1 or 2, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, characterized in that, Further, as shown in equation (II-3): in: each ring D is independently selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; Cy5 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R c5 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, =CF2, =CHF, =CH2, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted; L6 is selected from a bond, -(CH2) n3 -, -(CH2) n3 O(CH2) n4 -, -(CH2) n3 S(CH2) n4 -, -(CH2) n3 C(O)(CH2) n4 -, -(CH2) n3 C(O)O(CH2) n4 -, -(CH2) n3 S(O) m (CH2) n4 -, -(CH2) n3 NR gg (CH2) n4 -, -(CH2) n3 C(O)NR gg (CH2) n4 -, -(CH2) n3 NR ii C(O)NR gg (CH2) n4 -, -(CH2) n3 NR ii C(O)O(CH2) n4 -, -(CH2) n3 P(O)R gg (CH2) n4 -, -O(CH2) n3 P(O)R gg (CH2) n4 -, -(CH2) n3 C(=NR jj )(CH2) n4 -, -(CH2) n3 S(=NR jj )(O) m (CH2) n4 -, -(CH2) n3 C(=NR jj )NR gg (CH2) n4 -, -(CH2) n3 NR ii C(=NR jj )NR gg (CH2) n4 -, -(CH2) n3 NR hh S(O) m (CH2) n4 -, -(CH2) n3 S(=O)R ii = N(CH2) n4 -, -O(CR hh R ii ) n3 (CH2) n4 -, -NR hh (CH2) n3 -, -CH=CH(CH2) n3 -, -CH≡CH(CH2) n3 -, -CH=CH(CH2) n3 NR gg -, -CH=CH(CH2) n3 NR hh C(O)-, -CH=CH(CH2) n3 NR ii C(O)NR gg -, =N - O - or =CR gg -; R a-1 The definition is the same as R a ; q1 is independently selected from 0, 1, 2, 3, 4, 5, or 6; q2 is independently selected from 0, 1, 2, 3, 4, or 5; L1, L2, L3, L4, R a R gg、 R hh R jj R ii m, n3, n4, R n R 2 R 3 R 4 The definitions of x, y, ring B, and ring C are as described in claim 1.

4. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-3, characterized in that, Further details are shown below: in: Ring E is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; L5 molecules are independently selected from the bond and -(CH2). n -、-(CH2) n O(CH2) n′ -、-(CH2) n S(CH2) n′ -、-(CH2) n C(O)-、-(CH2) n C(O)O-、-(CH2) n S(O) m -、-(CH2) n NR bb -、-(CH2) n C(O)NR bb -、-(CH2) n NR bb C(O)-、-(CH2) n NR cc C(O)NR bb -、-(CH2) n P(O)R aa -、-O(CH2) n P(O)R aa -、-(CH2) n NR cc C(=NH)NR bb -、-(CH2) n NR bb S(O) m -、-(CH2) n S(=O)R cc =N-、-OC(R) aa R cc ) n (CH2) m -、-NR bb (CH2) n -, -CH=CH(CH2) n NR bb -, -CH=CH(CH2) n NR bb C(O), -CH=CH(CH2) n NR cc C(O)NR bb -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 Arene-ethylene or 5-14 membered heteroarylene-ethylene; wherein, the -(CH2) n -、-(CH2) n O-, -(CH2) n S、-(CH2) n C(O)-、-(CH2) n C(O)O-、-(CH2) n S(O) m -、-(CH2) n NR bb -、-(CH2) n C(O)NR bb -、-(CH2) n NR bb C(O)-、-(CH2)11NR cc C(O)NR bb -、-(CH2) n P(O)R aa -、-O(CH2) n P(O)R aa -、-(CH2) n NR cc C(=NH)NR bb -、-(CH2) n NR bb S(O) m -、-(CH2) n S(=O)R cc =N-、-OC(R) aa R cc ) n (CH2) m -、-NR bb (CH2) n -, -CH=CH(CH2) n NR bb -, -CH=CH(CH2) n NR bb C(O), -CH=CH(CH2) n NR cc C(O)NR bb -、C 1-6 Alkylene, C 1-6 imidene group, C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 The arylene and 5-14 heteroarylene groups may be further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Alternatively, each L5 may be independently selected from -(CH2). n C 2-6 alkenyl group, -(CH2) n C 2-6 Alynyl group, -(CH2) n C 3-12 Cycloalkylene, -(CH2) n 3-12 membered heterocyclic group, -(CH2) n C 6-14 aryl, -(CH2) n 5-14 heteroaryl groups, -O(CH2) n C 2-6 Alkenyl group, -O(CH2) n C 2-6 Alynyl group, -O(CH2) n C 3-12 Cycloalkylene, -O(CH2) n 3-12 membered heterocyclic group, -O(CH2) n C 6-14 aryl, -O(CH2) n 5-14 heteroaryl groups, -NH(CH2) n C 2-6 Alkenyl group, -NH(CH2) n C 2-6 Alynyl group, -NH(CH2) n C 3- 12 Cycloalkylene, -NH(CH2) n 3-12 membered heterocyclic group, -NH(CH2) n C 6-14 aryl or -NH(CH2) n 5-14 heteroaryl groups, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; R a-2 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1- 6-alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -SF3, -SF5, -(CH2) n3 R gg -O(CH2) n4 R hh -S(CH2) n4 R hh -C(O)(CH2) n4 R ii -C(O)O(CH2) n4 R ii -S(O) m (CH2) n4 R ii -NR gg (CH2) n4 R hh -C(O)NR gg (CH2) n4 R hh -NR hh C(O)(CH2) n4 R ii -NR ii C(O)NR gg (CH2) n4 R hh -NR ii C(O)O(CH2) n4 R hh -P(O)R gg (CH2) n4 R hh -O(CH2) n3 P(O)R gg R hh -C(=NR) jj (CH2) n4 R hh -S(=NR) jj (O) m (CH2) n4 R hh -C(=NR) jj )NR gg (CH2) n4 R hh -NR cc C(=NR jj )NR gg (CH2) n4 R hh -NR hh S(O) m (CH2) n4 R ii -(CH2) n3 S(=O)R ii =N(CH2) n4 R hh -CH=CH(CH2) n3 NR gg R hh -CH=CH(CH2) n3 NR hh C(O)R ii -CH=CH(CH2) n3 NR ii C(O)NR gg R hh =N-OR hh or = CR gg R ii ; wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, R a-2 Each is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Each ring D is independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; u is independently selected from 0, 1, 2, 3, 4, 5 or 6; z is independently selected from 0, 1, 2, 3, 4, 5 or 6; R aa R bb R cc R gg R hh R ii R jj ,m,n,n3,n4,L1,L2,L3,L4,R n R 2 R 3 The definitions of x, y, ring B, and ring C are as described in claim 1; Preferably, the compound has the structure shown below. Among them, ring Q is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; v can be 0, 1, 2, 3, 4, 5, or 6.

5. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, characterized in that, Ring B is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl or Preferably, ring B is selected from phenyl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, or... Preferably, ring B is selected from 5-6 member heteroaryl, 8-10 member heteroaryl, or... Among them, ring F is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclic, C 6- 10 Aryl or 5-10 quinone heteroaryl; C is preferred 6-10 aryl or 5-10 heteroaryl, with ring G selected from C 5-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl or 5-10 quinone heteroaryl; C is preferred 5-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably, ring F is connected to L2 and ring G is connected to L3; Preferably, ring B is selected from thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridonel, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzobenzenethio, benzothiophenyl, benzotriazolyl, imidazopyridyl, imidazothiophenyl Azolyl, indazinyl, indoleyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindoleyl, isoquinolinyl, naphridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purine, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridinyl, acridineyl, benzoindoleyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, ketoxanyl, [The last part is incomplete and likely refers to a different group of groups, so it's left as is.] Preferably, ring B is selected from thienyl, Preferred Among them, M j M k M a M b M c M d M e M and M0 are each independently selected from C, N, or CH; M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; X4 independently selected from O, S, NR 2-1 or CR 2-2 R 2- 3 ;R 2-1 R 2-2 and R 2-3 The definition is the same as R 2 k1 and k2 are each independently 0, 1, 2, 3, 4, 5, or 6; k3 is 0, 1, or 2; M 31 and M 32 Each group is independently selected from CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; preferably, ring B is selected from thiophene, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl, Preferably, ring B is selected from thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl, and others. M6 is selected from CH or N; ring B1 and ring B2 are each independently selected from substituted or unsubstituted C. 4-12 Cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl or substituted or unsubstituted 5-10 heteroaryl groups; wherein the substitution refers to being replaced by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2- 6-alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substitutions are made from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, ring B is selected from phenyl, Preferably, ring B is selected from 6. The compound, its nitrogen oxide compound, or its pharmaceutically acceptable salt as claimed in any one of claims 1-5, characterized in that, Further details are shown below. in: M 22 Selected from N or CH; M j M k M a M b M c M d M e M0 and M0 are each independently selected from C, N, or CH; X5 is independently selected from O, S, and NR. L Among them, R L Selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted; X6 and X7 are each independently selected from O, S, N, NH, CH2 or CH; X8 are each independently selected from bonds, O, S, NH or CH2; X9 is independently selected from N or CH; X 10 Each is independently selected from O, S, NH or CH2; It can be a single bond or a double bond; Cy8 is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R m0-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Or any two R m0-1 Links form substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, aryl or substituted or unsubstituted, wherein the substitution refers to being substituted by 1-6 R groups. c2 replace; o can be 0, 1, 2, 3, 4, 5, or 6; v1 is 0, 1, 2, 3, 4, 5, or 6; t2, t3, t4, t5, t6 and t7 are each independently 0, 1, 2 or 3.

7. The compound, its nitrogen oxide compound, or its pharmaceutically acceptable salt as claimed in any one of claims 1-6, characterized in that, Further details are shown below. in: Cy1 is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups; Cy6 is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic groups; M a M b M c M d M e M0 is selected from C, N, or CH; M7 is selected from C, N, or CH; M8 is selected from C, N, or CH; M 23 Selected from N or CR5; M f Independently selected from CH, CH2, CH2CH2, NH, O, S, CO, CH2O, CH2S, CH2NH; M g Independently selected from N or CR n1 ; M h Independently selected from N or CR n2 ; R H-1 and R H-2 The definition is the same as R H ; X9 is independently selected from N or CH; X 10 Each is independently selected from O, S, NH or CH2; X 11 Independently selected from N or CH; L 5-1 and L 5-3 Each is independently selected from bonds, O, S, NH, and C. 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group, C 3- 12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Cy10 is selected from C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene; R L-1 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; t1 is 0, 1, 2, 3 or 4; t2, t3, t4 and t5 are each independently 0, 1, 2 or 3; X4 is independently selected from O, S, and NR. 2-1 or CR 2-2 R 2-3 ;R 2-1 R 2-2 and R 2-3 The definition is the same as R 2 ; X5 is independently selected from O, S, and NR. L Among them, R L Selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 5-14 heteroaryl groups, either substituted or unsubstituted; Ring Q is selected from C 4-14 Cycloalkyl, 4-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl; Ring I is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups; R m4-1 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl, 5-14 heteroaryl, -SF3 or -SF5, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; y1 is 0, 1, 2, 3, 4, 5, or 6; It can be a single bond or a double bond; X1, X2, and X3 are each independently selected from CR m01 R m02 O, S, NR m03 CR m01 ,N,=N-,CO,SO,SO2 or POR m03 ; M 24 Selected from C, N, CH or CO; v is 0, 1, 2, 3, 4, 5, or 6; t can be 0, 1, 2, 3, 4, 5, or 6; R n1 and R n2 The definition is the same as R n ; R m01 R m02 and R m03 The definition is the same as R m0 ;R m4 R 2 R H R n and R m0 The definition is as described in claim 1.

8. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-7, characterized in that, Ring C is selected from C 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, 5-6-membered heterocyclic 5-6-membered heteroaryl Preferably, ring C is selected from C 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, 5-6-membered heterocyclic 5-6-membered heteroaryl Among them, Cy2, Cy3, and Cy4 are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; Preferably, ring C is selected from C 6-10 Aryl, 5-10 heteroaryl, C 5-6 Cycloalkylphenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic phenyl, or 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably phenyl, More preferably phenyl, More preferably, Selected from 9. The compound, its nitrogen oxide compound, or its pharmaceutically acceptable salt as described in any one of claims 1-8, characterized in that, R 1 Selected from the following group of substituent or unsubstituted groups: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 quinone heteroaryl, C 3-8 cycloalkyl, 4-8 membered heterocyclic, 5-6 membered heteroaryl, and C 4-6 Cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic, =N-OC 1-6 Alkyl or =CR aa R cc Preferably, R 1 Selected from the following group of substituent or unsubstituted groups: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl benzo[C] 4-6 Cycloalkyl, 5-6-membered heteroaryl and 4-6-membered heterocyclic, =N-OC 1-6 Alkyl or =CR aa R cc ; Or R 1 Selected from C(O)NR aa NR aa OR aa ; Or R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; preferably, R 1 Selected from hydrogen, methyl, ethyl, isopropyl, CF3, CH2F, CHF2, methoxy, ethoxy, OCF3, OCH2F, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Preferably, R 1 Selected from the following group (substituted or unsubstituted): thiophene, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl. methoxy Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, aziridine, oxacyclopentyl, piperazinyl, piperidinyl, oxacyclohexyl, vinyl, ethynyl Preferably, R 1 Selected from the following group, whether substituted or unsubstituted: methoxy, NHCH3, Wherein, the substitution refers to being replaced by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more groups selected from aryl, 5-14 heteroaryl, -SF3, or -SF5 are substituted, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Furthermore, R 1 Selected from More More preferably, R 1 Selected from And / or, L1 is selected from bond, CH2, CH2CH2, NH, O, S, CO, NHCO, CONH, NHCONH, NCH3, N(CH3)CO, NHCOO, N(CH3)COO, N(CH3)CONH or N(CH3)CON(CH3); preferably, L1 is selected from bond, CH2, CH2CH2, NH, O, S, CO, NHCO, CONH, NHCONH; And / or, L2 is selected from bond or O; preferably, L2 is selected from bond; And / or, L3 is selected from bond, O, S, C=O, C=S, NR dd , C=O(CH2), C=S(CH2), (CH2)NR dd C=ONR dd (CH2), C 3-6 Cycloalkyl C=O, 4-6 membered heterocyclic C=O, C 1-3 Alkylene, C 2-4 Alkenyl, 5-6 membered heterocyclic, 5-6 membered heteroaryl, 5-6 membered heterocyclic CH2, 5-6 membered heteroaryl CH2, 5-6 membered heterocyclic CH2CH2, 5-6 membered heteroaryl CH2CH2, 5-6 membered heterocyclic O, 5-6 membered heteroaryl O, 5-6 membered heterocyclic NH or 5-6 membered heteroaryl NH; Or L3 is selected from Preferably, Cy9 is selected from C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; The H in the above CH2 can be optionally replaced by R H Instead, the C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 1-3 Alkylene, C 2-4 The alkenyl, 5-6 membered heterocyclic, and 5-6 membered heteroaryl groups may be further substituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or unsubstituted C groups. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1- 6-Haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, L3 is selected from the following: bond, CONH, CH2, CD2, CH2CH2, CONHCH2, NH, NHCH2, And / or, L4 is selected from bond, O, CH2, P(=O)R dd SO2, CO, CONH, NHCO, NHCOO, S(=NH)O, NH, NHCONH, SO2NH or S(=NH)ONH, preferably, L4 is selected from bonds, P(=O)R dd SO2, CO, CONH, NHCO, NHCOO, S(=NH)O, preferably, L4 is selected from bond, CO, CONH, NHCO, NHCOO, S(=NH)O, preferably, L4 is selected from bond, CO, CONH, NHCO or NHCOO; And / or, R 4 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -SF3, -SF5, R aa -O(CH2) n R aa -S(CH2) n′ R bb -C(O)(CH2) n′ R cc -C(O)O(CH2) n′ R cc -S(O) m (CH2) n′ R cc -NR aa (CH2) n′ R bb -C(O)NR aa (CH2) n′ R bb -NR bb C(O)(CH2) n′ R cc -NR cc C(O)NR aa (CH2) n′ R bb -NR cc C(O)O(CH2) n′ R bb -P(O)R aa (CH2) n′ R bb -O(CH2) n P(O)R aa R bb -C(=NR) ff )R bb -C(=NR) ff )NR aa R bb -NR cc C(=NR ff )NR aa R bb -NR bb S(O) m (CH2) n′ R cc -S(=O)R cc =N(CH2) n′ R bb -OC(R) aa R cc ) n (CH2) m R aa -NR bb (CH2) n R aa -CH=CH(CH2) n R aa -CH≡CH(CH2) n R aa -CH=CH(CH2) n NR aa R bb -CH=CH(CH2) n NR bb C(O)R cc -CH=CH(CH2) n NR bb C(O)NR aa R bb =N-OR bb or = CR aa R cc The C mentioned therein 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally further divided by 1-6 R groups. n replace; More preferably, -L4-R 4 Selected from CONH2, NH2, And / or, L5 is selected from bonds S, O, NH, CO, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, (CH2)C 3-12 Cycloalkylene, (CH2)3-12-membered heterocyclic group, (CH2)2C 3-12 Cycloalkylene, (CH2)23-12-membered heterocyclic group, -OC 3-12 Cycloalkylene, -O-3-12-membered heterocyclic alkylene, -O-(CH2)C 3-12 Cycloalkylene, -O-(CH2)3-12-membered heterocyclic alkylene, -O-(CH2)2C 3-12 Cycloalkylene, -O-(CH2)23-12-membered heterocyclic alkylene, -NH-C 3-12 Cycloalkylene, -NH-3-12-membered heterocyclic alkylene, -NH-(CH2)C 3-12 Cycloalkylene, -NH-(CH2)3-12-membered heterocyclic alkylene, -NH-(CH2)2C 3-12 Cycloalkylene, -NH-(CH2)23-12-membered heterocyclic alkylene, phenyl, 5-6-membered heteroaryl or 8-10-membered heteroaryl; wherein, the C 1-3 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-12 Cycloalkylene, 3-12-membered heterocyclic alkylene, phenyl, 5-6-membered heteroaryl, and 8-10-membered heteroaryl, optionally further modified by hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 One or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5; preferably L5 is selected from bond, S, O, NH, CO, C. 1-3 Alkylene, C 3-8 Cycloalkylene, 3-8-membered heterocyclic alkylene, 5-6-membered heteroaryl, or 8-10-membered heteroaryl; wherein, the C 1-3 Alkylene, C 3-8 Cycloalkylene, 3-8-membered heterocyclic, 5-6-membered heteroaryl, and 8-10-membered heteroaryl groups may be further modified by hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Preferably, L5 is selected from the following groups: -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CF2)(CF2)-, -(CF2)(CH2)-, -(CHF)(CHF)-, -(CD2)-, -(CF2)-, -(CHF)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferably, L5 is selected from -(CH2)-, S, O, -(CH2)(CH2)-, Alternatively, L5 can be selected from the following: -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-. Preferred Where L 5-1 and L 5-3 Each is independently selected from bonds, O, S, NH, and C. 1-6 Alkylene, C 1-6 imide or C 1-6 Ethyne group, C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 heteroarylene, optionally further modified by hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1- 6-Hydroalkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1- 6-Haloalkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; Cy10 is selected from C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene, C 6-14 arylene or 5-14 quinone heteroarylene; R L-1 Each is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; t1 is 0, 1, 2, 3 or 4; Preferably, the Cy10 ring is selected from C 3-12 Cycloalkylene, 3-12 membered heterocyclic alkylene; preferably C 3-8 Cycloalkylene, 4-8 membered heterocyclic alkylene; more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Preferably, L 5-1 and L 5-3 Each is independently selected from the following: bond, -(CH2)-, S, O, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CD2)(CD2)-, -(CD2)(CH2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CF2)(CF2)-, -(CF2)(CH2)-, -(CHF)(CHF)-, -(CD2)-, -(CF2)-, -(CHF)-; And / or, ring E is selected from phenyl, 5-6-membered heteroaryl, 8-10-membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 5-6 Cycloalkylphenyl, 5-6 membered heterocyclic phenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably, ring E is selected from phenyl, 5-6-membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-6 Cycloalkylphenyl, 5-6 membered heterocyclic phenyl, C 5-6 Cycloalkyl 5-6-membered heteroaryl, 5-6-membered heterocyclic 5-6-membered heteroaryl; preferably, ring E is selected from phenyl, cyclohexyl, piperidinyl, piperazine, etc. Preferably, ring E is selected from phenyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, pyrazinyl, pyridinyl, pyridoneyl, pyrimidinoneyl, etc. And / or, ring D is selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl fused C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocyclic; preferably, ring D is selected from 5-6-membered heteroaryl, 5-6-membered heterocyclic, and 5-6-membered heteroaryl-C. 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclic, preferably thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridoneyl, Or ring D is selected from And / or, R a R b R c R a-2、 R m4 R 2 R 3 Each group is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, SC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C6- 10 aryl, 5-10 heteroaryl, -SF3 or -SF5, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, SC 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally further divided by 1-6 R groups. n replace; Preferably R a Selected from R aa -(CH2)R aa -(CH2)2R aa -OR aa -(CH2)NR aa R bb -(CH2)NR aa R bb (CH2)NR bb C(O)R cc The H in the above CH2 can be optionally replaced by R. H Replace; or any two Rs H The atoms bonded to it together form substituted or unsubstituted C atoms. 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 Aryl groups and substituted or unsubstituted 5-14 heteroaryl groups, wherein the substitution refers to the presence of 1-6 R groups. H1 Replace; more preferably R a Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, isopropyl, Preferably R a-1 Selected from Among them, R a-4 Selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The C group is substituted with one or more substituents selected from aryl, 5-14 heteroaryl, -SF3, or -SF5, wherein the C group is... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 14 aryl and 5-14 heteroaryl groups, optionally further substituted or unsubstituted with hydrogen, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, -SF3, -SF5, or C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic groups, substituted or unsubstituted C 6-14 The aryl group is substituted with one or more substituents in a group consisting of substituted or unsubstituted 5-14 heteroaryl groups; And / or, ring Q is selected from 4-6-membered cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclic or 7-12-membered heterocyclic; preferably, ring Q is selected from 7-12-membered heterocyclic. Preferably, Selected from Or preferably Selected from Or preferably Selected from Or preferably Selected from Further preferred Selected from in, It can be a single bond or a double bond; X1, X2, and X3 are each independently selected from CR m01 R m02 O, S, NR m03 CR m01 ,N,=N-,CO,SO,SO2 or POR m03 ; M 24 Selected from C, N, CH or CO; R m01 R m02 and R m03 The definition is the same as R m0 ;R m0 The definition is as described in claim 1; And / or, the ring I is selected from C 3-14 Cycloalkyl, 3-8-membered heterocyclic, 5-6-membered heteroaryl or phenyl; preferably 5-membered heterocyclic, 6-membered heterocyclic, 5-membered heteroaryl or 6-membered heteroaryl; Preferably, Selected from 10. The compound of claim 9, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from L1 is selected from the key; L5 is selected from the key; Ring E is selected from 11. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-10, characterized in that, Further as shown in equations (IV-1-1) to (IV-1-40) The definitions of each substituent in the general formula are as described in claims 1-9.

12. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as described in any one of claims 3-11, characterized in that, L6 is selected from bonds, O, S, CO, NH or CH2; And / or, Cy5 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; C is preferred 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, piperazineyl, More preferably, Selected from Or Cy6 is selected from C 3-11 Cycloalkyl or 3-11 membered heterocyclic groups, Or Cy8 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 quinone heteroaryl; C is preferred 5-6 Cycloalkyl or 5-6 membered heterocyclic group; preferably, Cy8 is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclic or 5-6 membered heteroaryl; Alternatively, ring B1 and ring B2 can be independently selected from substituted or unsubstituted C. 5-8 Cycloalkyl, substituted or unsubstituted 5-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The aryl group is a substituted or unsubstituted 5-6 membered heteroaryl group; more preferably, ring B1 and ring B2 are each independently selected from substituted or unsubstituted 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups.

13. The compound, its nitrogen oxides, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-12, characterized in that, The compounds are selected from those shown in Table 1, namely compounds 1-4477.

14. A compound as shown below, its nitrogen oxides, or a pharmaceutically acceptable salt thereof. in, M6 is selected from CH or N; L1, L2, L3, L4, L5, L6, R a M j M k M a M b M c M d M e M0, R 2 R 3 R 4 R n R c5 The definitions of q1, q2, x, y, ring Cy5, ring D, ring E, and ring C are as described in claim 6; Preferably, the compound is selected from...

15. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 13, its nitrogen oxides or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. The use of the compound, its nitrogen oxide, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, or the pharmaceutical composition of claim 15, in the preparation of a calcitonin receptor and / or amylin receptor agonist medicament.

17. The use of the compound, its nitrogen oxide, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating endocrine disorders, orthopedic disorders, metabolic disorders, pain, neurodegenerative disorders, or cardiovascular disorders; preferably, the disease is selected from osteoporosis, Paget's disease, hypercalcemia, Sudeck's atrophy, multiple fibrous dysplasia, interclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or periodontal defects, osteolytic osteopathy, metastatic osteopathy, or malignant tumors. Bone loss, autoimmune arthritis, fractures or breaks, bone disease pain, phantom limb pain, general pain, hyperalgesia, pain associated with diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, Syndrome X, complications of diabetes, primary or secondary hyperthyroidism, endocrine disorders, disorders related to inhibition of gastric acid secretion, gastrointestinal disorders, renal osteodystrophy, or male infertility.

18. The compound, its nitrogen oxide compound, or its pharmaceutically acceptable salt according to any one of claims 1 to 13, characterized in that, The compound shown contains its stereoisomers.

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